Marys Medicine

File:///c /library downloads/jdi.htm

Journal of Drug Issues 31(2), 325-394, 2001
Nicotine as an Addictive Substance: A Critical Examination of the Basic Concepts and EmpiricalEvidence Dale M. Atrens
Dale Atrens received a B.A. from the University of Windsor, an A.M. from Hollins College, and a Ph.D. from Rutgers University. He has held
appointments at universities in North America, Europe, Asia, and Australia. He is currently a Reader in psychobiology at the University of Sydney.
He is the author of several neuroscience textbooks and a number of popular books on diet and lifestyle.
The present review is a critical analysis of the concepts behind and the empirical data supporting the view that tobaccouse represents an addiction to nicotine. It deals with general aspects of the notion of addiction, while concentrating onspecific problems associated with incorporating nicotine into current frameworks. The notion of addiction suffers fromunprecedented definitional difficulties. The definitions offered by various authorities are very different, even contradictory.
Definitions that reasonably include nicotine are so broad and vague that they allow many trivial things, such as salt,sugar, and watching television, to be considered addictive. Definitions that exclude the trivia also exclude nicotine. Theaddiction hypothesis, in general, is strongly shaped by views that certain drugs bring about a molecular level subversionof rationality. The main human evidence for this is verbal reports of smokers who say that they can't quit. On the otherhand, the existence of many millions of successful quitters suggests that most people can quit. Some smokers don't quit, butwhether they can't is another matter. The addiction hypothesis would be greatly strengthened by the demonstration thatany drug of abuse produces special changes in the brain. It has yet to be shown that any drug produces changes in thebrain different from those produced by many innocuous substances and events. The effects of nicotine on the brain aresimilar to those of sugar, salt, exercise, and other harmless substances and events. Apart from numerous conceptual anddefinitional inadequacies with the addiction concept in general, the notion that nicotine is addictive lacks reasonableempirical support. Nicotine does not have the properties of reference drugs of abuse. There are so many findings thatconflict so starkly with the view that nicotine is addictive that it increasingly appears that adhering to the nicotineaddiction thesis is only defensible on extra-scientific grounds.
Introduction
The addiction model has dominated smoking research for over a generation (Benowitz, 1988; Benowitz,
1996; Henningfield & Heishman, 1995; Peele, 1990a; Rose, 1996; Russell, 1990a; Stolerman & Jarvis,
1995). Tobacco smoke is said to contain numerous agents that cause ill health (Gupta, Murti, & Bhonsle,
1996; Trichopoulos, Li, & Hunter 1996) as well as a powerful addictive drug, nicotine (Altman et al.,
1996; Anonymous, 1996; Benowitz, 1996; Busto, Bendayan, & Sellers, 1989; Dewey et al., 1999;
Griffiths, 1996; Grunberg, 1994; Henningfield, 1984; Henningfield, Cohen, & Slade, 1991; Rose, 1996;
Shytle, Silver, & Sanberg, 1996; Stephenson, 1996; Waldum, Nilsen, Nilsen, Rorvik, Syversen, Sandvik,
Haugen, Torp, & Brenna, 1996; Altman et al., 1996). According to the dominant model, as the nicotine
addiction develops, the smoker becomes progressively less able to stop (Anonymous, 1995; Foulds &
Ghodse, 1995; Frantzen, 1996; Henningfield, 1983). The essence of the nicotine addiction hypothesis is
that smokers are unable to stop because nicotine changes the brain in such a way as to perpetuate its use.
More broadly, drug addictions are seen as representing brain dysfunctions. It is this hypothesis and
related issues that are examined in the present work.
The 1988 Surgeon General's Report on Smoking and Health states the nicotine addiction viewpointsuccinctly: Cigarettes and other forms of tobacco are addicting. Nicotine is the drug in tobacco that file:///C /Library Downloads/jdi.htm (1 of 58) [09-Jun-2001 07:02:06] causes addiction. The pharmacologic and behavioral processes that determine tobaccoaddiction are similar to those that determine addiction to drugs such as heroin and cocaine.
(United States Department of Health and Human Services, 1988, p. 4) The addiction model continues to generate strong views. This is reflected in titles such as: "The nicotineaddiction trap: A 40-year sentence for four cigarettes" (Russell, 1990b, p. 293). Goldstein refers tosmoking as "addictive suicide" (Goldstein, 1994, p. 7). Another article indicted cigarettes as being amongthe most addictive substances known to man (Schelling, 1992). The eminent biologist, D.S. Jordan, whowas the first president of Stanford University, expressed his opinion of smoking in 1913: "The boy whosmokes cigarettes need not be anxious about his future, he has none" (Sullum, 1996, p. 32).
Thomas Edison stated that cigarette smoke ".has a violent action on the nerve centers, producingdegeneration of the cells of the brain, which is quite rapid among boys. Unlike most narcotics thisdegeneration is permanent and uncontrollable" (Sullum, 1998, p. 32). Edison's statement is a forerunnerof the contemporary view that cigarette smoking is maintained by changes in the brain produced bynicotine.
At the moment, it is nearly impossible to find a contemporary document on smoking that doesn't mentionnicotine addiction as an incontestable point in the first paragraph. Many believe that the recentadmissions of tobacco companies constitute further proof that nicotine is addictive (Allis, Lafferty,McAllister, & van Voorst, 1997; Carey, France, Dunham, & Greising, 1997). This belief is peculiar sincethe earlier denials of the tobacco companies were widely held to be false and self-serving (Sullum, 1998).
The validity of the nicotine addiction hypothesis is not about admissions, assertions, or concessions; it isabout logic and data.
Conceptual Analysis of the Addiction Model
With sufficient use, certain drugs are said to change the brain in such a way as to make cessation difficult
or impossible (Leshner, 1997, 1998, 1999a, 1999b). Drug users frequently state that they cannot help
themselves (Luik, 1996; Schaler, 2000). The nature of this alleged helplessness remains unclear. Drugs
such as opiates and cocaine are clearly very enjoyable, and users often report that such drugs produce
intense feelings of pleasure (Epstein, Silverman, Henningfield, & Preston 1999; Heishman, Schuh,
Schuster, Henningfield, & Goldberg, 2000). It is possible that intense pleasure could account for
persistent drug use. On the other hand, drugs such as nicotine have only small and variable subjective
effects (Duka, Tasker, Russell, & Stephens, 1998; Rusted, Mackee, Williams, & Willner, 1998).
Although smoking may be pleasant, the effects are not at all comparable to traditional drugs of abuse.
Nicotine's lack of potent subjective effects necessitates some other sort of mechanism to account for
persistent use. This other mechanism requires a unique pharmacological property, a pleasure-independent
ability to lead the user into repeated use. However, at the moment there is no evidence of any neural
mechanisms that could mediate such an unprecedented effect.
The most direct form of evidence supporting the belief that drugs induce a form of helplessness in certainusers is the verbal reports of the users themselves (Davies, 1998; Gori, 1996). That users may not stop isobvious; whether they cannot stop is another matter. The utility of the verbal reports of drug users iscompromised by at least two major factors. Drug users, including smokers, tend to suffer from diverseforms of psychopathology (Bergen & Caporaso, 1999; Coelho et al., 2000; Franken & Hendriks, 2000;Holmen, Barrett-Connor, Holmen, & Bjermer, 2000; Riggs, Mikulich, Whitmore, & Crowley, 1999;Stassen et al., 2000; Tanskanen et al., 2000). Thus, even with the best of intentions, the fidelity of their file:///C /Library Downloads/jdi.htm (2 of 58) [09-Jun-2001 07:02:06] verbal reports is uncertain (Davies, 1998). However, drug users often do not have good intentions. Theytend to explain their behavior in a manner that minimizes personal responsibility (Davies, 1997, 1998;Schaler, 2000). This has clear social and legal advantages. Such considerations suggest that the verbalreports of drug users may not be valid explanations of their behavior (Davies; Schaler). Such reports are,at best, pre-scientific data.
Determining why people continue drug use is greatly complicated by the fact that those who are attractedto drugs are constitutionally quite different from those who are not (Crowley, Mikulich, MacDonald,Young, & Zerbe, 1998; Franken & Hendriks, 2000; Healy & Tranter, 1999). These initial differencesconfound the interpretation of subsequent results. Random allocation of humans to treatment and controlgroups is not ethically permissible with dangerous drugs. This necessitates investigating drug use inlaboratory species that have little psychopathology, and no motives for dissimulation. Further, in markedcontrast to humans, laboratory species can be randomly allocated to potentially dangerous treatments.
Attractive though it may be, this approach faces the problem that no drug reliably produces compulsiveuse in any laboratory species. We will see below that even large doses over long periods of time leavelaboratory animals quite indifferent to continued use. Much the same applies to humans. Such findingsargue against the view that the propensity to produce cessation difficulties is a property of drugs (Ward,Li, Luedtke, & Emmett-Oglesby, 1996).
If addictive potential is a property of certain substances, it should show the temporal, geographic, andinter-individual stability common to all drug properties. For example, cocaine analgesia has beenformally recognized since at least 1884 (Haas, 1995; Hirschmuller, 1995), although it was known to theIncas two thousand years earlier (Siegel, 1985). Cocaine analgesia is equally apparent in Peoria and Peru,and it is seen in everyone who is given the drug. It is reasonable to say that local anesthesia is an inherentproperty of cocaine. Such constancy is not found for the putative addictive property of drugs (Nencini,1997b; Nencini, 1997a; US Government Office of Technology Assessment, 1994; Whitbread, 1995).
Which drugs are considered addictive varies enormously over time and in different locations. For manyyears tobacco was considered harmless and cannabis extremely dangerous (Das, 1993; Das & Laddu,1993). The head of a federal drug agency testified in court that when he tried a marijuana cigarette, hewas transformed into a bat and flew around the laboratory (Whitbread & Bonnie, 1970).
Cannabis-induced insanity was a successful defense strategy in several homicide trials (Whitbread &Bonnie). Alarmist views of cannabis are now considered quaint, whereas tobacco use is currentlyportrayed as a deadly addiction. Such position reversals can only be justified by the appearance ofdramatic new empirical evidence or theoretical developments. The fact that no momentous new evidenceor theoretical developments have appeared suggests that political and legal considerations have takenprecedence over scientific considerations (Davies, 1997; Epstein, 1990; Kutchins & Kirk, 1997; Pandina& Huber, 1990; Peele, 1991; Sullum, 1998).
It is becoming increasingly apparent that problem drug use is not simply a pharmacological issue(Coleman, 1976; Jonnes, 1995; Murray, 1991; Schoberberger, Kunze, & Schmeiser-Rieder, 1997;Shiffman, 1991; Shiffman, Paty, Gnys, Kassel, & Elash, 1995). The use of powerful drugs such asopiates and cocaine is subject to major social-environmental modulation (Coleman, 1976; Krause et al.,1993; Peele, 1987, 1990a, 1990b). Even opiates often do not cause problem behavior in humans (Goode,1999). Social-environmental factors are likely of even greater importance in the use of commonersubstances such as tobacco (Fahrenkrug & Gmel, 1996; Perkins, 1995) .
The addiction model is counterproductive to the aim of reducing problem drug use. Since its ascendancy file:///C /Library Downloads/jdi.htm (3 of 58) [09-Jun-2001 07:02:06] there has been little progress made in the treatment of drug taking (Chiauzzi & Liljegren, 1993;McMurran, 1994; Smart, 1994). In spite of a plethora of theory, research, and application, the successrate for treating common drug problems is so poor that it is rarely mentioned in scientific reports. Incontrast, some 50 million Americans alone have quit smoking (Fiore, Newcomb, & McBride, 1993;Giovino, Henningfield, Tomar, Escobedo, & Slade, 1995; Orleans & Slade, 1993; Taylor, 1984).
The main reason given by smokers for their failure to stop smoking is that they see themselves asaddicted (Hennrikus, Jeffery, & Lando, 1995; Stewart et al., 1996). Smokers are widely portrayed asvictims of rogue molecular processes in their brains (Chiauzzi & Liljegren, 1993; Russell, 1990b;Schelling, 1992). As long as smoking is portrayed as an inexorable addictive process, the success ofcessation programs will be limited by a self-fulfilling prophecy (Coleman, 1976; Drew, 1986; Fingarette,1979; Fingarette, 1981; Fingarette, 1990; Jensen & Coambs, 1994; Schwartz, 1992).
Defining Addiction
Addiction and related terms have such broad and variable usage that they can mean almost anything
(Chiauzzi & Liljegren, 1993; Coleman, 1976; Gori, 1996; Linsen, Zitman, & Breteler, 1995; Stepney,
1996; Warburton, 1985). Addiction is used to describe behaviors ranging from injecting heroin and
cocaine, to smoking or chewing tobacco, drinking coffee, eating chocolate, shopping, watching television
soap operas (Jaffe, 1992), and falling in love (Griffin-Shelley, 1993). There are reports of addiction to
water (Kaplan, 1998), cardiac defibrillators (Fricchione, Olson, & Vlay, 1989), carrots (Cerny & Cerny,
1992; Kaplan 1996), hormone replacement therapy (Bewley & Bewley, 1992), and numerous other
unusual entities (Glatt & Cook, 1987; Griffin-Shelley, 1993; Hodge, 1992; Robinson, 1997; Solursh,
1989). The clinical literature is replete with examples of people who develop unfortunate, even
destructive, relationships with a great many substances, objects, events, and people (American
Psychiatric Association, 1994). It is questionable whether these problems are illuminated by invoking the
concept of addiction.
The disarray in this area is reflected in the terminology (Di Chiara, 1995). Reviews often includeglossaries explaining just what they mean by each of the many terms in common usage in this work (DiChiara, 1995; Robinson & Berridge, 1993; Stolerman, 1992). This greatly complicates any overallevaluation since different papers often appear to be discussing quite different processes.
Even with respect to drug addiction, there is a great deal of confusion. A recent review identified 126definitions in 51 different publications (Linsen, Zitman, & Breteler, 1995). And this was only forbenzodiazepine addiction. There is no consensus concerning the definition of addiction or the relatedconcepts of physical and psychological dependence. This has important implications. It means that anycriticism of the notion of addiction can be circumvented merely by referring to a different definition. Itsvagueness and plurality make addiction a non-falsifiable concept. It is uncertain whether such conceptsserve a useful function. The present analysis tries to avoid these problems by dealing with issues that arecommon to many, but never all, current definitions.
In a medico-legal context where the use of the term addiction has major implications for treatment, socialpolicy, and litigation, one would expect a degree of definitional precision at least comparable to that ofother major diagnostic categories. This sort of precision, or even a rough approximation thereof, is notavailable.
Addiction is commonly used to describe drug problems. There can be little objection to such looseeveryday use of addiction. The difficulties arise when addiction is used to explain drug problems. There file:///C /Library Downloads/jdi.htm (4 of 58) [09-Jun-2001 07:02:06] is a persistent tendency to confuse description with explanation. There are substantial difficulties evenwhen addiction is used in a descriptive sense. However, there are still greater difficulties when addictionis used to explain persistent drug use.
Hundreds of definitions of addiction have been published, but there is no agreement as to which, if any,should be used (Warburton, 1985). Apart from that of the Surgeon General, two other definitions havebecome de facto standards: they are that of the American Psychiatric Association (DSM-III-R) andWorld Health Organization. They and others will be considered below with special reference to thenotion of nicotine addiction.
The Surgeon General's 1988 Report on Smoking and Health is easily the most influential document inthis area. Because its definition occupies such a prominent place in addiction, it will be considered insome detail.
The central element among all forms of drug addiction is that the user's behavior is largely controlled bya psychoactive substance (i.e., a substance that produces transient alterations in mood that are primarilymediated by effects in the brain). There is often compulsive use of the drug despite damage to theindividual or to society, and drug-seeking behavior can take precedence over other important priorities.
The drug is "reinforcing"--that is, the pharmacologic activity of the drug is sufficiently rewarding tomaintain self-administration. "Tolerance" is another aspect of drug addiction whereby a given dose of adrug produces less effect or increasing doses are required to achieve a specified intensity of response.
Physical dependence on the drug can also occur, and is characterized by a withdrawal syndrome thatusually accompanies drug abstinence. After cessation of drug use, there is a strong tendency to relapse.
(United States Department of Health and Human Services, 1988, p. 7) The Surgeon General's definition states that "the user's behavior is largely controlled by a psychoactivesubstance" (United States Department of Health and Human Services, 1988, p. 7). Whereas nicotinecertainly affects behavior, it is questionable whether it can properly be said to control behavior. It has yetto be demonstrated that nicotine can exert more control over behavior than that exerted by any of scoresof innocuous substances and events. Moreover, smoking is almost always done along with somethingelse. The fact that smoking enhances a broad range of abilities (Pritchard & Robinson, 1994) suggeststhat the user's behavior is not controlled by the substance. In this context the behavioral consequences ofnicotine are little different from those of eating a carrot.
Although the Surgeon General stresses that an addiction "takes precedence over other importantpriorities" (United States Department of Health and Human Services, 1988, p. 7), this rarely applies tosmoking. The overwhelming majority of smokers know when they can and cannot smoke, and theyusually find increasingly severe restrictions only a minor nuisance. Certain religions prohibit smoking onthe Sabbath, and even the heaviest smokers report no difficulty in observing this rule (Shiffman, 1991). Itis difficult to imagine a molecular dysfunction of the brain that respects the Sabbath.
The Surgeon General stresses that addictive substances are reinforcing (rewarding). We will see belowthat, at best, nicotine may be slightly more rewarding than saline. Even under the most carefullycontrived circumstances, nicotine is probably no more rewarding than a flash of light or a brief sound.
Such feeble reward does not suggest abuse potential.
Sugar can exert far more powerful and reliable effects over the behavior of both laboratory animals andhumans than nicotine (Allsop & Miller, 1996; Bock, Kanarek, & Aprille, 1995; Davis, 1995; Gibney, file:///C /Library Downloads/jdi.htm (5 of 58) [09-Jun-2001 07:02:06] Sigman-Grant, Stanton, Jr., & Keast, 1995; Gold, 1995; Lindroos, Lissner, & Sjöström, 1996;McDonald, 1995). Moreover, much as is the case with nicotine, sugar has been associated with ill health(DiBattista & Shepherd, 1993; Furth & Harding, 1989; Wu, Yu, & Mack, 1997). Similar considerationsapply to salt (Feldman, Logan, & Schmidt, 1996; Goldbloom, 1997; Kochar, 1992). The ability to controlbehavior and to produce adverse effects on health are certainly not adequate evidence that anything isaddictive. Poorly-specified, overinclusive definitions subsume so many things that the entire issuebecomes trivialized (Jaffe, 1990a).
Next the Surgeon General's definition refers to the substance use continuing: ".despite damage to theindividual or to society" (United States Department of Health and Human Services, 1988, p. 7).
However, smoking produces no damage in many people and most smokers respond to danger signs bystopping (Schachter, 1990). Few people with clear signs of smoking-related illness persist in smoking;they are not representative of smokers in general (Taylor, 1984).
In 1969 the World Health Organization discarded the term addiction and replaced it with dependencedefined as: A state, psychic and sometimes also physical, resulting from the interaction between a livingorganism and a drug, characterized by behavioral and other responses that always include acompulsion to take the drug on a continuous or periodic basis in order to experience itspsychic effects, and sometimes to avoid the discomfort of its absence. Tolerance may ormay not be present. (World Health Organization, 1969, p. 4) This definition is instructive for a number of reasons. First, it refers to a state that is psychic andsometimes also physical. Given that all states are probably both psychological and physical, this part ofthe definition excludes nothing and is thus uninformative.
Next the definition mentions the interaction between a living organism and a drug. Thus dependenceconcerns drugs. Then the definition refers to behavioral and other responses; this excludes nothing. Eventhe term 'compulsion' requires further specification since it may mean anything from a minor inclinationto an overwhelming desire. The undefined compulsion to take the drug may either be on a continuous orperiodic basis, which once again excludes nothing.
Next comes reference to the drug being taken out of the desire to experience its psychic effects. Thisappears to refer to drug effects on behavior, mood, or sensation. Under certain circumstances, nearlyevery substance taken by man is psychoactive. Merely being detectable could mean psychoactive(Goudie, 1991) . This is another part of the definition that is so over-inclusive as to be meaningless.
Lastly, the definition specifies that tolerance may or may not be present. This widely used definition is anamalgam of ill-specified and over-inclusive catch phrases. It fails to meet the most minimal standards ofa definition.
The vagaries in official views of nicotine addiction are reflected in the attitudes of the World HealthOrganization (WHO). WHO did not consider tobacco to be dependence producing until 1974 (WHO,1974). Even in 1978 they still listed tobacco dependence separately because they said that tobacco wasnot psychotoxic (WHO, 1978). The American Psychiatric Association didn't recognize smoking as anaddiction until 1980 in the DSM-III (APA,1980).
The essential definitional inadequacies of addiction are sometimes addressed by referring to secondary file:///C /Library Downloads/jdi.htm (6 of 58) [09-Jun-2001 07:02:06] constructs such as craving, habit, psychological dependence, physical dependence, etc.(Goudie, 1991;Linsen, Zitman, & Breteler, 1995; Peele, 1977; Warburton, 1990a, 1990b, 1994a). However, rather thanclarify the definition, these poorly-defined constructs merely obfuscate it (Nestler, Hope, & Widnell,1993). Thus the current situation is based on fundamentally inadequate definitions, the problems ofwhich are compounded by making reference to secondary explanatory constructs that are frequently evenmore poorly specified (Linsen, Zitman, & Breteler, 1995).
Some of the problems in this area reflect the intrusion of extra-scientific agenda: ".at least in the UnitedStates, definitions of addiction have come to be based more on legislative fiat and judicial rulings than onpharmacologic or clinical evidence" (Newman, 1983, p. 1097). In the 1964 report on smoking and health,the Surgeon General stated unequivocally that nicotine was not addictive (Ruxton & Kirk, 1997). In 1988he reversed this view (US Department of Health and Human Services, 1988). There were no scientific orclinical breakthroughs in this interval, but there was a great deal of legal and political activity (Jones,1992; Peele, 1992; Seltzer, 1997; Taylor, 1984; Vallin, 1984; Warburton, 1994b).
Any workable definition of addiction must differentiate between the use of innocuous substances andthose that present a real danger. At the moment, none even approaches this most basic criterion. Whatuse are definitions that cannot differentiate crack smoking from coffee drinking, glue sniffing fromjogging, heroin injection from eating carrots, and snorting cocaine from drinking colas? (Hilts, 1994).
Existing definitions of addiction and related concepts do not appear to be valid scientific or medicalconcepts. They serve an important function in that they bring the use of certain substances within theprovince of the medical and legal professions (Chiauzzi & Liljegren, 1993; Coleman, 1976; Peele, 1977,1986, 1987, 1990a).
No other diagnostic category suffers from anything like the definitional uncertainty that characterizesaddiction (Goudie, 1991; Peele, 1977; Warburton, 1985). The fact that the combined efforts of thousandsof scientists and legislators for fifty-odd years have not produced a single rigorous definition suggeststhat they may be trying to define an undefinable.
Animal Models of Addiction
Advocates of animal experimentation maintain that the essential features of human drug taking may be
represented in other species (Hogg, 1996; Klopfer, 1996; Willner, 1991a). By allowing precise control of
variables that inevitably remain uncontrolled in human experimentation, animal experiments offer
important advantages (Mogensen, 1994). On the other hand, this very control complicates extrapolation
across species. Human drug taking occurs in environments that are very different from those of
laboratories.
Critics also point out that human drug taking is subject to many influences that can not be investigated inlaboratory animals (Goudie, 1991; Slotkin, 1983; Willner, 1991b). It is difficult to imagine anunemployed, guilt-ridden rat, or a monkey suffering from low self-esteem. Peer pressure, which is soimportant in human drug use, has no parallel in lab species. It is questionable whether animals couldcorrectly be said to 'abuse' drugs (Goudie). An animal that was chronically intoxicated would not lose itsjob, be evicted, shunned by its peers, or be jailed.
Most laboratory experiments measuring the rewarding properties of drugs use operant technology(Stolerman, 1993). The animal is placed in a small box inside a sound attenuated chamber. The blanduniformity of laboratory conditions is very different from the complex and changing environments in file:///C /Library Downloads/jdi.htm (7 of 58) [09-Jun-2001 07:02:06] which humans take drugs (Iwamoto & Martin, 1988; Richelle, 1989; Stephens, 1986; Woolverton, 1992).
The uniformity and solitary confinement to which laboratory species are subject while taking drugs arestressful (Deroche, Piazza, Le Moal, & Simon, 1994; Kim & Kirkpatrick, 1996; Phillips, Howes,Whitelaw, Robbins, & Everitt, 1994; Phillips et al., 1994). Social isolation and stress undoubtedly play arole in human drug use, but in rodent models these factors appear to be of much greater importance.
Since nicotine alleviates stress (Onaivi et al., 1994; Parrott, 1995; Pomerleau, 1986; Pomerleau &Pomerleau, 1991), any effects on pleasure (Lovaas, Newsom, & Hickman, 1987; Shoaib & Shippenberg,1996) are confounded with stress reduction.
Experimental conditions used with primates are also very different from human drug-taking conditions.
Primates are strapped into a chair and allowed just enough freedom of movement to press a lever.
Laboratory paradigms reduce the animal's choice to taking the drug or doing virtually nothing. This isvery different from human drug taking in which the subject typically has many behavioral options.
.animal drug self-administration requires a specific experimental environment and can be "turned off"by such minor modifications as increasing the amount of bar pressing required to obtain the drug. Inother circumstances, animals can hardly be forced to take a drug. Falk similarly noted animals thatconsume drugs and alcohol excessively when under extremely uncomfortable experimental conditionscease to do so as soon as normal laboratory conditions are reinstated. Findings like these led Dole (1980)to note: "Most animals cannot be made into addicts." In response to drugs reported regularly to addicthuman beings, "animals generally avoid such drugs when they are given a choice." (Peele, 1990a, p. 213) Alexander's classic "Rat Park" experiments illustrate the difficulties in getting rats 'hooked' even afterlong periods of forced drug administration: No matter how much we induced, seduced, or tempted them, the Rat Park rats resisteddrinking the narcotic solution. The caged rats drank plenty, however, ranging up to sixteentimes as much as the Rat Park residents in one experimental phase, and measuring ten timesas much in some other phases. The females, curiously, drank more morphine in bothenvironments, but the Rat Park rats always drank far less than the caged rats. (Alexander,Coambs, & Hadaway, 1980, p. 35) Lab animals rarely, if ever, show any behavior that could reasonably be called addictive. When given nochoice, they may self-administer drugs. However, when given alternative responses such as occur whenthey are housed with other animals, drug use is very infrequent (Dole, 1980). Indifference to drugs is alsoseen after long periods of forced exposure to morphine and alcohol (Gentry & Dole, 1987). Under certainconditions, animals may vigorously self-administer drugs, but they do not have any trouble stopping.
Self-administration may indicate reinforcement, and drugs such as heroin and cocaine are reinforcing.
However, simply being reinforcing is not equivalent to being addictive. Animals vigorouslyself-administer sucrose, air, and many other innocuous substances. Vigorous self-administration may bea necessary condition for substance abuse, but it is not a sufficient condition.
Nicotine as a Psychoactive Substance
Nicotine meets some of the criteria for being psychoactive, although even here there is a good deal of
definitional uncertainty. Altered transmission in nicotinic systems produces a wide range of effects on
autonomic, endocrine, and neural processes (Ashton & Stepney, 1982; Carstens, Saxe, & Ralph, 1995;
Grenhoff & Svensson, 1989; Gribkoff, Christian, Robinson, Deadwyler, & Dudek, 1988; Houlihan,
file:///C /Library Downloads/jdi.htm (8 of 58) [09-Jun-2001 07:02:06] Pritchard, Krieble, Robinson, & Duke, 1996; Murray, 1991). Humans and animals can usually tell whenthey have been given nicotine (Chandler & Stolerman, 1997; Mariathasan, Stolerman, & White, 1997;Mariathasan, White, & Stolerman, 1996; Perkins, D'Amico et al., 1996; Stolerman & Jarvis, 1995; Terryet al., 1996). However, being psychoactive is a necessary, but not sufficient, condition for abusepotential. A large number of psychoactive substances have no abuse potential.
Psychoactive is frequently used to mean mood altering, but the National Institute on Drug Abuse (NIDA)has given it a more specific meaning. Their definition refers to ".a distortion of the perception of time,space, and the location of objects within space.a dose-related reduction in physical coordination orpsychomotor functioning" (Robinson & Pritchard, 1992, p. 399). This is very similar to definitions ofintoxication. Nicotine does not produce anything like intoxication. Indeed, nicotine facilitates manycognitive and motor functions (Danion et al., 1997; Levin, Briggs, Christopher, & Rose, 1992; Rusted,Graupner, & Warburton, 1995; Rusted & Warburton, 1995; Warburton 1994c, 1994d; Warburton &Arnall, 1994). According to NIDA criteria, nicotine is not psychoactive.
Evaluating the role of nicotine in smoking is complicated by the fact that tobacco contains a number ofother alkaloids (Benowitz, Porchet, & Jacob III, 1990). Nornicotine, anabasine, myosmene, nicotyrine,and anatabine typically account for around 10% of the alkaloid content of tobacco (Dwoskin et al., 1995;Hoffmann, Adams, Piade, & Hecht, 1980). However, in some tobaccos these alkaloids may outweighnicotine (Benowitz et al., 1990). Little is known about the psychopharmacology of these other alkaloids,but they appear to be quite potent (Benowitz et al., 1990). How they interact with each other and withnicotine is largely unknown. Thus nicotine self-administration is a poor model of even the alkaloidaspects of smoking. It is possible that some of these deficiencies may be rectified by using alkaloidmixtures that more closely approximate those encountered in tobacco.
Dose equivalence
The nicotine dose delivered by a typical cigarette is about 1.0 mg (Ashton & Stepney, 1982; Benowitz et
al., 1990). In a 75 kg human, a cigarette yields a nicotine dosage of 13 µg/kg. If a cigarette is smoked in
20 puffs, the nicotine dose is .70 µg/kg/puff. Primate self-administration studies generally use 10-100
µg/kg/infusion (Wakasa, Takada, & Yanagita, 1995). Thus, the primate dose is 15-150 times higher than
humans typically self-administer while smoking.
Even very heavy smokers self-administer nicotine nasal spray at a rate of only 200 µg/kg/day (Tonnesen,Mikkelsen, Norregaard, & Jorgensen, 1996). Humans can reliably detect nicotine at doses of 2 µg/kgdelivered by nasal spray (Perkins, DiMarco, Grobe, Scierka, 1994). As little as 40 µg/kg of intravenousnicotine produces aversive effects in humans (Henningfield, Miyasato, & Jasinski, 1983). In regularsmokers of 1.0 mg nicotine cigarettes, a single 2.4 mg nicotine cigarette often produces signs of nausea,sicknessm, and unpleasantness (Gilbert, Meliska, Williams, & Jensen, 1992).
The nicotine doses commonly used in animal experiments are in the range of those producing nausea andvomiting in humans and other species (Matsushima, Prevo, & Gorsline, 1995; Smith et al., 1996).
Although there are few data on nicotine lethality, one report suggests that a bolus of less than 1 mg/kg isfatal in humans (Eysenck, 1965). Another suggests that an intravenous injection of the nicotine from onesmall cigar would be fatal (Royal College of Physicians of London, 1977).
The most common nicotine dose used in rodent self-administration studies is 30 µg/kg (Chiamulera,Borgo, Falchetto, Valerio, & Tessari, 1996; Corrigall & Coen, 1991a), which is over 40 times higher thantypical human self-dosage. Studies in which nicotine is given as a pre-treatment use even higher doses. In file:///C /Library Downloads/jdi.htm (9 of 58) [09-Jun-2001 07:02:06] one such study, rats were given 400 µg/kg, which is over 500 times higher than humans self-administerin a single puff and more than twice as much as even very heavy smokers self-administer nasally over thecourse of an entire day (Tonnesen, Mikkelsen, Norregaard, & Jorgensen, 1996).
Typical experiments with laboratory species use nicotine doses that are equivalent to those achieved if ahuman consumed several cigarettes in a single puff. Humans find even much lower doses of nicotineaversive. Foulds et al. have shown that less than 10 µg/kg of intravenous nicotine causes dizziness, mooddeterioration, and pain even in regular smokers. The nicotine pretreatment studies administer theequivalent of a full pack of cigarettes in a single dose. An investigation of receptor kinetics used 12mg/kg/day (Kirch, Taylor, Creese, Xu, & Wyatt, 1992). This is the rough human equivalent of smoking1,000 cigarettes.
It is unlikely that any human would ever self-administer nicotine doses even remotely approaching thelowest doses used in laboratory experimentation (Ashton & Stepney, 1982). The fact that laboratoryspecies can withstand doses of nicotine that would be dangerous or lethal in humans suggests a majorspecies difference. Because the metabolism of nicotine in the rat is quite different from that in humans,rabbits and hamsters may be more suitable subjects (George, 1993).
The issue of dose is particularly critical in considering the reinforcing effects of nicotine (see below). Athigh doses, nicotine produces marked effects on monoaminergic transmission (Vizi & Lendvai, 1999).
Since dopamine, serotonin, and norepinephrine all have important roles in reinforcement (Berke &Hyman, 2000; Curtin et al., 1997; Di Chiara, 2000), high doses of nicotine could produce neurochemicaleffects quite unrelated to those of the low doses produced by smoking tobacco. The high, sometimesastronomically so, nicotine doses used in laboratory research with infra-human species confoundbehavioral and neurochemical investigations.
Nicotine, reinforcement, and addiction
The Surgeon General and other authorities emphasize the importance of reinforcement in the
development of addiction (Colle & Wise, 1987; US Department of Health and Human Services, 1988).
Few would disagree with the notion that a substance is unlikely to be abused if it is not liked. Although
humans can be asked whether they like various substances, this issue can only be approached indirectly
in laboratory species (De Wit & Griffiths, 1991). There are major unresolved problems in inferring
complex psychological processes, such as liking from simple behaviors such as lever pressing (Goudie,
1991).
If laboratory species will voluntarily take a drug, it is assumed that humans will too. Laboratory speciesand humans vigorously self-administer heroin (Hand, Stinus, & Le Moal, 1989), morphine (Di Chiara,Acquas, & Carboni, 1992), cocaine (White, 1996; Woolverton, 1992), and amphetamine (Peltier, Li,Lytle, Taylor, & Emmett-Oglesby, 1996). Heroin, morphine, cocaine, and amphetamine sustain highrates of self-administration and are enjoyed and abused by humans. Moreover, the experimental literatureis consistent for these drugs. Apart from sustaining vigorous self-administration, the self-administrationis acquired quickly and easily. Failures to self-administer any of these drugs are rare (Iwamoto & Martin,1988). Such data are consistent with abuse potential.
However, many drugs self-administered by laboratory species have no abuse potential in humans. Theseexceptions include the anti-hypertensive clonidine (Asin & Wirtshafter, 1985; Weerts & Griffiths, 1999),the appetite suppressant phentermine (Papasava, Singer, & Papasava, 1985a; Papasava, Singer, &Papasava, 1985b), the anti-schizophrenic drug chlorpromazine (Hoffmeister & Goldberg, 1973), and the file:///C /Library Downloads/jdi.htm (10 of 58) [09-Jun-2001 07:02:06] anti-depressants nomifensine and bupropion (Tella, Ladenheim, & Cadet, 1997). Iwamoto andMartin(Iwamoto and Martin 1988) add to this list: ketocyclazocine, ethylketocyclazocine, apomorphine,piribedil, procaine, N-allynormetazocine, metazocine, and phenylethanolamine.
Conversely, laboratory species often do not self-administer drugs that humans do. These exceptionsinclude tranquillizers (Lee, Flegel, Greden, & Cameron, 1988), hallucinogens (Stolerman, 1993), andcannabis (Frances & Franklin, 1996). Whereas humans find both tranquillizers and cannabis pleasant,rats are generally indifferent to them (McGregor, Issakidis, & Prior, 1996). Humans find alcohol,barbiturates and benzodiazepines reinforcing, but these drugs generally support only weakself-administration in laboratory species and failures to show reinforcement with these drugs arecommon (Ator & Griffiths, 1987; Dominguez, Bocco, Chotro, Spear, & Molina, 1993; Keane &Leonard, 1989; Meisch & Stewart, 1994).
The self-administration of nicotine is surrounded by uncertainty and controversy. This is reflected inJaffe's assessment: "It has not been possible to develop reliable animal models of self-administration oftobacco products."(Jarvik, 1977, p. 122). There are reports of failures to establish nicotineself-administration in spite of intensive efforts (Ator & Griffiths, 1983; Goudie, 1991). Although noinfra-human species smokes, smoking can sometimes be established in primates. However, in markedcontrast to humans, smoking in infra-human primates can only be established by coercive procedures(Ando, Hironaka, & Yanagita, 1986). Moreover, once established, smoking in primates does not produceany evidence of a habit; they stop at the first opportunity (Swedberg, Henningfield, & Goldberg, 1990;Wood, 1990).
Even when smoking is established in laboratory primates, it appears to be very different from that seen inhumans. Primates do not inhale tobacco smoke. Rucker trained monkeys to puff cigarettes using water asa reinforcer (Wood, 1990). However, he details exhaustive and unsuccessful attempts to get the monkeysto inhale. Additionally, when the water reinforcement was discontinued, the monkeys immediatelystopped puffing. Smoking does not appear to be reinforcing for laboratory primates.
Baboons can be coerced into smoking by making water contingent on their puffing (McGill, Rogers,Wilbur, & Johnson, 1978; Roehrs, Rogers, & Johanson Jr., 1981; Rogers et al., 1980; Rogers et al., 1988;Rogers, McCullough, & Caton, 1981; Rogers, Wilbur, Bass, & Johnson, 1985; Sepkovic et al., 1988).
Unfortunately, none of these experiments reported whether the baboons would continue smoking when itwas no longer required to obtain water. Others have also coerced laboratory primates into smoking(Ando, 1975; Ando, Hironaka, & Yanagita, 1986; Ando & Yanagita, 1981; Yanagita, Ando, Kato, &Takada, 1983). In the latter reports, even after the most intensive training efforts, the vast majority of themonkeys would not smoke. Given the coercive nature of the training and the amount of aversivestimulation (electric shock) given in these experiments, it is questionable whether even the fewexceptional cases should be viewed as representative of human smoking.
The establishment of nicotine self-administration in laboratory species is time consuming and unreliable(Goldberg & Henningfield, 1988; Henningfield & Goldberg, 1983a; Naruse, Asami, Ikeda, & Ohmura,1986; Swedberg et al., 1990). Moreover, once established, the rate of nicotine self-administration is verylow. For example, Singer and Wallace (1984) show maximum nicotine self-administration rates that arescarcely greater than those supported by saline. This is far from being compulsive drug use. Animals willquickly learn to press a lever thousands of times per hour to get cocaine (Iwamoto & Martin, 1988; Wardet al., 1996). With nicotine, the highest self-administration rates ever reported in rats are around 25 per file:///C /Library Downloads/jdi.htm (11 of 58) [09-Jun-2001 07:02:06] hour (Corrigall & Coen, 1989).
Corrigal is one of the few researchers reporting consistent nicotine self-administration in rats (Corrigall,1991; Corrigall & Coen, 1989, 1991a, 1991b, 1994a; Corrigall, Coen, & Adamson, 1994; Corrigall,Franklin, Coen, & Clarke, 1992; Rose & Corrigall, 1997). The credibility of these studies is increased bythe fact that the rats were not food deprived nor were they previously trained for other drugs. Moreover,Corrigal's rats had access to an inactive lever that provided an index of response specificity. In addition,Corrigal's rats were trained to respond on a fixed interval of five seconds, and others have replicated hisbasic findings (Donny, Caggiula, Knopf, & Brown, 1995; Tessari, Valerio, Chiamulera, & Beardsley,1995).
The Corrigall et al. findings are the best indicators that nicotine may be reinforcing in rats. Whether theyare adequate demonstrations of reinforcement is open to question, but in any case, they do not indicateabuse potential. First, whereas the authors use the term robust self-administration, the highest responserate obtained in any of these experiments is about 25/hour. This sort of performance is near the verylowest rates of responding reported for any reinforcer. Woolverton (1992) has shown that monkeysrespond at rates greater than 20 per hour for saline.
There is a more serious deficiency in the Corrigall and related papers. None appears to have used salineself-injection as a control for nonspecific injection effects. The data from Corrigall and Coen (1989)replotted by Stolerman and Shoaib (1991) show a flat dose-response curve that falls off only at a veryhigh dose of nicotine (60 µg/kg). Since the lowest dose (3.0 µg/kg) is one-tenth of the most commonlyused dose in this work, it could well be, in effect, a zero dose. If this is the case, then the responding atthe two higher doses represents nothing more than operant rate of intravenous injections. This issuecannot be resolved until appropriate experiments are conducted. Until then Corrigall et al.
self-administration studies may only be considered to be suggestive of weak reinforcement, nothingmore.
Moreover, the few reports of self-administration of nicotine in laboratory species use intravenousadministration. This is very different from the inhalation route by which humans normally take nicotine.
Humans have been reported to find intravenous nicotine rewarding (Henningfield & Goldberg, 1983b),but nicotine injections have also been shown to be aversive (Goldberg & Spealman, 1982; Jarvik, 1977).
Monkeys will work to postpone nicotine injections (Spealman, 1983). The fundamental uncertainties inthis area are reflected in Jaffe's statement: "We don't even know for sure what the principal reinforcingingredient in tobacco is" (Jarvik, 1977, p. 122).
There are two notable exceptions to the normally sluggish performance seen in nicotineself-administration experiments. Monkeys pressed a lever for a brief visual stimulus occasionallyaccompanied by an intravenous injection of nicotine (Goldberg, Spealman, & Goldberg, 1981). Thissecond-order schedule produced lever-press rates much higher than anyone has ever reported fornicotine. However, there are a number of points that temper the usefulness of these data. First, three ofthe four monkeys had been previously trained on a similar schedule for cocaine. Additionally, in theabsence of the signal, the monkeys performed as vigorously when the drug was no longer available. Thissuggests an extremely strange phenomenon. The peculiarity of these findings is further indicated by thefact that they have never been replicated. A single, well-controlled and replicable instance of vigorousnicotine self-administration would greatly strengthen the reinforcement thesis, yet no such instanceexists.
file:///C /Library Downloads/jdi.htm (12 of 58) [09-Jun-2001 07:02:06] Monkeys are capable of extraordinarily vigorous operant behavior. However, this vigor can also lead tointerpretational difficulties. Monkeys may respond at extremely high rates for almost anything. Theymay make hundreds of thousands of responses to self-administer painful electric shocks (McKearney,1968). This paradoxical behavior illustrates the problems in interpreting operant behavior. To inferreinforcement processes, let alone hedonic experience or addiction, from operant behavior requiresnumerous and tenuous assumptions.
Risner and Goldberg (1983) have reported mean breaking points of 390 responses for nicotine in beagles.
This performance is vastly more vigorous than any seen in rats where 5 appears to be the highestbreaking point rate ever achieved. As with his primate work (Goldberg, Spealman, & Goldberg, 1981),the finding with beagles has not been replicated. A common difficulty with both of the Goldberg studiesis that the animals were previously trained to self-administer cocaine. Thus it is unclear to what extentthe nicotine data merely represent an after-effect of the cocaine experience.
The fragility of nicotine self-administration is illustrated by large strain differences (Shoaib, Schindler, &Goldberg, 1997). Of four strains of rats, only two acquired nicotine self-administration, and even then itwas weak and unreliable. Sprague-Dawley rats pretreated with either saline or nicotine showed someintravenous self-administration of nicotine. However, Long-Evans rats acquired the self-administrationonly when pretreated with saline. It is puzzling why nicotine pretreatment would inhibit theestablishment of self-administration in one strain and facilitate it in another.
Fisher and Lewis inbred strains failed to acquire nicotine self-administration under any conditions(Shoaib et al., 1997). To establish any self-administration of nicotine requires the right strain of animal,the right pretreatment, and optimizing numerous other parameters as well (Wakasa et al., 1995). Thecrucial combination of so many and such diverse parameters indicate that this is not a robustphenomenon. It is not one that suggests abuse potential.
There are large contrasts in the acquisition of nicotine self-administration as compared to reference drugsof abuse. When nicotine injections only require making a few responses, monkeys take from two to ninemonths of daily training before they respond at rates higher than for saline (Swedberg et al., 1990). Incontrast, they quickly learn to make thousands of responses for a single injection of cocaine (Ambrosio etal., 1996; Foltin & Fischman, 1994; Tella, Ladenheim, Andrews, Goldberg, & Cadet, 1996).
Animals self-administer aspirin (Hoffmeister & Wuttke, 1973) and caffeine (Atkinson & Enslen, 1976;Deneau, Yangita, & Seevers, 1969; Sekita et al., 1992) As with nicotine, aspirin and caffeineself-administration is not very vigorous and sometimes it may not occur at all (Heishman &Henningfield, 1992). Since adverse effects on health have been associated with both aspirin and caffeine(Bednar & Gross, 1999; Kiyohara et al., 1999) as with nicotine, their use could be seen as meeting theprinciple criteria for addiction.
Rats cannot be trained to smoke, but they can be trained to take nicotine orally. If nicotine is reinforcing,it should enhance the reinforcing value of the solution in which it is presented. However, nicotine doesnot enhance the reinforcing value of any solution (Robinson, Marks, & Collins, 1996; Smith & Roberts,1995). To the contrary, as the nicotine concentration increases, the rats drink progressively less of thesolutions.
As models of human addiction, laboratory self-administration experiments lack face validity (Goudie,1991). In marked contrast to humans, laboratory species do not appear to organize their lives around any file:///C /Library Downloads/jdi.htm (13 of 58) [09-Jun-2001 07:02:06] drugs (Dole, 1980). Quite simply, there is no evidence that laboratory animals ever get "hooked." This isparticularly true of nicotine where there is not even the slightest suggestion of compulsive use inlaboratory species. Since getting any voluntary use of nicotine is difficult, it seems unlikely thatcompulsive use will ever be demonstrated.
The self-administration model also lacks predictive validity (Goudie, 1991). Many drugs that humansabuse are not self-administered in laboratory species and vice versa. These false positives and negativesgreatly reduce the usefulness of information derived from such paradigms. The fact that there is someconcordance for certain drugs suggests that such experimentation may elucidate the human use of thesedrugs. However, nicotine is not one of the drugs for which there is a reasonable degree of concordance.
Sensory-contingent ReinforcementRats can be trained to press a lever simply to get a brief flash of light (Glow & Russell, 1973; Glow &Winefield, 1979, 1982; Winefield & Glow, 1980). This behavior is at least as vigorous and reliable asnicotine self-administration. In a uniform environment with few options, rats will do a little of almostanything (Lovaas et al., 1987). Rats will lick at a drinking tube through which a stream of air is passingor even just a chilled drinking tube (Mendelson & Chillag, 1970a, 1970b; Mendelson, Zec, & Chillag1971, 1972). These strange behaviors are much more vigorous than nicotine self-administration, yet fewwould be willing to attribute abuse potential to air or cold metal. Under certain circumstances, unusual,even compulsive, behavior can be produced in laboratory species. However, there are no remotelycomparable human behaviors. This lack of face validity means that it is perilous to use these laboratoryanomalies as models of any human behavior.
Place PreferenceIn drug self-administration experiments, the animals are tested while under the influence of the drug.
This means that drug side-effects can be confused with changes in the motivation to take the drug. Oneway around the performance problem is to test the animals when they are not under the influence of thedrug. For example, if a rat is given heroin or cocaine in a distinctive environment, they come to prefer theenvironment in which the drug was given (Perks & Clifton, 1997). They appear to remember the positiveexperience, and the preference may last for many weeks. The place preference procedure is minimallyaffected by behavioral incapacitation since the animals are tested in a non-drugged state.
Place preference experimentation provides only weak and equivocal support for nicotine beingrewarding. The tone for this work was set some time ago. "Although nicotine has been reported toproduce conditioned place preference, the present results suggest that it is not a robust phenomenon"(Clarke & Fibiger, 1987, p. 84). Some have failed to get a place preference with nicotine (Clarke &Fibiger, 1987; Parker, 1992). Others have shown place aversion (Jorenby, Steinpreis, Sherman, & Baker,1990). Still others have shown both preference and aversion in the same experiment (Calcagnetti &Schechter, 1994; Shoaib, Stolerman, & Kumar, 1994). Much like the self-administration experiments,these experiments show that if nicotine has any rewarding properties at all, they are both weak andunreliable. Such findings do not suggest abuse potential.
The state of the animal literature on the rewarding properties of nicotine has been summarised by Collins(1990): "Studies do not provide unequivocal evidence for nicotine producing reward either via euphoricactions or through reduction of pain, anxiety, or negative affect" (p. 20).
Conditioned Taste AversionConditioned taste aversion is another technique for evaluating the motivational properties of drugs file:///C /Library Downloads/jdi.htm (14 of 58) [09-Jun-2001 07:02:06] (Andrews & Holtzman, 1987; Franklin & Robertson, 1992; Hunt & Atrens, 1992; Hunt, Atrens, &Jackson, 1994; Lin, Atrens, Christie, Jackson, & McGregor, 1993; Olds, 1994; Wise & Munn, 1993). Ifcocaine or amphetamine is administered at the time the animal is exposed to a novel flavor, onsubsequent exposure to the flavor the rats show an aversion for it. It is paradoxical why the sameexperience can produce a place preference and a taste aversion (Grigson, 1997). Since clearly aversivesubstances such as lithium chloride also produce taste aversion (Bourne, Calton, Gustavson, &Schachtman, 1992; Turenne, Miles, Parker, & Siegel, 1996), the taste aversion model appears to havelittle face validity (Parker, 1991).
As with the other models of reinforcement, the data concerning nicotine and place preference areinconsistent. For example, some strains of mice show conditioned taste aversions, but others do not(Risinger & Brown, 1996). Another experiment showed that only extremely high doses of eitheramphetamine or nicotine produced conditioned taste aversions (Parker, 1991). These doses did notproduce a place preference. Thus one model suggests reinforcement, but the other does not.
Reinforcement in HumansThere is one widely cited paper suggesting that nicotine is powerfully reinforcing for humans(Henningfield, Miyasato, & Jasinski, 1985). Humans reported that intravenous injections of nicotine feltsimilar to cocaine. The face appeal of these findings is reduced by methodological problems. First, all ofthe subjects were hospitalized with unspecified histories of substance abuse. Additionally, some of thesubjects who reported that nicotine was like cocaine had never experienced cocaine (Clark, 1990).
Additionally, some subjects thought nicotine was like cannabis, morphine, or Valium®. Such grosserrors suggest that the subjects were fairly confused. Some subjects reported a "rush" from the nicotineinjection. Considering that they were given the nicotine content of three cigarettes in one bolus, such aneffect is not surprising. High doses of nicotine often produce dizziness (Perkins et al., 1994) .
Another study in a similar group of patients reported that intravenous caffeine produced subjectiveeffects similar to those of cocaine (Rush, Sullivan, & Griffiths, 1995). These subjects identified caffeineas cocaine more often than they identified cocaine as cocaine! The subjective reports of intravenous drugusers are influenced by many processes with little relevance to human drug taking (Iwamoto & Martin,1988).
Paid volunteers given 40 µg/kg of intravenous nicotine reported transient respiratory problems, tightnessin the chest, and feeling faint (Henningfield, Miyasato, & Jasinski, 1983). Paradoxically, it was only thisdose that produced reports of liking. On the other hand, one of the subjects said he would pay not to haveanother injection. These data do not suggest reinforcing effects of nicotine that are in any waycomparable to those of drugs such as cocaine or heroin.
The above experiments and many others illustrate the difficulties with introspection (Altman et al., 1996;Chiauzzi & Liljegren, 1993; Fischman & Foltin, 1991; Henningfield, Cohen, & Heishman, 1991). Ifthese experiments showed that the hedonic effects of nicotine were at all similar to drugs such as cocaine,the findings would still be difficult to interpret. However, the human experiments show such weak andinconsistent hedonic effects of nicotine that they do not merit extensive interpretational effort.
The fact that smokers generally prefer regular cigarettes to nicotine-free cigarettes suggests theimportance of nicotine to smoking. However, nicotine-free cigarettes differ from regular cigarettes innumerous respects apart from nicotine content (Ashton & Stepney, 1982; Eysenck, 1965; Westman,Behm, & Rose, 1996). If nicotine is the basis of cigarette smoking, adding nicotine to nicotine-free file:///C /Library Downloads/jdi.htm (15 of 58) [09-Jun-2001 07:02:06] cigarettes should greatly increase their acceptability. Jaffe describes his experiments in this area: "Thefact that lettuce cigarettes reinforced with nicotine were not accepted more than non-nicotine cigaretteshas been a cause for concern and seriously undermined our support of the pure nicotine hypothesis"(Jarvik,1977, p. 141).
In another study, smokers rated a nicotine-free cigarette as pleasant as their regular brand. The samesubjects reported that a high nicotine cigarette was less pleasant (Gilbert et al., 1992). Although smokersfind smoking pleasant, the pleasantness is a mild effect that bears no relationship to the powerful hedoniceffects of drugs of abuse (Russell, 1989). The dissociation of nicotine from the reinforcing properties ofsmoking is further indicated by the fact that nicotine chewing gum produces mildly unpleasant effectsand has little abuse potential (Henningfield & Keenan, 1993; Hughes et al., 1989; Nemeth-Coslett,Henningfield, O'Keeffe, & Griffiths, 1987).
In summary, the literature on nicotine reinforcement in humans is congruent with that from laboratoryspecies. If nicotine is reinforcing, it is only weakly so. It is no more reinforcing than caffeine or manyother innocuous substances. Nicotine reinforcement is not in any way comparable to the powerful andconsistent effects produced by reference drugs such as cocaine and heroin. These findings provide nosupport for the notion that nicotine is sufficiently reinforcing to suggest abuse potential.
Interpreting Behavioral PersistenceMany find it difficult to quit smoking. This is reflected in high relapse rates of those in smokingcessation programs (Brigham, Henningfield, & Stitzer, 1990; Chassin, Presson, Rose, & Sherman, 1996;Fisher, Lichtenstein, Hairejoshu, Morgan, & Rehberg, 1993; Gibbons, Eggleston, & Benthin, 1997;Grunberg et al., 1995; Hymowitz & Eckholdt, 1996; Law & Tang, 1995; Schneider et al., 1996; Ter,Kleijnen, & Knipschild, 1990). The vast majority of successful quitters simply quit (Kozlowski &Schachter, 1975; Lennox & Taylor, 1994; Schachter, 1977, 1982, 1983, 1990; Schachter, Silverstein, &Perlick, 1977; Silverstein, Kozlowski, & Schachter, 1977). Moreover, many quit with little or nodifficulty (Brauer, Hatsukami, Hanson, & Shiffman, 1996; Shiffman, 1989; Shiffman et al., 1995;Shiffman et al., 1994; Shiffman, Paty, Gnys, & Zettler-Segal, 1992). Strong resistance to change is not ageneral characteristic of smoking.
Whereas the public and professionals alike find addiction a convenient explanation for behavioralpersistence, there are other explanations that are at least equally plausible (Ritzman, 1992; Warburton,1994a, 1994c, 1994d, 1995). In any case, no explanation at all is always preferable to a bad explanation.
The fact that humans engage in many behaviors in spite of numerous warnings of the attendant harms isnot evidence of addictive processes. It is testimony to human frailty and the ineffectiveness of fear incontrolling behavior.
Addiction and the Brain
Addiction is commonly portrayed as a brain disease (Anonymous, 1997; Balter, 1996; Brautbar, 1995;
Dani & Heinemann, 1996; Leshner, 1996; Nash, 1997; Nutt, 1996; Rose, 1996) In spite of such claims,
there is no brain pathology or even special brain state uniquely associated with the use of any drug in any
species. Drugs of abuse change brain function (Di Chiara, 1995; Joseph, Young, & Gray, 1996; Peele,
1990c). However, similar changes are also produced by relatively innocuous substances and everyday
events (Hernandez & Hoebel, 1988a, 1988b; Pfaus, Damsma, Wenkstern, & Fibiger, 1995; Wilson,
Nomikos, Collu, & Fibiger, 1995; Yoshida, Yokoo, Mizoguchi, Kawahara, Tsuda, Nishikawa, & Tanaka,
1992; Young, Joseph, & Gray, 1992). Such changes cannot reasonably be said to represent the neural
file:///C /Library Downloads/jdi.htm (16 of 58) [09-Jun-2001 07:02:06] substrate of addiction.
Some of nicotine's effects on dopamine resemble those of reference drugs, such as cocaine andamphetamines (Fung, Schmid, Anderson, & Lau, 1996; Koob, 1996; Levin, Kim, & Meray, 1996; Pich etal., 1997; Pontieri, Tanda, Orzi, & Di Chiara, 1996). These effects are consistent with abuse potential.
However, there is also a great deal of evidence arguing against a major role for dopamine in nicotine'seffects (Acquas, Carboni, Leone, & Di Chiara, 1989; Balfour, 1994; Corrigall & Coen, 1994b; Horger,Valadez, Wellman, & Schenk, 1994; Stolerman, 1991). These data will be discussed below.
Dopamine and the Nucleus AccumbensInvestigations of the neural basis of addiction have focused largely on the nucleus accumbens and theneurotransmitter, dopamine (Blum, Cull, Braverman, & Comings, 1996; Corrigall et al., 1994; Corrigallet al., 1992; Di Chiara et al., 1992; Koob & Weiss, 1992; Nisell, Nomikos, & Svensson, 1995; Robbins& Everitt, 1996; Self, McClenahan, Beitner-Johnson, Terwilliger, & Nestler, 1995; Self & Nestler, 1995;Volkow et al., 1997). This has led to what has become known as the dopamine hypothesis of reward(Salamone, Cousins, & Snyder, 1997). According to this view, the nucleus accumbens dopamine systemis the final common denominator of diverse types of reinforcement (Koob, 1996; Koob & Bloom, 1988;Mitchell & Epstein, 1996; Wise, 1994, 1996a, 1996b, 1997; Wise & Leeb, 1993).
Amphetamine, cocaine, and morphine increase dopamine metabolism in the nucleus accumbens (DiChiara & Imperato, 1988; Pontieri, Tanda, & Di Chiara, 1995). These drugs are frequently associatedwith problem use. Nicotine also increases dopamine metabolism in the nucleus accumbens (Benwell,Holtom, Moran, & Balfour, 1996; Mirza, Pei, Stolerman, & Zetterström, 1996; Pontieri et al., 1996), andthis is used as evidence that nicotine is addictive (Pich et al., 1997). However, several considerationssuggest that such a conclusion may not be warranted. Like nicotine, cannabis and synthetic cannabinoidsalso increase extracellular dopamine in the accumbens (Tanda, Pontieri, & Di Chiara, 1997) . Saccharinalso has similar effects (Mark, Blander, & Hoebel, 1991). The effects of cannabis, saccharin, andsynthetic cannabinoids are further evidence of the broad range of stimuli that increase extracellulardopamine release. Mild tail pinches also increase extracellular dopamine in the shell of the accumbens(Brake, Noel, Boksa, & Gratton, 1997). Whatever increased extracellular dopamine in the accumbensmay mean, and this is by no means clear (Di Chiara, 1995; Di Chiara, Tanda, & Carboni, 1996), it is notan indicator of addictive potential.
Additionally, the effect of these drugs on dopamine metabolism could simply be due to motor activation.
All of these drugs stimulate motor activity, and the nucleus accumbens is an important part of the brain'smotor control circuitry (Angulo & McEwen, 1994; Salamone, Cousins, & Snyder, 1997). Locomotoractivity also increases dopamine metabolism (Sabol, Richards, & Freed, 1990). Further, the effect ofnicotine on dopamine metabolism is extremely small--from one third to one sixth of that produced byreference drugs. Thus, in terms of its effects on dopamine metabolism in the nucleus accumbens, nicotinehas quantitatively weak commonality with reference drugs. It is more similar to numerous other innocoussubstances and events.
Dopamine release in the nucleus accumbens is not even unequivocally associated with positivereinforcement. Dopamine may be released by a neutral stimulus (Young, Joseph, & Gray, 1993) as wellas a variety of aversive events including tail shock, foot shock, restraint, and release from restraint(Joseph, Young, & Gray, 1996). Gratton has recently reported similar effects of stress (Doherty &Gratton, 1996; Noel & Gratton, 1995). Thus enhanced dopamine release in the accumbens may mean file:///C /Library Downloads/jdi.htm (17 of 58) [09-Jun-2001 07:02:06] almost anything; it is not an unequivocal indicator of anything.
Additionally, the enhanced release of dopamine in the nucleus accumbens reported by Di Chiara andImperato (1988) was produced by an extremely high dose of nicotine (600 µg/kg). The equivalent humandose would be about 50 cigarettes taken at once. Reid, Ho, and Berger (1996) also found increaseddopamine release in the nucleus accumbens in response to 600 µg/kg but only in rats that had beenconditioned to the testing environment. Nisell, Nomikos, Hertel, Panagis, and Svensson (1996) alsoobtained enhanced dopamine release in the accumbens with 500 µg/kg. Others have also found enhanceddopamine release in the accumbens at slightly lower nicotine doses (Benwell, Balfour, & Khadra, 1994;Mirza et al., 1996; Shoaib & Shippenberg, 1996).
All of the experiments described above used nicotine doses at least an order of magnitude greater thanthose used in animal self-administration experiments (typically 30 µg/kg) (Chiamulera et al., 1996;Corrigall & Coen, 1991a). Since self-administration of nicotine falls off at even 60 µg/kg (Stolerman &Shoaib, 1991), it appears that the nicotine doses used in the dopamine release work would be aversive.
One hundred µg/kg of nicotine given intravenously produces whole body tremor even in rats givenhexamethonium bromide to reduce peripheral effects (McNamara, Larson, Rapoport, & Soncrant, 1990).
There is only one study of dopamine metabolism that has used nicotine doses in the range of thoseself-administered by laboratory species (Pontieri et al., 1996). An intravenous bolus of nicotine (25µg/kg) had no effect on glucose utilization. However, a higher dose (50 µg/kg) increased energymetabolism in the accumbens. These data stand in contrast to demonstrations that intraperitoneal,subcutaneous (London, Connolly, Szikszay, Wamsley, & Dam, 1988; McNamara et al., 1990) orcontinuous intravenous infusions (Grunwald, Schrock, & Kuschinsky, 1987) of nicotine have no effecton dopamine metabolism in the accumbens.
The tenuous relationship of dopamine release in the accumbens to behavioral processes is indicated bythe effects of dopamine antagonists and neurotoxic lesions. Tone-shock pairings release dopamine in theaccumbens, yet systemic or intra-accumbens administration of dopamine antagonists has no effect on thelearning or retention of the association (Joseph, Young, & Gray, 1996). Moreover, low doses ofsystemically-administered dopamine antagonists may enhance reinforcement (Smith, Neill, & Costall,1997). Selective neurotoxic lesions of the dopamine terminals in the accumbens before training also haveno effect on the above association (Gray et al., 1995). It is premature to use dopamine release in thenucleus accumbens as a definitional characteristic of any aspect of drug use.
Compulsive Drug UseInjury and death associated with the use of opiates and stimulants in humans are common (Benbow,Roberts, & Cairns, 1996; Darke & Zador, 1996; Logan, Weiss, & Harruff, 1996; Mash, 1997;Osterwalder, 1996). Being able to model this lethal aspect of drug use would be of great value. However,self-induced drug-associated deaths in laboratory species are rare. An exception is Bozarth and Wise's(Bozarth & Wise, 1985) report of a poor health and high mortality in rats given free access to intravenouscocaine and heroin.
Drug self-administration that leads to injury or death in laboratory species is commonly used to indicatethat the drug in question has addictive potential (Dworkin, Mirkis, & Smith, 1995; Epling & Pierce,1994; Koob, 1992, 1996). However, there are more parsimonious explanations for such maladaptivebehavior. For example, food deprived rats given access to a running wheel may run and starvethemselves to death (Beneke, Schulte, & Vander Tuig, 1995; Pierce & Epling, 1991; Rieg & Aravich, file:///C /Library Downloads/jdi.htm (18 of 58) [09-Jun-2001 07:02:06] 1994). The anorexia and weight loss are similar to that reported by Bozarth and Wise (1985) during drugself-administration. Recent experiments have led to a fundamental reinterpretation of this behavior. Ifrats are given experience with the altered feeding schedule before they are given access to the runningwheels, the excessive running and self-starvation do not occur (Boakes & Dwyer, 1997; Dwyer &Boakes, 1997). The self-destructive behavior merely reflects the rat's inability to adjust to alteredconditions of feeding (Boakes & Dwyer; Dwyer & Boakes). In laboratory species, even behavior thatappears to be sufficiently compulsive to lead to ill health and death requires cautious interpretation.
Tolerance
Although tolerance was long considered an important indicator of addiction, in 1969 WHO relegated it to
a minor role. On the other hand, the Surgeon General still gives it a prominent place (US Department of
Health and Human Services, 1988). It is peculiar to include tolerance as an indicator of addiction since
tolerance is a common characteristic of responding to most forms of stimulation in almost all
physiological systems (Atrens & Curthoys, 1982; Kalat, 1992).
As with nearly every other drug, tolerance has been shown to nicotine effects in laboratory species(Bullock, Barke, & Schneider, 1994; Damaj, Welch, & Martin, 1996; Domino & Lutz, 1973; Geng,Savage, Razanai-Boroujerdi, & Sopori, 1996; McAllister et al., 1994; Villanueva, James, & Rosecrans,1989) and humans (Becona & Garcia, 1995; Henningfield & Keenan, 1993; Ochoa, 1994; Parrott, 1994;Perkins et al., 1994; Perkins et al., 1995). At the same time, it is noteworthy that these experiments showthat tolerance occurs to some of nicotine's effects but not to others. Nicotine tolerance is a highlyspecific, not a general, phenomenon.
The major problem with tolerance as a criterion of addiction is the lack of any reasonable explanation ofwhy it should indicate addiction. Tolerance occurs in diverse systems in response to nearly everysubstance encountered by every species. The mere fact that tolerance may be a conspicuous aspect ofopiate use is not sufficient reason to elevate this ubiquitous phenomenon to the status of a symptom ofaddiction.
Withdrawal and Craving
In contrast to the dubious conceptual status of tolerance as an element in the definitions of addiction,
there are reasonable grounds for including withdrawal. Withdrawal and associated craving are widely
thought to be the main forces that drive relapse from drug abstinence (Henningfield, Gopalan, &
Shiffman, 1998; Klein, 1998; Weaver, Jarvis, & Schnoll, 1999). However, there are major deficiencies in
this approach. Even with opiates, the role of withdrawal in relapse remains in doubt (DuPont, 1998;
Hughes, Higgins, & Bickel, 1994).
Many years of intensive investigation have failed to identify nicotine withdrawal effects that persist formore than a few weeks, at the very most (Hughes, 1992). In contrast, the tendency to relapse to smokingmay persist for years (Henningfield et al., 1998; Patton et al., 1998; Razavi et al., 1999). The greatdifferences in the temporal courses of withdrawal and relapse potential suggest that withdrawal cannot bea significant factor in relapse. Thus, withdrawal fails to account for the very behavior that it was invokedto explain (Satel, Kosten, Schuckit, & Fischman, 1993). A recent review stated: "It is concluded that theresearch to date does not appear to strongly implicate nicotine withdrawal in adversely affecting smokingcessation or maintenance of abstinence" (Patten & Martin, 1996, p. 190).
West, Russell, Jarvis, & Feyerabend (1984) investigated the effects in smokers of switching to an file:///C /Library Downloads/jdi.htm (19 of 58) [09-Jun-2001 07:02:06] ultra-low nicotine cigarette. They found an increase in hunger and decrease in heart rate but ".othercommon cigarette withdrawal symptoms, such as irritability, depression, and inability to concentrate,were not detected" (p. 120). Increased hunger and decreased heart rate are reliably associated withsmoking cessation (Altman et al., 1996), but the other symptoms are not. The failure to find consistentpsychological signs of abstinence is significant since it is this constellation of psychological dysfunctionthat is said to be the reason for relapse to smoking (Benowitz, 1996; Griffiths, 1996; Heishman et al.,1997; Kozlowski et al., 1989; Scholte & Breteler, 1997).
Craving is often invoked as a cause of relapse (Jaffe , 1990b). Craving has been characterized as anintense motivational state that arises as a consequence of withdrawal (Markou et al., 1993). Howeverthere is no workable definition of or procedure for measuring craving in any species (Altman et al., 1996;Tiffany, 1991). Until this deficiency is rectified, invoking craving merely further obfuscates an alreadyconfused area.
Human brain imaging studies have shown relatively long-duration changes in brain function of smokers,but the authors point out that it is unclear whether such changes are relevant to, let alone cause,withdrawal and/or craving (Kuhar & Pilotte, 1996). Changes in monoamine oxidase A activity in the ratbrain following chronic high doses of nicotine have also been reported (Bhattacharya, Chakrabarti,Sandler, & Glover, 1995). However, apart from the fundamental problem of what such changes mean, itis not clear whether they occur to reasonable doses of nicotine and whether they last longer than 14 days.
Indeed, given the monoaminergic effects of high nicotine doses (Sershen, Toth, Lajtha, & Vizi, 1995;Vizi & Lendvai, 1999), it is not even clear whether these may be consdered true nicotine effects.
In spite of the widespread acceptance of withdrawal symptoms as an index of addiction (Benowitz, 1988;Koob, Sanna, & Bloom, 1998; Lyvers, 1998; West, 1984), this consensual faith does not appear to bejustified. Striking, even dangerous withdrawal symptoms are also produced by antidepressants,antihypertensives, neuroleptics, and steroids (Haddad, 1999; Hughes et al., 1994). None of these diversetypes of drugs has abuse potential, and humans tend to find them unpleasant. However, polydrug usersmay sometimes abuse almost any drug, including antidepressants (Kaminer, 1994).
The nicotine withdrawal literature is full of contradictions. For example, although anxiety is one of thecommonest withdrawal symptoms, it is often not seen in animal models (Grasing, Wang, & Schlussman,1996). Alternately, signs of anxiety are seen in some models and not in others and only under highlyspecific conditions (Balfour, 1994). Moreover, anxiolytic drugs are of little use in treating withdrawal ineither animals or humans (Goudie & Leathley, 1995; Schneider et al., 1996). Even when nicotinewithdrawal symptoms can be produced in laboratory species, they are very short lived. After seven daysof continuous intravenous nicotine infusions, withdrawal signs in rats were not detectable after 16 hours(Malin et al., 1992).
Nicotine Replacement Therapy
The beneficial effects of nicotine replacement therapy on smoking cessation are often used in support of
the nicotine addiction hypothesis. Nicotine replacement therapy may have significant effects
(Hjalmarson, Nilsson, Sjöström, & Wiklund, 1997; Law & Tang, 1995; Silagy, Mant, Fowler, & Lodge,
1994a, 1994b). However, these effects are modest and vary considerably. There have been numerous
failures of nicotine replacement therapy (Jorenby et al., 1999; Patten & Martin, 1996; Schneider et al.,
1996; Sonderskov, Olsen, Sabroe, Meillier, & Overvad, 1997). Almost any smoking cessation treatment
is effective in the short term, but the effectiveness diminishes progressively at longer follow-up intervals
file:///C /Library Downloads/jdi.htm (20 of 58) [09-Jun-2001 07:02:06] (Curry, Grothaus, McAfee, & Pabiniak, 1998; Jones, Nguyen, & Man, 1998; Razavi et al., 1999).
It is even possible that the effects observed in nicotine replacement therapy are not true pharmacologicaleffects. The double-blind placebo trials use inactive agents to control for placebo effects. However,inactive agents are a poor placebo for an easily discriminable drug such as nicotine (Gilbert et al., 1992;Henningfield, Miyasato, & Jasinski, 1983; Perkins et al., 1994). There is evidence that the sensoryexperience provided by nicotine, apart from its pharmacological properties, may be important. Reducedcraving in abstinent smokers has been produced by the vapor of black pepper (Rose & Behm, 1994) andcitric acid (Westman, Behm, & Rose, 1995). By providing a facsimile of the oral and bronchialstimulation caused by tobacco smoke, the black pepper vapor and the fumes of citric acid functionedmuch like tobacco.
In any case, the success or lack thereof of nicotine replacement is orthogonal to the question of whethernicotine is addictive. There is no doubt that nicotine is involved in smoking, but whether its involvementis that of an addictive substance has yet to be demonstrated.
Conclusions
The notion of nicotine addiction suffers from numerous and major conceptual, definitional, and empirical
inadequacies. Some reflect general problems with the concept of addiction, whereas others are specific to
nicotine.
A recurring source of difficulty for the nicotine addiction hypothesis is the continuing lack of consensusconcerning a definition of addiction. Hundreds of definitions have been offered, yet none withstands anyscrutiny. Rigorous definitions of addiction clearly exclude nicotine, whereas those that reasonablyinclude nicotine also include so many other substances and events that the notion of addiction becomestrivialized.
Lacking a reasonable definition of addiction, the putative addictiveness of drugs has become a matter oflegislative fiat, judicial rulings, and committee edicts. Not surprisingly, which drugs are consideredaddictive varies markedly over time and in different places. Cannabis was long considered to be thescourge of our youth while tobacco was considered relatively harmless. Recently this position has beenreversed. This is not science, but politics.
Self-administration studies in laboratory species are said to support the view that nicotine, much likeheroin and cocaine, is powerfully reinforcing. However, nicotine self-administration doesn't remotelyapproach the vigor or reliability of that supported by drugs such as cocaine and heroin. The strongestreinforcing effects of nicotine in laboratory species are less than those of innocuous reinforcers such aslight, sound, sugar, or salt.
Moreover, nicotine self-administration requires doses that are far higher than humans ever encounter.
These effects may well represent monoaminergic effects of high nicotine doses. There are no reports ofnicotine self-administration in laboratory species at doses even approaching those self-administered byhumans. It is unjustified to use weak and inconsistent reinforcement effects obtained with highintravenous doses in laboratory species as evidence for human abuse potential.
Perhaps the most serious deficiency in using animal models to study human drug taking is that animalsdo not seem to get 'hooked' on any substance. This is particularly true of nicotine. It is difficult to showany rewarding effects of nicotine in laboratory species, let alone the powerful effects associated withdrugs of abuse. It is possible that drug abuse is a uniquely human phenomenon.
file:///C /Library Downloads/jdi.htm (21 of 58) [09-Jun-2001 07:02:07] Like the data from animal experimentation, the data on nicotine reinforcement in humans do not suggestthat nicotine has abuse potential. There are no credible demonstrations in humans that nicotine is anymore reinforcing than many other substances and events that have no abuse potential. The subjectiveeffects of nicotine suggest a drug that is pleasant, nothing more. In this crucial respect, nicotine contrastsmarkedly with reference drugs such as cocaine and heroin that consistently produce strong feelings ofeuphoria.
There have been attempts to lend credibility to the notion of addiction by describing it as a brain disease.
However, there is little evidence for such a view. There is no special brain state associated with nicotineuse. Although nicotine has diverse effects on the brain, none has any significant potential to perpetuatenicotine use. Moreover, the neural effects of nicotine and other putatively addictive drugs areindistinguishable from those produced by many relatively harmless substances and everyday experiences.
Nicotine has effects on dopaminergic transmission that, in certain respects, resemble those of cocaine orheroin. However, almost anything that alters arousal alters dopaminergic transmission. Suchneurochemical effects should not be interpreted as a correlate of addiction. The fact that some of theeffects on dopamine transmission may be restricted to the shell of the nucleus accumbens is interesting,but irrelevant to whether nicotine or anything else is addictive.
The finding that dopamine may be involved in the effects of nicotine and reinforcement processes lendsno support to the notion that nicotine is addictive. The dopamine hypothesis of reinforcement remains anintensely debated issue in which the theory, methodology, and empirical findings are all disputed. Claimsto the contrary notwithstanding, none of the many variants of the dopamine theory has, as yet, anyimplications for human drug use. There is no justification for making the major leap from the poorlyunderstood neural sequelae of reinforcement in laboratory species to the still more poorly defined andunderstood notion of addiction in humans.
The effects of nicotine, like those of virtually every other drug, psychoactive or not, show a degree oftolerance. It is questionable whether this ubiquitous phenomenon says anything about abuse potential. Itcertainly does not distinguish nicotine from many other innocuous substances.
Nicotine use may sometimes produce withdrawal effects. However, many drugs with no abuse potentialproduce withdrawal effects that are much more dramatic than those produced by nicotine. Conversely,many drugs with substantial abuse potential produce little in the way of withdrawal effects. Additionally,nicotine withdrawal effects last for no more than a few weeks, whereas relapse potential may last foryears. The fact that withdrawal and relapse potential have such different temporal characteristicsindicates that they cannot be causally related.
In summary, apart from numerous conceptual and definitional inadequacies, the notion that nicotine is anaddictive substance lacks reasonable empirical support. There are so many and such grossly conflictingfindings that adhering to the nicotine addiction thesis is only defensible on political, not scientific,grounds. More broadly, addiction may have some use as a description of certain types of behavior, but itfails badly as an explanation of such behaviors.
It is commonly assumed that questioning the addiction hypothesis is to condone and even advocate druguse. Such an assumption is incorrect. In order to develop effective treatments for drug problems, it isnecessary to escape from the unproductive ideology that is currently dominant. Abandoning the conceptof addiction is a step in this direction.
file:///C /Library Downloads/jdi.htm (22 of 58) [09-Jun-2001 07:02:07] References
Acquas, E., Carboni,, E., Leone, P., & Di Chiara, G.
1989 SCH 23390 blocks drug-conditioned place-preference and place- aversion: Anhedonia (lack ofreward) or apathy (lack of motivation) after dopamine-receptor blockade? Psychopharmacology, 99(2),151-155.
Alexander,B.K., Coambs, R.B., & Hadaway, P.F.
1980 Rat park chronicle. British Columbia Medical Journal, 22(2), 32-45.
Allis, S., Lafferty, E., McAllister, J.F.O., &and van Voorst, B.
1997 Sorry pardner - Big Tobacco fesses up and pays up $368.5 billion, but Congress must approve thedeal. Time, 25-29.
Allsop, K.A., & Miller, J.B.
1996 Honey revisited: A reappraisal of honey in pre-industrial diets. British Journal of Nutrition, 75(4),513-520.
Altman, J., Everitt, B.J., Glautier, S., Markou, A., Nutt, D., Oretti, R., Phillips, G.D., & Robbins, T.W.
1996 The biological, social and clinical bases of drug addiction: commentary and debate.
Psychopharmacology, 96(4), 285-345.
Ambrosio, E.,Tella, S.R., Goldberg, S.R., Schindler, C.W., Erzouki, H., & Elmer, G.I.
1996 Cardiovascular effects of cocaine during operant cocaine self- administration. European Journal ofPharmacology, 315(1), 43-51.
American Psychiatric Association1980 Diagnostic and statistical manual of mental disorders. Washington, DC: American PsychiatricAssociation.
American Psychiatric Association1994 Diagnostic and statistical manual of mental disorders. Washington DC: American PsychiatricAssociation.
Ando,K.
1975 Profile of drug effects on temporally spaced responding in rats. Pharmacology Biochemistry andBehavior, 3(5), 833-841.
Ando,K., Hironaka, N., Yanagita, T.
1986 Development of cigarette smoking in rhesus monkeys. (National Institute on Drug Abuse ResearchMonograph 153) .
Ando,K., & Yanagita, T.
1981 Cigarette smoking in rhesus monkeys. Psychopharmacology, 72(2), 117-127.
Andrews, J.S., & Holtzman, S.G.
1987 The interaction of d-amphetamine and naloxone differs for rats trained on separate fixed-interval orfixed-ratio schedules of reinforcement. Pharmacology Biochemistry and Behavior, 26, 167-171.
file:///C /Library Downloads/jdi.htm (23 of 58) [09-Jun-2001 07:02:07] Angulo,J.A., & McEwen, B.S.
1994 Molecular aspects of neuropeptide regulation and function in the corpus striatum and nucleusaccumbens. Brain Research Reviews, 19(1), 1-28.
Anonymous1995 Indicators of nicotine addiction among women--United States, 1991-1992. Morbidity & MortalityWeekly Report, 44(6), 102-105.
Anonymous1996 Tobacco control: reducing cancer incidence and saving lives. American Society of ClinicalOncology. Journal of Clinical Oncology, 14(6), 1961-1963.
Anonymous1997 Making the case for drug-addiction research. Foundation for Biomedical Research Facts, II(6), 1-1.
Ashton, H., & Stepney, R.,1982 Smoking: Psychology and pharmacology. London: Tavistock Publications.
Asin, K.E., & Wirtshafter, D.
1985 Clonidine produces a conditioned place preference in rats. Psychopharmacology, 85, 383-385.
Atkinson, J., & Enslen, M.
1976 Self-administration of caffeine by the rat. Arzneimittel-Forschung , 26(11), 2059-2061.
Ator, N.A., & Griffiths, R.R.
1983 Nicotine self-administration in baboons. Pharmacology Biochemistry and Behavior, 19(6),993-1003.
Ator, N.A., & Griffiths, R.R.
1987 Self-administration of barbiturates and benzodiazepines: A review. Pharmacology Biochemistryand Behavior, 27(2), 391-398.
Atrens, D.M., & Curthoys, I.S.
1982 The neurosciences and behavior: An introduction. Sydney, Australia: Academic Press.
Balfour, D.J.K.
1994 Neural mechanisms underlying nicotine dependence. Addiction, 89(11), 1419-1423.
Balter, M.
1996 New clues to brain dopamine control, cocaine addiction [news]. Science, 271(5251), 909.
Becona, E., & Garcia, M.P.
1995 Relation between the Tolerance Questionnaire (nicotine dependence) and assessment of carbonmonoxide in smokers who participated in treatment for smoking. Psychological Reports, 77(3 Pt 2),1299-1304.
Bednar, M.M., & Gross, C.E.
1999 Aspirin reduces experimental cerebral blood flow in vivo. Neurological Research, 21(5), 488-490.
Benbow, E.W., Roberts, I.S., & Cairns, A.
1996 Fatal methadone overdose. Better understanding of body's handling of methadone is needed. British file:///C /Library Downloads/jdi.htm (24 of 58) [09-Jun-2001 07:02:07] Medical Journal, 313(7070), 1479.
Beneke,W.M., Schulte, S.E., & Vander Tuig, J.G.
1995 An analysis of excessive running in the development of activity anorexia. Physiology & Behavior,58, 451-457.
Benowitz, N.L.
1988 Pharmacologic aspects of cigarette smoking and nicotine addition. New England Journal ofMedicine, 319(20), 1318-1330.
Benowitz, N.L.
1996 Pharmacology of nicotine: Addiction and therapeutics. Annual Review of Pharmacology &Toxicology, 36, 597-613.
Benowitz, N.L., Porchet, H., & Jacob III, P.
1990 Pharmacokinetics, metabolism, and pharmacodynamics of nicotine. In S.Wonnacott, M.A.H.
Russell, & I.P.Stolerman (Eds.). Nicotine psychopharmacology: Molecular, cellular, and behaviouralaspects (pp. 112-157). Oxford UK: Oxford University Press.
Benwell,M.E., Balfour, D.J., & Khadra, L.F.
1994 Studies on the influence of nicotine infusions on mesolimbic dopamine and locomotor responses tonicotine. Clinical Investigator, 72(3), 233-239.
Benwell,M.E., Holtom, P.E., Moran, R.J., & Balfour, D.J.
1996 Neurochemical and behavioural interactions between ibogaine and nicotine in the rat. BritishJournal of Pharmacology, 117(4), 743-749.
Bergen, A.W., & Caporaso, N.
1999 Cigarette smoking. Journal of the National Cancer Institute, 91(16), 1365-1375.
Berke, J.D., & Hyman, S.E.
2000 Addiction, dopamine, and the molecular mechanisms of memory. Neuron, 25(3), 515-532.
Bewley,S., & Bewley, T.H.
1992 Drug dependence with oestrogen replacement therapy. Lancet, 339(8788), 290-291.
Bhattacharya, S.K., Chakrabarti, A., Sandler, M., & Glover, V.
1995 Rat brain monoamine oxidase A and B inhibitory (tribulin) activity during drug withdrawal anxiety.
Neuroscience Letters, 199(2), 103-106.
Blum, K., Cull, J.G., Braverman, E.R., & Comings, D.E.
1996 Reward deficiency syndrome. American Scientist, 84(2), 132-145.
Boakes, R.A., & Dwyer, D.M.
1997 Weight loss in rats produced by running: Effects of prior experience and individual housing. TheQuarterly Journal of Experimental Psychology, 50B(2), 129-148.
Bock, B.C., Kanarek, R.B., & Aprille, J.R.
1995 Mineral content of the diet alters sucrose-induced obesity in rats. Physiology & Behavior, 57,659-668.
file:///C /Library Downloads/jdi.htm (25 of 58) [09-Jun-2001 07:02:07] Bourne, M.J., Calton, J.L., Gustavson, K.K., & Schachtman, T.R.
1992 Effects of acute swim stress on LiCl-induced conditioned taste aversions. Physiology & Behavior,(51), 1227-1234.
Bozarth, M.A., & Wise, R.A.
1985 Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat.
Journal of the American Medical Association, (25), 481-483.
Brake,W.G., Noel, M.B., Boksa, P., & Gratton, A.
1997 Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stressduring adulthood: an electrochemical study in the rat. Neuroscience, 77(4), 1067-1076.
Brauer, L.H., Hatsukami, D., Hanson, K., Shiffman, S.
1996 Smoking topography in tobacco chippers and dependent smokers. Addictive Behavior, 21(2),233-238.
Brautbar, N.
1995 Direct effects of nicotine on the brain: evidence for chemical addiction. Archives of EnvironmentalHealth, 50(4), 263-266.
Brigham, J., Henningfield, J.E., & Stitzer, M.L.
1990 Smoking relapse: A review. Special Issue: Relapse prevention in substance misuse. InternationalJournal of the Addictions, 25(9), 1239-1255.
Bullock, A.E., Barke, K.E., & Schneider, A.S.
1994 Nicotine tolerance in chromaffin cell cultures: acute and chronic exposure to smoking-relatednicotine doses. Journal of Neurochemistry, 62(5), 1863-1869.
Busto,U., Bendayan, R., & Sellers, E.M.
1989 Clinical pharmacokinetics of non-opiate abused drugs. Clinical Pharmacokinetics, 16(1), 1-26.
Calcagnetti, D.J., & Schechter, M.D.
1994 Nicotine place preference using the biased method of conditioning. Progress inNeuro-Psychopharmacology & Biological Psychiatry, 94(5), 925-933.
Carey, J., France, M., Dunham, R.S., & Greising, D.
1997 Not so fast - The tobacco deal, under heavy fire, is likely to undergo major changes. How muchtinkering can it take before it comes apart? Business Week, 34-37.
Carstens, E., Saxe, I., & Ralph, R.
1995 Brainstem neurons expressing c-Fos immunoreactivity following irritant chemical stimulation ofthe rat's tongue. Neuroscience, 69(3), 939-953.
Cerny, L., & Cerny, K.
1992 Can carrots be addictive? An extraordinary form of drug dependence. British Journal of Addiction,87(8), 1195-1197.
Chandler, C.J., & Stolerman, I.P.
1997 Discriminative stimulus properties of the nicotinic agonist cytisine. Psychopharmacology, 129(3),257-264.
file:///C /Library Downloads/jdi.htm (26 of 58) [09-Jun-2001 07:02:07] Chassin, L., Presson, C.C., Rose, J.S., & Sherman, S.J.
1996 The natural history of cigarette smoking from adolescence to adulthood: Demographic predictors ofcontinuity and change. Health Psychology, 96(6), 478-484.
Chiamulera, C., Borgo, C., Falchetto, S., Valerio, E., & Tessari, M.
1996 Nicotine reinstatement of nicotine self-administration after long-term extinction.
Psychopharmacology, 127(2), 102-107.
Chiauzzi, E.J., & Liljegren, S.
1993 Taboo topics in addiction treatment: An empirical review of clinical folklore. Journal of SubstanceAbuse Treatment, 10(3), 303-316.
Clark D.
1990 Discriminative properties of drugs of abuse. In D.M.Warburton (Ed.), Addiction controversies (pp.
185-200). London: Harwood.
Clarke, P.B., & Fibiger, H.C.
1987 Apparent absence of nicotine-induced conditioned place preference in rats. Psychopharmacology,92(1), 84-88.
Coelho, R., Rangel, R. Ramos, E., Martins, A. Prata, J., & Barros, H.
2000 Depression and the severity of substance abuse. Psychopathology, 33(3), 103-109.
Coleman, J.W.
1976 The myth of addiction. Journal of Drug Issues, 6(2), 135-141.
Colle, L.M., & Wise, R.A.
1987 Opposite effects of unilateral forebrain ablations on ipsilateral and contralateral hypothalamicself-stimulation. Brain Research, 407, 285-293.
Collins, A.C.
1990 An analysis of the addiction liability of nicotine. Advances in Alcohol & Substance Abuse, 9(1-2),83-101.
Corrigall,W.A.
1991 Understanding brain mechanisms in nicotine reinforcement. British Journal of Addiction, 86(5),507-510.
Corrigall,W.A., & Coen, K.M.
1989 Nicotine maintains robust self-administration in rats on a limited-access schedule.
Psychopharmacology, 99(4), 473-478.
Corrigall,W.A., & Coen, K.M.
1991a Opiate antagonists reduce cocaine but not nicotine self-administration. Psychopharmacology,104(2), 167-170.
Corrigall,W.A., & Coen, K.M.
1991b Selective dopamine antagonists reduce nicotine self-administration. Psychopharmacology, 104(2),171-176.
file:///C /Library Downloads/jdi.htm (27 of 58) [09-Jun-2001 07:02:07] Corrigall, W.A., & Coen, K.M.
1994a Nicotine self-administration and locomotor activity are not modified by the 5-HT3 antagonistsICS 205-930 and MDL 72222. Pharmacology Biochemistry and Behavior, 49(1), 67-71.
Corrigall, W.A., & Coen, K.M.
1994b Dopamine mechanisms play at best a small role in the nicotine discriminative stimulus.
Pharmacology Biochemistry and Behavior, 48(3), 817-820.
Corrigall, W.A., Coen, K.M., & Adamson, K.L.
1994 Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmentalarea. Brain Research, 653(1-2), 278-284.
Corrigall, W.A., Franklin, K.B., Coen, K.M., & Clarke, P.B.
1992 The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine.
Psychopharmacology, 107(2-3), 285-289.
Crowley, T.J., Mikulich, S.K., MacDonald, M., Young, S.E., & Zerbe, G.O.
1998 Substance-dependent, conduct-disordered adolescent males: Severity of diagnosis predicts 2-yearoutcome. Drug and Alcohol Dependence, 49(3), 225-237.
Curry, S.J., Grothaus, L.C., McAfee, T., & Pabiniak, C.
1998 Use and cost effectiveness of smoking-cessation services under four insurance plans in a healthmaintenance organization. New England Journal of Medicine, 339(10), 673-679.
Curtin, F., Walker, J.P., Peyrin, L., Soulier, V., Badan, M., & Schulz, P.
1997 Reward dependence is positively related to urinary monoamines in normal men. BiologicalPsychiatry, 42(4), 275-281.
Damaj, M.I., Welch, S.P., & Martin, B.R.
1996 Characterization and modulation of acute tolerance to nicotine in mice. Journal of Pharmacology &Experimental Therapeutics, 277(1), 454-461.
Dani, J.A., & Heinemann, S.
1996 Molecular and cellular aspects of nicotine abuse. Neuron, 16(5), 905-908.
Danion, J.M., Weingartner, H., File, S.E., Jaffard, R., Sutherland, T., Tulving, E., & Warburton, D.M.
1997 Pharmacology of human memory and cognition: illustrations from the effects of benzodiazepinesand cholinergic drugs. Journal of Psychopharmacology, 7(4), 371-377.
Darke,S., & Zador, D.
1996 Fatal heroin 'overdose': A review. Addiction, 91(12), 1765-1772.
Das,G.
1993 Cocaine abuse in North America: A milestone in history. Journal of Clinical Pharmacology, 93(4),296-310.
Das, G., & Laddu, A.
1993 Cocaine: Friend or foe? International Journal of Clinical Pharmacology, Therapy, & Toxicology,93(9), 449-455.
file:///C /Library Downloads/jdi.htm (28 of 58) [09-Jun-2001 07:02:07] Davies, J.B.,1997 The myth of addiction. London: Harwood.
Davies, J.B.
1998 Pharmacology versus social process: Competing or complementary views on the nature ofaddiction? Pharmacology and Therapeutics, 80(3), 265-275.
Davis, E.A.
1995 Functionality of sugars: Physicochemical interactions in foods. American Journal of ClinicalNutrition, 62(Suppl.), 170S-177S.
De Wit, H., & Griffiths, R.R.
1991 Testing the abuse liability of anxiolytic and hypnotic drugs in humans. Drug & AlcoholDependence, 28(1), 83-111.
Deneau, G., Yangita, T., & Seevers, M.H.
1969 Self-administration of psychoactive substances by the monkey. Psychopharmacologia (Berlin), 16,30-48.
Deroche, V., Piazza, P.V., Le Moal, M., & Simon, H.
1994 Social isolation-induced enhancement of the psychomotor effects of morphine depends oncorticosterone secretion. Brain Research, 640(1-2), 136-139.
Dewey, S.L., Brodie, J.D., Gerasimov, M., Horan, B., Gardner, E.L., & Ashby Jr., C.R.
1999 A pharmacologic strategy for the treatment of nicotine addiction. Synapse, 31(1), 76-86.
Di Chiara,G.
1995 The role of dopamine in drug abuse viewed from the perspective of its role in motivation. Drug &Alcohol Dependence, 38(2), 95-137.
Di Chiara,G.
2000 Role of dopamine in the behavioural actions of nicotine related to addiction. European Journal ofPharmacology, 393(1-3), 295-314.
Di Chiara, G., Acquas, E., & Carboni, E.
1992 Drug motivation and abuse: A neurobiological perspective. In P.W. Kalivas and H.H. Samson(Eds.), Annals of the New York Academy of Sciences: Vol. 654. The neurobiology of drug and alcoholaddiction (pp. 207-219). New York, NY, US: New York Academy of Sciences.
Di Chiara, G., & Imperato, A.
1988 Drugs abused by humans preferentially increase synaptic dopamine concentrations in themesolimbic system of freely moving rats. Proceedings of the National Academy of Sciences of the UnitedStates of America, 85(14), 5274-5278.
Di Chiara, G., Tanda, G., & Carboni, E.
1996 Estimation of in-vivo neurotransmitter release by brain microdialysis: The issue of validity.
Behavioral Pharmacology, 7(7), 640-657.
DiBattista, D., & Shepherd, M.L.
1993 Primary school teachers' beliefs and advice to parents concerning sugar consumption and activity in file:///C /Library Downloads/jdi.htm (29 of 58) [09-Jun-2001 07:02:07] children. Psychological Reports, 93(1), 47-55.
Doherty, M.D., & Gratton, A.
1996 Medial prefrontal cortical D1 receptor modulation of the meso-accumbens dopamine response tostress: an electrochemical study in freely-behaving rats. Brain Research, 715(1-2), 86-97.
Dole,V.P.
1980 Addictive behavior. Scientific American, 243(6), 138-154.
Dominguez, H.D., Bocco, G., Chotro, M.G., Spear, N.E., & Molina, J.C.
1993 Operant responding controlled by milk or milk contaminated with alcohol as positive reinforcers ininfant rats. Pharmacology Biochemistry and Behavior, 44, 403-409.
Domino, E.F., & Lutz, M.P.
1973 Tolerance to the effects of daily nicotine on rat bar pressing behavior for water reinforcement.
Pharmacology Biochemistry and Behavior, 1(4), 445-448.
Donny, E.C., Caggiula, A.R., Knopf, S., & Brown, C.
1995 Nicotine self-administration in rats. Psychopharmacology, 122(4), 390-394.
Drew, L.R.
1986 Beyond the disease concept of addiction: Drug use as a way of life leading to predicaments.
Journal of Drug Issues, 16(2), 263-274.
Duka, T., Tasker, R., Russell, K., & Stephens, D.N.
1998 Discriminative stimulus properties of nicotine at low doses: The effects of caffeine preload.
Behavioral Pharmacology, 9(3), 219-229.
DuPont, R.L.
1998 Addiction: A new paradigm. Bulletin of the Menninger Clinic, 62(2), 231-242.
Dworkin, S.I., Mirkis, S., & Smith, J.E.
1995 Response-dependent versus response-independent presentation of cocaine: differences in the lethaleffects of the drug. Psychopharmacology, 117(3), 262-266.
Dwoskin, L.P., Teng, L., Buxton, S.T,, Ravard, A., Deo, N., & Crooks, P.A.
1995 Minor alkaloids of tobacco release [3H]dopamine from superfused rat striatal slices. EuropeanJournal of Pharmacology, 276(1-2), 195-199.
Dwyer, D.M., & Boakes, R.A.
1997 Activity-based anorexia in rats as failure to adapt to a feeding schedule. Behavioral Neuroscience,111(1), 195-205.
Epling,W.F., & Pierce, W.D.
1994 Activity-based anorexia: A biobehavioral perspective. International Journal of Eating Disorders, 7,475-485.
Epstein, D.H., Silverman, K., Henningfield, J.E., & Preston, K.L.
1999 Low-dose oral cocaine in humans: acquisition of discrimination and time-course of effects.
Behavioral Pharmacology, 10(5), 531-542.
file:///C /Library Downloads/jdi.htm (30 of 58) [09-Jun-2001 07:02:07] Epstein, E.J.
1990 Agency of fear: Opiates and political power in America. London/New York: Verso.
Eysenck, H.J.
1965 Smoking, health, and personality. London: Weidenfeld and Nicolson.
Fahrenkrug,H., & Gmel, G.
1996 Addictiveness: How Swiss experts rate alcohol and other drugs. Alcologia, 8(3), 225-229.
Feldman, R.D., Logan, A.G., & Schmidt, N.D.
1996 Dietary salt restriction increases vascular insulin resistance. Clinical Pharmacology andTherapeutics, 60(4), 444-451.
Fingarette, H.
1979 How an alcoholism defense works under the ALI Insanity Test. International Journal of Law &Psychiatry, 2(3), 299-322.
Fingarette, H.
1981 Legal aspects of alcoholism and other addictions: some basic conceptual issues. British Journal ofAddiction 76(2), 125-132.
Fingarette, H.
1990 Alcoholism: Can honest mistake about one's capacity for self control be an excuse? InternationalJournal of Law & Psychiatry, 13(1-2), 77-93.
Fiore M.C., Newcomb, P., & McBride, P.
1993 Natural history and epidemiology of tobacco use and addiction. In C.Tracy Orleans and J.D.Slade(Eds.), Nicotine addiction: Principles and management (pp. 89-104). New York: Oxford UniversityPress.
Fischman, M.W., & Foltin, R.W.
1991 Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. BritishJournal of Addiction, 86(12), 1563-1570.
Fisher, E.B., Lichtenstein, E., Haire-Joshu, D., Morgan, G.D.
1993 Methods, successes, and failures of smoking cessation programs. Annual Review of Medicine, 44,481-513.
Foltin, R.W., & Fischman, M.W.
1994 Cocaine self-administration research: Treatment implications. (National Institute of Drug AbuseResearch Monograph No. 145), 139-162.
Foulds, J., & Ghodse, A.H.
1995 The role of nicotine in tobacco smoking: Implications for tobacco control policy. Journal of theRoyal Society of Health, 115(4), 225-230.
Foulds, J., Stapleton, J.A., Bell, N., Swettenham, J., Jarvis, M.J., & Russell, M.A.
1997 Mood and physiological effects of subcutaneous nicotine in smokers and never-smokers. Drug &Alcohol Dependence, 44(2-3), 105-115.
file:///C /Library Downloads/jdi.htm (31 of 58) [09-Jun-2001 07:02:07] Frances, R.J., & Franklin, J.E.
1996 Alcohol and other psychoactive substance use. In R.E.Hales and S.C.Yudofsky (Eds.), TheAmerican Psychiatric Press synopsis of psychiatry (pp. 345-391). Washington, DC: AmericanPsychiatric Press.
Franken, I.H.A., & Hendriks, V.M.
2000 Early-onset of illicit substance use is associated with greater axis-II comorbidity, not with axis-Icomorbidity. Drug and Alcohol Dependence, 59(3), 305-308.
Franklin, K.B.J., & Robertson, A.
1992 Effects and interactions of naloxone and amphetamine on self-stimulation of the prefrontal cortexand dorsal tegmentum. Pharmacology Biochemistry and Behavior, 16, 433-436.
Frantzen, J.
1996 Sifting the ashes. The New Yorker (May 13), 40-48.
Fricchione, G.L., Olson, L.C., & Vlay, S.C.
1989 Psychiatric syndromes in patients with the automatic internal cardioverter defibrillator: Anxiety,psychological dependence, abuse, and withdrawal. American Heart Journal, 117(6), 1411-1414.
Fung, Y.K., Schmid, M.J., Anderson, T.M., & Lau, Y.S.
1996 Effects of nicotine withdrawal on central dopaminergic systems. Pharmacology Biochemistry andBehavior, 53(3), 635-640.
Furth, A., & Harding, J.
1989 Why sugar is bad for you. New Scientist, 120(1683), 26-29.
Geng, Y., Savage, S.M., Razanai-Boroujerdi, S., & Sopori, M.L.
1996 Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy.
Journal of Immunology, 156(7), 2384-2390.
Gentry, R.T., & Dole, V.P.
1987 Why does a sucrose choice reduce the consumption of alcohol in C57BL/6J mice? Life Sciences,40(22), 2191-2194.
George, F.R.
1993 Genetic models in the study of alcoholism and substance abuse mechanisms. Progress inNeuro-Psychopharmacology & Biological Psychiatry, 17(3), 345-361.
Gibbons, F.X., Eggleston, T.J., & Benthin, A.C.
1997 Cognitive reactions to smoking relapse: The reciprocal relation between dissonance andself-esteem. Journal of Personality & Social Psychology, 97(1), 184-195.
Gibney, M., Sigman-Grant, M., Stanton Jr., J.L., & Keast, D.R.
1995 Consumption of sugars. American Journal of Clinical Nutrition, 62(Suppl.), 178S-194S.
Gilbert, D.G., Meliska, C.J., Williams, C.L., & Jensen, R.A.
1992 Subjective correlates of cigarette-smoking-induced elevations of peripheral beta-endorphin andcortisol. Psychopharmacology, 106(2), 275-281.
file:///C /Library Downloads/jdi.htm (32 of 58) [09-Jun-2001 07:02:07] Giovino, G.A., Henningfield, J.E., Tomar, S.L., Escobedo, L.G., & Slade, J.
1995 Epidemiology of tobacco use and dependence. Epidemiologic Reviews, 17, 48-65.
Glatt, M.M., & Cook, C.C.
1987 Pathological spending as a form of psychological dependence. British Journal of Addiction, 82(11),1257-1258.
Glow, P.H., & Russell, A.
1973 Drug enhanced sensory contingent bar pressing: comparing the effect of contingent andnoncontingent sensory change. Psychopharmacologia, 73(3), 285-292.
Glow, P.H., & Winefield, A.H.
1979 Control over sensory change versus sensory state preference in sensory contingent bar pressing.
Quarterly Journal of Experimental Psychology, 79(2), 339-347.
Glow, P.H., & Winefield, A.H.
1982 Effect of regular noncontingent sensory changes on responding for sensory change. Journal ofGeneral Psychology, 107(July), 121-137.
Gold, P.E.
1995 Role of glucose in regulating the brain and cognition. American Journal of Clinical Nutrition,61(Suppl.), 987S-995S.
Goldberg, S.R., & Henningfield, J.E.
1988 Reinforcing effects of nicotine in humans and experimental animals responding under intermittentschedules of IV drug injection. Pharmacology Biochemistry and Behavior, 30(1), 227-234.
Goldberg, S.R., & Spealman, R.D.
1982 Maintenance and suppression of behavior by intravenous nicotine injections in squirrel monkeys.
Federation Proceedings, 41(2), 216-220.
Goldberg, S.R., Spealman, R.D., & Goldberg, D.M.
1981 Persistent behavior at high rates maintained by intravenous self- administration of nicotine.
Science, 214(4520), 573-575.
Goldbloom, R.B.
1997 Weighing the evidence: The Canadian experience. American Journal of Clinical Nutrition, 65(2),584S-586S.
Goldstein, A.
1994 Addiction: From biology to drug policy. New York: W. H. Freeman & Co.
Goode, E.
1999 Drugs in American society. New York: McGraw-Hill.
Gori, G.B.
1996 Failings of the disease model of addiction. Human Psychopharmacology, 11(Suppl. 1), S33-S38.
Goudie A.J.
1991 Animal models of drug abuse and dependence. In P.Willner (Ed.), Behavioural models in file:///C /Library Downloads/jdi.htm (33 of 58) [09-Jun-2001 07:02:07] psychopharmacology: Theoretical, industrial and clinical perspectives (pp.453-484). Cambridge,England: Cambridge University Press.
Goudie, A.J., & Leathley, M.J.
1995 Effects of the CCKB antagonist L-365, 260 on benzodiazepine withdrawal-induced hypophagia inrats. Psychopharmacology, 118(1), 57-64.
Grasing, K., Wang, A., & Schlussman, S.
1996 Behavioral measures of anxiety during opiate withdrawal. Behavioral Brain Research, 80(1-2),195-201.
Gray, J.A., Joseph, M.H., Hemsley, D.R., Young, A.M., Warburton, E.C., Boulenguez, P., Grigoryan,G.A., Peters, S.L., Rawlins, J.N., & Taib, C.L.
1995 The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens inlatent inhibition: Implications for schizophrenia. Behavioral Brain Research, 71(1-2), 19-31.
Grenhoff, J., & Svensson, T.H.
1989 Pharmacology of nicotine. British Journal of Addiction, 84(5), 477-492.
Gribkoff, V.K., Christian, E.P., Robinson, J.H., Deadwyler, S.A., & Dudek, F.E.
1988 Cholinergic excitation of supraoptic neurons in hypothalamic slices of rat. Neuropharmacology,27(7), 721-727.
Griffin-Shelley, E.
1993 Sex and love addiction: Definition and overview. In E.Griffin-Shelley (Ed.), Outpatient treatmentof sex and love addicts (pp. 5-19). Westport, CT: Praeger.
Griffiths, M.
1996 Nicotine, tobacco and addiction. Nature, 384(6604), 18-18.
Grigson, P.S.
1997 Conditioned taste aversions and drugs of abuse: A reinterpretation. Behavioral Neuroscience,111(1), 129-136.
Grunberg, N.E.
1994 Overview: biological processes relevant to drugs of dependence. Addiction, 89(11), 1443-1446.
Grunberg, N.E., Acri, J.B., Fredrickson, P.A., Hurt, R.D., Lee, G.M., & Wingender, L.
1995 Conceptual and methodological considerations for tobacco addiction research. British Journal ofAddiction, 122(3), 215-222.
Grunwald, F., Schrock, H., & Kuschinsky, W.
1987 The effect of an acute nicotine infusion on the local cerebral glucose utilization of the awake rat.
Brain Research, 400(2), 232-238.
Gupta, P.C., Murti, P.R., & Bhonsle, R.B.
1996 Epidemiology of cancer by tobacco products and the significance of TSNA. Critical Reviews inToxicology, 26(2), 183-198.
file:///C /Library Downloads/jdi.htm (34 of 58) [09-Jun-2001 07:02:07] 1995 Coca shrub (Erythroxylum coca). Journal of Neurology, Neurosurgery & Psychiatry, 59(1), 25.
Haddad, P.
1999 Do antidepressants have any potential to cause addiction? Journal of Psychopharmacology, 13(3),300-307.
Hand, T.H., Stinus, L., & Le Moal, M.
1989 Differential mechanisms in the acquisition and expression of heroin-induced place preference.
Psychopharmacology, 98, 61-67.
Healy, D., & Tranter, R.
1999 Pharmacological stress diathesis syndromes. Journal of Psychopharmacology, 13(3), 287-290.
Heishman, S.J., Balfour, D.J., Benowitz, N.L., Hatsukami, D.K., Lindstrom, J.M., & Ockene, J.K.
1997 Society for Research on Nicotine and Tobacco. Addiction, 92(5), 615-633.
Heishman, S.J., & Henningfield, J.E.
1992 Stimulus functions of caffeine in humans: relation to dependence potential. Neuroscience &Biobehavioral Reviews, 16(3), 273-287.
Heishman, S.J., Schuh, K.J., Schuster, C.R., Henningfield, J.E., & Goldberg, S.R.
2000 Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose andalternative reinforcer. Psychopharmacology, 148(3), 272-280.
Henningfield, J.E.
1983 Measurement issues in cigarette smoking research: Basic behavioral and physiological effects andpatterns of nicotine self-administration. (National Institute on Drug Abuse Research Monograph No. 38).
Henningfield, J.E.
1984 Pharmacologic basis and treatment of cigarette smoking. Journal of Clinical Psychiatry, 45(12),24-34.
Henningfield, J.E., Cohen, C., & Heishman, S.J.
1991 Drug self-administration methods in abuse liability evaluation. British Journal of Addiction,86(12), 1571-1577.
Henningfield, J.E., Cohen, C., & Slade, J.D.
1991 Is nicotine more addictive than cocaine? British Journal of Addiction, 86(5), 565-569.
Henningfield, J.E., & Goldberg, S.R.
1983a Nicotine as a reinforcer in human subjects and laboratory animals. Pharmacology Biochemistryand Behavior, 19(6), 989-992.
Henningfield, J.E., & Goldberg, S.R.
1983b Control of behavior by intravenous nicotine injections in human subjects. PharmacologyBiochemistry and Behavior, 19(6), 1021-1026.
Henningfield, J.E., Gopalan, L., & Shiffman, S.
1998 Tobacco dependence: fundamental concepts and recent advances. Current Opinion in Psychiatry,11(3), 259-263.
file:///C /Library Downloads/jdi.htm (35 of 58) [09-Jun-2001 07:02:07] Henningfield, J.E., & Heishman, S.J.
1995 The addictive role of nicotine in tobacco use. Psychopharmacology, 117(1), 11-13.
Henningfield, J.E.,& Keenan, R.M.
1993 Nicotine delivery kinetics and abuse liability. Journal of Consulting & Clinical Psychology, 61(5),743-750.
Henningfield, J.E., Miyasato, K., & .Jasinski, D.R.
1983 Cigarette smokers self-administer intravenous nicotine. Pharmacology Biochemistry and Behavior,(5), 887-890.
Henningfield, J.E., Miyasato, K., & Jasinski, D.R.
1985 Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine. Journalof Pharmacology & Experimental Therapeutics, 234(1), 1-12.
Hennrikus, D.J., Jeffery, R.W., & Lando, H.A.
1995 The smoking cessation process: longitudinal observations in a working population. PreventiveMedicine, 24(3), 235-244.
Hernandez, L., & Hoebel, B.G.
1988a Feeding and hypothalamic stimulation increase dopamine turnover in the accumbens. Physiology& Behavior, 44(4-5), 599-606.
Hernandez, L., & Hoebel, B.G.
1988b Food reward and cocaine increase extracellular dopamine in the nucleus accumbens as measuredby microdialysis. Life Sciences, 42(18), 1705-1712.
Hilts, P.J.
1994 Is nicotine addictive? It depends on whose criteria you use. The New York Times, C3.
Hirschmuller, A.
1995 [E. Merck and cocaine. On Sigmund Freud's cocaine studies and their relation to the Darmstadtindustry]. [German]. Gesnerus, 52(1-2), 116-132.
Hjalmarson, A., Nilsson, F., Sjöström, L., & Wiklund, O.
1997 The nicotine inhaler in smoking cessation. Archives of Internal Medicine, 157(15), 1721-1728.
Hodge, J.E.
1992 Addiction to violence: A new model of psychopathy. Criminal Behavior & Mental Health, 2(2),212-223.
Hoffmann, D., Adams, J.D., Piade, J.J., & Hecht, S.S.
1980 Chemical studies on tobacco smoke LXVIII. Analysis of volatile and tobacco-specific nitrosaminesin tobacco products. IARC Scientific Publications, (31), 507-516.
Hoffmeister, F., & Goldberg, S.R.
1973 A comparison of chlorpromazine, imipramine, morphine and d- amphetamine self-administration incocaine-dependent rhesus monkeys. Journal of Pharmacology & Experimental Therapeutics, 187(1),8-14.
file:///C /Library Downloads/jdi.htm (36 of 58) [09-Jun-2001 07:02:07] Hoffmeister, F., & Wuttke, W.
1973 Self-administration of acetylsalicylic acid and combinations with codeine and caffeine in rhesusmonkeys. Journal of Pharmacology & Experimental Therapeutics, 186(2), 266-275.
Hogg, S.
1996 A review of the validity and variability of the elevated plus- maze as an animal model of anxiety.
Pharmacology Biochemistry and Behavior, 54(1), 21-30.
Holmen, T.L., Barrett-Connor, E., Holmen, J., & Bjermer, L.
2000 Health problems in teenage daily smokers versus nonsmokers, Norway, 1995-1997 - TheNord-Trondelag health study. American Journal of Epidemiology, 151(2), 148-155.
Horger, B.A., Valadez, A., Wellman, P.J., & Schenk, S.
1994 Augmentation of the neurochemical effects of cocaine in the ventral striatum and medial prefrontalcortex following preexposure to amphetamine, but not nicotine: An in vivo microdialysis study. LifeSciences, 55(15), 1245-1251.
Houlihan, M.E., Pritchard, W.S., Krieble, K.K., Robinson, J.H., & Duke, D.W.
1996 Effects of cigarette smoking on EEG spectral-band power, dimensional complexity, andnonlinearity during reaction-time task performance. Psychophysiology, 33(6), 740-746.
Hughes, J.R.
1992 Tobacco withdrawal in self-quitters. Journal of Consulting & Clinical Psychology, 60(5), 689-697.
Hughes, J.R., Higgins, S.T., & Bickel, W.K.
1994 Nicotine withdrawal versus other drug withdrawal syndromes: Similarities and dissimilarities.
Addiction, 89(11), 1461-1470.
Hughes, J.R., Strickler, G., King, D., Higgins, S.T., Fenwick, J.W., Gulliver, S.B., Mireault, G.
1989 Smoking history, instructions and the effects of nicotine: Two pilot studies. PharmacologyBiochemistry and Behavior, 34(1), 149-155.
Hunt, G.E., & Atrens, D.M.
1992 Reward summation and the effects of pimozide, clonidine, and amphetamine on fixed-intervalresponding for brain stimulation. Pharmacology Biochemistry and Behavior, 42, 563-577.
Hunt,G.E., Atrens, D.M., & Jackson, D.M.
1994 Reward summation and the effects of dopamine D1 and D2 agonists and antagonists onfixed-interval responding for brain stimulation. Pharmacology Biochemistry and Behavior, 48(4),853-862.
Hymowitz, N., & ckholdt, H.
1996 Effects of a 2.5-mg silver acetate lozenge on initial and long- term smoking cessation. PreventiveMedicine, 25(5), 537-546.
Iwamoto, E., & Martin, W.
1988 A critique of drug self-administration as a method for predicting abuse potential of drugs.
(National Institute on Drug Abuse Research Monograph No. 81), 457-465.
file:///C /Library Downloads/jdi.htm (37 of 58) [09-Jun-2001 07:02:07] 1990b Tobacco smoking and nicotine dependence. In S.Wonnacott, M.A.H. Russell, & I.P.Stolerman(Eds.), Nicotine psychopharmacology: Molecular, cellular and behavioural aspects (pp. 1-37). Oxford:Oxford University Press.
Jaffe, J.H.
1990a Trivializing dependence. British Journal of Addiction, 85(11), 1425-7.
Jaffe, J.H.
1992 Current concepts of addiction. In C.P.O'Brien & J.H.Jaffe (Eds.), Research publications,Association for Research in Nervous and Mental Disease: Vol. 70. Addictive states (pp. 1-21). NewYork, NY, US: Raven Press.
Jarvik, M.E.
1977 Biological factors underlying the smoking habit. (National Institute on Drug Abuse ResearchMonograph 17), 122-148.
Jensen, P.M., & Coambs, R.B.
1994 Health and behavioral predictors of success in an intensive smoking cessation program for women.
Women & Health, 21(1), 57-72.
Jones, R.L., Nguyen, A., & Man, S.F.P.
1998 Nicotine and cotinine replacement when nicotine nasal spray is used to quit smoking.
Psychopharmacology, 137(4), 345-350.
Jones, R.T.
1992 Alternative strategies. Ciba Foundation Symposium, 166, 224-232.
Jonnes, J.
1995 The rise of the modern addict. American Journal of Public Health, 85(8), 1157-1162.
Jorenby, D.E., Leischow, S.J., Nides, M.A., Rennard, S.I., Johnston, J.A., Hughes, A.R., Smith, S.S.,Muramoto, M.L., Daughton, D.M., Doan, K., Fiore, M.C., & Baker, T.B.
1999 A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.
New England Journal of Medicine, 340(9), 685-691.
Jorenby, D.E., Steinpreis, R.E., Sherman, J.E., & Baker, T.B.
1990 Aversion instead of preference learning indicated by nicotine place conditioning in rats.
Psychopharmacology, 101(4), 533-538.
Joseph, M.H., Young, A.M.J., & Gray, J.A.
1996 Are neurochemistry and reinforcement enough - Can the abuse potential of drugs be explained bycommon actions on a dopamine reward system in the brain? Human Psychopharmacology - Clinical andExperimental, 11(Suppl. 1), S55-S63.
Kalat, J.W.
1992 Biological psychology. Belmont, CA: Wadsworth.
Kaminer,Y.
1994 Cocaine craving. Journal of the American Academy of Child & Adolescent Psychiatry, 33(4), 592- file:///C /Library Downloads/jdi.htm (38 of 58) [09-Jun-2001 07:02:07] Kaplan,R.
1996 Carrot addiction. Australian & New Zealand Journal of Psychiatry, 96(5), 698-700.
Kaplan, R.
1998 When a patient is addicted to tap water. Medical Observer (June 15), 12- Keane,B., & Leonard, B.E.
1989 Rodent models of alcoholism: a review. Alcohol & Alcoholism, 24(4), 299-309.
Kim, J.W., & Kirkpatrick, B.
1996 Social isolation in animal models of relevance to neuropsychiatric disorders. Biological Psychiatry,40(9), 918-922.
Kirch, D.G., Taylor, T.R., Creese, I., Xu, S.X., & Wyatt, R.J.
1992 Effect of chronic nicotine treatment and withdrawal on rat striatal D1 and D2 dopamine receptors.
Journal of Pharmacy & Pharmacology, 44(2), 89-92.
Kiyohara,C., Kono, S., Honjo, S., Todoroki, I., Sakurai, Y., Nishiwaki, M., Hamada, H., Nishikawa, H.,Koga, H., Ogawa, S., & Nakagawa, K.
1999 Inverse association between coffee drinking and serum uric acid concentrations in middle-agedJapanese males. British Journal of Nutrition, 82(2), 125-130.
Klein, M.
1998 Research issues related to development of medications for treatment of cocaine addiction. Annals ofthe New York Academy of Sciences, 844, 75-91.
Klopfer, P.H.
1996 "Mother Love" revisited: On the use of animal models. American Scientist, 84(4), 319-321.
Kochar, M.S.
1992 Hypertension in elderly patients. The special concerns in this growing population. PostgraduateMedicine, 91(4), 393-400.
Koob, G.F.
1992 Neural mechanisms of drug reinforcement. In P.W.Kalivas & H.H.Samson (Eds.), Annals of theNew York Academy of Sciences: Vol. 654. The neurobiology of drug and alcohol addiction, 171-191.
New York, NY, US: New York Academy of Sciences.
Koob,G.F.
1996 Drug addiction: the yin and yang of hedonic homeostasis. Neuron, 16(5), 893-896.
Koob,G.F., & Bloom, F.E.
1988 Cellular and molecular mechanisms of drug dependence. Science, 242(4879), 715-723.
Koob, G.F., Sanna, P.P., & Bloom, F.E.
1998 Neuroscience of addiction. Neuron, 21(3), 467-476.
Koob, G.F., & Weiss, F.
1992 Neuropharmacology of cocaine and ethanol dependence. Recent Developments in Alcoholism, 10,201-233.
file:///C /Library Downloads/jdi.htm (39 of 58) [09-Jun-2001 07:02:07] Kozlowski, L.T., & Schachter, S.
1975 Effects of cue prominence and palatability on the drinking behavior of obese and normal humans.
Journal of Personality & Social Psychology, 32(6), 1055-1059.
Kozlowski, L.T., Wilkinson, D.A., Skinner, W., Kent, C., Franklin, T., & Pope, M.
1989 Comparing tobacco cigarette dependence with other drug dependencies. Greater or equal 'difficultyquitting' and 'urges to use,' but less 'pleasure' from cigarettes. Journal of the American MedicalAssociation, 261(6), 898-901.
Krause, B.R., Black, A., Bousley, R., Essenburg, A., Cornicelli, J., Holmes, A., Homan, R., Kieft, K.,Sekerke, C., Shaw-Hes, M.K., Stanfield, R., Trivedi, B., & Woolf, T.
1993 Divergent pharmacologic activities of PD 132301-2 and CL 277,082, urea inhibitors ofacyl-CoA:cholesterol acyltransferase. Journal of Pharmacology and Experimental Therapeutics, 267,734-743.
Kuhar, M.J., & Pilotte, N.S.
1996 Neurochemical changes in cocaine withdrawal. Trends in Pharmacological Sciences, 96(7),260-264.
Kutchins, H., & Kirk, S.A.
1997 Making us crazy - DSM: The psychiatric bible and the creation of mental disorders. New York:Free Press.
Law, M., & Tang, J.L.
1995 An analysis of the effectiveness of interventions intended to help people stop smoking. Archives ofInternal Medicine, 155(18), 1933-1941.
Lee, M.A., Flegel, P., Greden, J.F., & Cameron, O.G.
1988 Anxiogenic effects of caffeine on panic and depressed patients. American Journal of Psychiatry,145(5), 632-635.
Lennox, A.S., & Taylor, R.J.
1994 Factors associated with outcome in unaided smoking cessation, and a comparison of those whohave never tried to stop with those who have. British Journal of General Practice, 44(383), 245-250.
Leshner, A.I.
1996 Understanding drug addiction: Implications for treatment. Hospital Practice, 31(10), 47-58.
Leshner, A.I.
1997 Addiction is a brain disease, and it matters. Science, 278(5335), 45-47.
Leshner, A.I.
1998 Drug addiction research: moving toward the 21st century. Drug and Alcohol Dependence, 51(1-2),5-7.
Leshner, A.I.
1999b Science-based views of drug addiction and its treatment. Journal of the American MedicalAssociation, 282(14), 1314-1316.
Leshner, A.I.
file:///C /Library Downloads/jdi.htm (40 of 58) [09-Jun-2001 07:02:07] 1999a Science is revolutionizing our view of addiction - and what to do about it. American Journal ofPsychiatry, 156(1), 1-3.
Levin, E.D., Briggs, S.J., Christopher, N.C., & Rose, J.E.
1992 Persistence of chronic nicotine-induced cognitive facilitation. Behavioral & Neural Biology, 58(2),152-158.
Levin, E.D., Kim, P., & Meray, R.
1996 Chronic nicotine working and reference memory effects in the 16- arm radial maze: Interactionswith D1 agonist and antagonist drugs. Psychopharmacology, 127(1), 25-30.
Lin, H.Q., Atrens, D.M., Christie, M.J., Jackson, D.M., & McGregor, I.S.
1993 Comparison of conditioned taste aversions produced by MDMA and d- amphetamine.
Pharmacology Biochemistry and Behavior, 46(1), 153-156.
Lindroos, A.K., Lissner, L., & Sjöström, L.
1996 Weight change in relation to intake of sugar and sweet foods before and after weight reducinggastric surgery. International Journal of Obesity, 20(7), 634-643.
Linsen, S.M., Zitman, F.G., & Breteler, M.H.M.,1995 Defining benzodiazepine dependence: The confusion persists. European Psychiatry, 10(6),306-311.
Logan, B.K., Weiss, E.L., & Harruff, R.C.
1996 Case report: distribution of methamphetamine in a massive fatal ingestion. Journal of ForensicSciences, 41(2), 322-323.
London, E.D., Connolly, R.J., Szikszay, M., Wamsley, J.K., & Dam, M.
1988 Effects of nicotine on local cerebral glucose utilization in the rat. Journal of Neuroscience, 8(10),3920-3928.
Lovaas, I., Newsom, C., & Hickman, C.
1987 Self-stimulatory behavior and perceptual reinforcement. Journal of Applied Behavior Analysis, 20,45-68.
Luik, J.C.
1996 'I can't help myself': Addiction as ideology. Human Psychopharmacology, 11(Suppl. 1), S21-S32.
Lyvers, M.
1998 Drug addiction as a physical disease: The role of physical dependence and other chronicdrug-induced neurophysiological changes in compulsive drug self-administration. Experimental andClinical Psychopharmacology, 6(1), 107-125.
Malin,D.H., Lake, J.R., Newlin-Maultsby, P., Roberts, L.K., Lanier, J.G., Carter, V.A., Cunningham,J.S., & Wilson, O.B.
1992 Rodent model of nicotine abstinence syndrome. Pharmacology Biochemistry and Behavior, 43(3),779-784.
Mariathasan,E.A., Stolerman, I.P, & White, J.A.W.
1997 Antagonism of AND and AND-OR drug mixture discriminations in rats. Drug and Alcohol file:///C /Library Downloads/jdi.htm (41 of 58) [09-Jun-2001 07:02:07] Dependence, 44(1), 31-34.
Mariathasan,E.A., White, J.A.W., & Stolerman, I.P.
1996 Training dose as a decisive factor for discrimination of a drug mixture in rats. BehaviouralPharmacology, 7(4), 364-372.
Mark,G.P., Blander, D.S., & Hoebel, B.G.
1991 A conditioned stimulus decreases extracellular dopamine in the nucleus accumbens after thedevelopment of a learned taste aversion. Brain Research, 551(1-2), 308-310.
Markou,A., Weiss, F., Gold, L.H., Caine, S.B.,Schulteis, F., & Koob, G.
1993 Animal models of drug craving. Psychopharmacology, 112(2-3), 163-182.
Mash, D.C.
1997 D3 receptor binding in human brain during cocaine overdose. Molecular Psychiatry, 2(1), 5-6.
Matsushima,D., Prevo M.E., & Gorsline, J.
1995 Absorption and adverse effects following topical and oral administration of three transdermalnicotine products to dogs. Journal of Pharmaceutical Sciences, 84(3), 365-369.
McAllister, C.G., Caggiula, A.R., Knopf, S., Epstein, L.H., Miller, A.L., Antelman, S.M., & Perkins,K.A.
1994 Immunological effects of acute and chronic nicotine administration in rats. Journal ofNeuroimmunology, 50(1), 43-49.
McDonald, R.B.
1995 Influence of dietary sucrose on biological aging. American Journal of Clinical Nutrition,62(Suppl.), 284S-293S.
McGill,H.J., Rogers, W.R., Wilbur, R.L., & Johnson, D.E.
1978 Cigarette smoking baboon model: demonstration of feasibility. Proceedings of the Society forExperimental Biology & Medicine, 157(4), 672-676.
McGregor, I.S., Issakidis, C.N., & Prior, G.
1996 Aversive effects of the synthetic cannabinoid CP 55,940 in rats. Pharmacology Biochemistry andBehavior, 53(3), 657-664.
McKearney, J.W.
1968 Maintenance of responding under a fixed-interval schedule of electric shock-presentation. Science,160(833), 1249-1251.
McMurran, M.
1994 The psychology of addiction. England: Taylor & Francis.
McNamara, D., Larson, D.M., Rapoport, S.I., & Soncrant, T.T.
1990 Preferential metabolic activation of subcortical brain areas by acute administration of nicotine torats. Journal of Cerebral Blood Flow & Metabolism, 10(1), 48-56.
Meisch, R.A., & Stewart, R.B.
1994 Ethanol as a reinforcer: A review of laboratory studies of non-human primates. Behavioural file:///C /Library Downloads/jdi.htm (42 of 58) [09-Jun-2001 07:02:07] Mendelson, J., & Chillag, D.
1970b Schedule-induced air licking in rats. Physiology & Behavior, (4), -537.
Mendelson, J., & Chillag, D.
1970a Tongue cooling: A new reward for thirsty rodents. Science, (3965) ,-1420.
Mendelson, J., Zec, R., & Chillag, D.
1971 Schedule dependency of schedule-induced air-licking. Physiology & Behavior, (2), 205-210.
Mendelson, J., Zec. R., & Chillag, D.
1972 Effects of desalivation on drinking and air licking induced by water deprivation and hypertonicsaline injections. Journal of Comparative & Physiological Psychology, (1), 37-42.
Mirza, N.R., Pei, Q., Stolerman, I.P., & Zetterström, T.S.C.
1996 The nicotinic receptor agonists(-)-nicotine and isoarecolone differ in their effects on dopaminerelease in the nucleus accumbens. European Journal of Pharmacology, 295 (2-3), 207-210.
Mitchell, S.L., & Epstein, L.H.
1996 Changes in taste and satiety in dietary-restrained women following stress. Physiology & Behavior,60(2), 495-499.
Mogensen, J.
1994 Animal models in neuroscience. In P. Svendsen & J.Hau (Eds.), Handbook of laboratory animalscience, (pp. 125-136). Boca Raton, FL: Press.
Murray, J.B.
1991 Nicotine as a psychoactive drug. Journal of Psychology, 125(1), 5-25.
Naruse, T., Asami, T., Ikeda, N., & Ohmura, I.
1986 [Rapid establishment of nicotine intravenous self-administration behavior in rats]. [Japanese].
Yakubutsu, Seishin, Kodo [Japanese Journal of Psychopharmacology], 6(3), 367-371.
Nash, J.M.
1997 Addicted. Time, Oct. 12, 53-58.
Nemeth-Coslett, R., Henningfield, J.E., O'Keeffe, M.K., & Griffiths, R.R.
1987 Nicotine gum: dose-related effects on cigarette smoking and subjective ratings.
Psychopharmacology, 92(4), 424-430.
Nencini, P.
1997a The rules of drug taking: Wine and poppy derivatives in the ancient world. VIII. Lack of evidenceof opium addiction. Substance Use and Misuse, 32(11), 1581-1586.
Nencini, P.
1997b The rules of drug taking: Wine and poppy derivatives in the ancient world. IX. Conclusions.
Substance Use and Misuse, 32(14), 2111-2119.
Nestler, E.J., Hope, B.T., & Widnell, K.L.
1993 Drug addiction: a model for the molecular basis of neural plasticity. Neuron, 11(6), 995-1006.
file:///C /Library Downloads/jdi.htm (43 of 58) [09-Jun-2001 07:02:07] Newman, R.G.
1983 The need to redefine "addiction.'' New England Journal of Medicine, 308(18), 1096-1098.
Nisell, M., Nomikos, G.G., Hertel, P., Panagis, G., & Svensson, T.H.
1996 Condition-independent sensitization of locomotor stimulation and mesocortical dopamine releasefollowing chronic nicotine treatment in the rat. Synapse, 22(4), 369-381.
Nisell, M., Nomikos, G.G., & Svensson, T.H.
1995 Nicotine dependence, midbrain dopamine systems and psychiatric disorders. Pharmacology &Toxicology, 76(3), 157-162.
Noel, M.B., & Gratton, A.
1995 Electrochemical evidence of increased dopamine transmission in prefrontal cortex and nucleusaccumbens elicited by ventral tegmental mu-opioid receptor activation in freely behaving rats. Synapse,21(2), 110-122.
Nutt, D.J.
1996 Addiction: brain mechanisms and their treatment implications. Lancet, 347(8993), 31-36.
Ochoa, E.L.
1994 Nicotine-related brain disorders: the neurobiological basis of nicotine dependence. Cellular &Molecular Neurobiology, 14(3), 195-225.
Olds, M.E.
1994 Opposite effects of PCA and chlorimipramine on ICSS and on its facilitation by amphetamine.
Pharmacology Biochemistry and Behavior, 47, 803-817.
Onaivi, E.S., Payne, S., Brock, J.W., Hamdi, A., Faroouqui, S., & Prasad, C.
1994 Chronic nicotine reverses age-associated increases in tail-flick latency and anxiety in rats. LifeSciences, 54(3), 193-202.
Orleans, C.T., & Slade, J.
1993 Nicotine addiction. New York: Oxford University Press.
Osterwalder, J.J.
1996 Naloxone--for intoxications with intravenous heroin and heroin mixtures--harmless or hazardous?A prospective clinical study. Journal of Toxicology - Clinical Toxicology, 34(4), 409-416.
Pandina, R.J., & Huber, G.L.
1990 Tobacco, nicotine and the question of addiction: What to do about a difficult problem? Seminars inRespiratory Medicine, 11, 50-68.
Papasava, M., Singer, G., & Papasava, C.L.
1985a Phentermine self-administration in naive free-feeding and food- deprived rats: A dose responsestudy. Psychopharmacology 85, 410-413.
Papasava, M., Singer, G., & Papasava, C.L.
1985b Self-administration of phentermine by naive rats: Effects of body weight and a food deliveryschedule. Pharmacology Biochemistry and Behavior 22, 1071-1073.
file:///C /Library Downloads/jdi.htm (44 of 58) [09-Jun-2001 07:02:07] Parker, L.A.
1991 Taste reactivity responses elicited by reinforcing drugs: a dose- response analysis. BehavioralNeuroscience, 91(6), 955-964.
Parker, L.A.
1992 Place conditioning in a three- or four-choice apparatus: role of stimulus novelty in drug-inducedplace conditioning. Behavioral Neuroscience, 92(2), 294-306.
Parrott, A.C.
1994 Acute pharmacodynamic tolerance to the subjective effects of cigarette smoking.
Psychopharmacology, 116(1), 93-97.
Parrott, A.C.
1995 Smoking cessation leads to reduced stress, but why? International Journal of the Addictions,30(11), 1509-1516.
Patten, C.A., & Martin, J.E.
1996 Does nicotine withdrawal affect smoking cessation? Clinical and theoretical issues. Annals ofBehavioral Medicine, 18(3), 190-200.
Patton, G.C., Carlin, J.B., Coffey, C., Wolfe, R., Hibbert, M., & Bowes, G.
1998 The course of early smoking: A population-based cohort study over three years. Addiction, 93(8),1251-1260.
Peele, S.
1977 Redefining addiction. I. Making addiction a scientifically and socially useful concept. InternationalJournal of Health Services, 7(1), 103-124.
Peele, S.
1986 The implications and limitations of genetic models of alcoholism and other addictions. Journal ofStudies on Alcohol, 47(1), 63-73.
Peele, S.
1987 A moral vision of addiction: How people's values determine whether they become and remainaddicts. Journal of Drug Issues, 17(1-2), 187-215.
Peele, S.
1990a Addiction as a cultural concept. Annals of the New York Academy of Sciences, 602(Sept.),205-220.
Peele, S.
1990b Behavior in a vacuum: Social-psychological theories of addiction that deny the social andpsychological meanings of behavior. Journal of Mind & Behavior, 11(3-4), 513-529.
Peele, S.
1990c Research issues in assessing addiction treatment efficacy: How cost effective are AlcoholicsAnonymous and private treatment centers? Drug & Alcohol Dependence, 25(2), 179-182.
Peele, S.
1991 Cold turkey: Is smoking an addiction? Reason (May), 54-55.
file:///C /Library Downloads/jdi.htm (45 of 58) [09-Jun-2001 07:02:07] Peele, S.
1992 Alcoholism, politics, and bureaucracy: the consensus against controlled-drinking therapy inAmerica. Addictive Behavior, 17(1), 49-62.
Peltier, R.L., Li, D.H., Lytle, D., Taylor, C.M., & Emmett-Oglesby, M.W.
1996 Chronic d-amphetamine or methamphetamine produces cross- tolerance to the discriminative andreinforcing stimulus effects of cocaine. Journal of Pharmacology & Experimental Therapeutics, 277(1),212-218.
Perkins, K.A.
1995 Individual variability in responses to nicotine. Behavior Genetics, 25(2), 119-132.
Perkins, K.A., D'Amico, D., Sanders, M., Grobe, J.E., Wilson, A., & Stiller, R.L. 1996 Influence of training dose on nicotine discrimination in humans. Psychopharmacology, 126(2),132-139.
Perkins K.A., Dimarco, A., Grobe J.E., Scierka, A., Stiller, R.L.
1994 Nicotine discrimination in male and female smokers. Psychopharmacology, 116(4), 407-413.
Perkins, K.A., Grobe, J.E., Fonte, C. Goettler, J., Caggiula, A.R., Reynolds, W.A., Stiller, R.L., Scierka,A., & Jacob, R.G.
1994 Chronic and acute tolerance to subjective, behavioral and cardiovascular effects of nicotine inhumans. Journal of Pharmacology & Experimental Therapeutics, 270(2), 628-638.
Perkins, K.A., Grobe, J.E., Mitchell, S.L., Goettler, J., Caggiula, A., Stiller, R.L., & Scierka, A.
1995 Acute tolerance to nicotine in smokers: Lack of dissipation within 2 hours. Psychopharmacology,118(2), 164-170.
Perkins, K.A., Sexton, J.E., Reynolds, W.A., Grobe, J.E., Fonte, C., & Stiller, R.L.
1994 Comparison of acute subjective and heart rate effects of nicotine intake via tobacco smoking versusnasal spray. Pharmacology Biochemistry and Behavior, 47(2), 295-299.
Perks, S.M., & Clifton, P.G.
1997 Reinforcer revaluation and conditioned place preference. Physiology & Behavior, 61(1), 1-5.
Pfaus, J.G., Damsma, G., Wenkstern, D., & Fibiger, H.C.
1995 Sexual activity increases dopamine transmission in the nucleus accumbens and striatum of femalerats. Brain Research, 693(1-2), 21-30.
Phillips, G.D., Howes, S.R., Whitelaw, R.B., Robbins, T.W., & Everitt, B.J.
1994 Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: Impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists.
Psychopharmacology, 115(3), 419-429.
Phillips, G.D., Howes, S.R., Whitelaw, R.B., Wilkinson, L.S., Robbins, T.W., & Everitt, B.J.
1994 Isolation rearing enhances the locomotor response to cocaine and a novel environment, but impairsthe intravenous self-administration of cocaine. Psychopharmacology, 115(3), 407-418.
Pich, E.M., Pagliusi, S.R., Tessari, M., Talabot-Ayer, D., Hooft van Huijsduijnen, R., & Chiamulera, C.
1997 Common neural substrates for the addictive properties of nicotine and cocaine. Science, 275(5296), file:///C /Library Downloads/jdi.htm (46 of 58) [09-Jun-2001 07:02:07] Pierce, W.D., & Epling, F.W.
1991 Activity anorexia: An animal model and theory of human self-starvation. In A. Boulton, G. Baker,& M. Martin-Iverson (Eds.), Neuromethods: Animal models in psychiatry (pp. 267-311). Humana Press.
Pomerleau, O.F.
1986 Nicotine as a psychoactive drug: anxiety and pain reduction. Psychopharmacology Bulletin, 22(3),865-869.
Pomerleau, O.F., & Pomerleau, C.S.
1991 Research on stress and smoking: progress and problems. British Journal of Addiction, 86(5),599-603.
Pontieri, F.E., Tanda, G., & Di Chiara, G.
1995 Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine inthe "shell" as compared with the "core" of the rat nucleus accumbens. Proceedings of the NationalAcademy of Sciences of the United States of America, 19(26), 12304-12308.
Pontieri, F.E., Tanda, G., Orzi, F., & Di Chiara, G.
1996 Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature,382(6588), 255-257.
Pritchard, W.S., & Robinson, J.H.
1994 Beneficial effects of nicotine: Two issues arising from West's editorial. Addiction, 89(4), 481-482.
Razavi, D., Vandecasteele, H., Primo, C., Bodo, M., Debrier, F., Verbist, H., Pethica, D., Eerdekens, M.,& Kaufman, L.
1999 Maintaining abstinence from cigarette smoking: Effectiveness of group counselling and factorspredicting outcome. European Journal of Cancer, Part A 35(8), 1238-1247.
Reid, M.S., Ho, L.B., & Berger, S.P.
1996 Effects of environmental conditioning on the development of nicotine sensitization: behavioral andneurochemical analysis. Psychopharmacology, 126(4), 301-310.
Richelle, M.
1989 Methodological critique of animal models in psychopharmacology. [French]. ConfrontationsPsychiatriques, 177.
Rieg, T.S., & Aravich, P.F.
1994 Systemic clonidine increases feeding and wheel running but does not affect rate of weight loss inrats subjected to activity-based anorexia. Pharmacology Biochemistry and Behavior, 47, 215-218.
Riggs, P.D., Mikulich, S.K., Whitmore, E.A., & Crowley, T.J.
1999 Relationship of ADHD, depression, and non-tobacco substance use disorders to nicotinedependence in substance-dependent delinquents. Drug and Alcohol Dependence, 54(3), 195-205.
Risinger, F.O., & Brown, M.M.
1996 Genetic differences in nicotine-induced conditioned taste aversion. Life Sciences, 58(12), 223-229.
file:///C /Library Downloads/jdi.htm (47 of 58) [09-Jun-2001 07:02:07] Risner, M.E., & Goldberg, S.R.
1983 A comparison of nicotine and cocaine self-administration in the dog: Fixed-ratio andprogressive-ratio schedules of intravenous drug infusion. Journal of Pharmacology & ExperimentalTherapeutics, 224(2), 319-326.
Ritzman, T.A.
1992 Smoking: Addiction or compulsion? II. Medical Hypnoanalysis Journal, 7(2), 41-52.
Robbins, T.W., & Everitt, B.J.
1996 Neurobehavioural mechanisms of reward and motivation. Current Opinion in Neurobiology, 6(2),228-236.
Robinson, B.R.
1997 Work addiction: Implications for EAP counseling and research. Employee Assistance Quarterly,12(4), 1-13.
Robinson, J.H., & Pritchard, W.S.
1992 The role of nicotine in tobacco use. Psychopharmacology, 108(4), 397-407.
Robinson, S.F., Marks, M.J., & Collins, A.C.
1996 Inbred mouse strains vary in oral self-selection of nicotine. Psychopharmacology, 124(4), 332-339.
Robinson, T.E., & Berridge, K.C.
1993 The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Research -Brain Research Reviews, 18(3), 247-291.
Roehrs, J.D., Rogers, W.R., & Johanson Jr., W.G.
1981 Bronchial reactivity to inhaled methacholine in cigarette-smoking baboons. Journal of AppliedPhysiology: Respiratory, Environmental & Exercise Physiology, 50(4), 754-760.
Rogers, W.R., Bass, R.L., Johnson, D.E., Kruski, A.W., McMahan, C.A., Montiel, M.M., Mott, G.E.,Wilbur, R.L., & McGill, H.J.
1980 Atherosclerosis-related responses to cigarette smoking in the baboon. Circulation, 61(6),1188-1193.
Rogers, W.R., Carey, K.D., McMahan, C.A., Montiel, M.M., .Mott, G.E., Wigodsky, H.S., & McGill,H.J.
1988 Cigarette smoking, dietary hyperlipidemia, and experimental atherosclerosis in the baboon.
Experimental & Molecular Pathology, 48(1), 135-151.
Rogers, W.R., McCullough, B., & Caton, J.E.
1981 Cigarette smoking by baboons: in vivo assessment of particulate inhalation using bronchoalveolarlavage to recover [14C]dotriacontane. Toxicology, 20(4), 309-321.
Rogers, W.R., Wilbur, R.L., Bass, R.L., & Johnson, D.E.
1985 Effects of cigarette nicotine content on smoking behavior of baboons. Addictive Behaviors, 10(3),225-233.
Rose, J.E.
1996 Nicotine addiction and treatment. Annual Review of Medicine , 47, 493-507.
file:///C /Library Downloads/jdi.htm (48 of 58) [09-Jun-2001 07:02:07] Rose, J.E., & Behm, F.M.
1994 Inhalation of vapor from black pepper extract reduces smoking withdrawal symptoms. Drug &Alcohol Dependence, 34(3), 225-229.
Rose, J.E., & Corrigall, W.A.
1997 Nicotine self-administration in animals and humans: similarities and differences.
Psychopharmacology, 130(1), 28-40.
Royal College of Physicians of London1977 Smoking or health: The third report from the Royal College of Physicians of London. Kent, UK:Pitman Medical.
Rush, C.R., Sullivan, J.T., & and Griffiths, R.R.
1995 Intravenous caffeine in stimulant drug abusers: subjective reports and physiological effects. Journalof Pharmacology & Experimental Therapeutics, 273(1), 351-358.
Russell, M.A.
1989 Subjective and behavioural effects of nicotine in humans: some sources of individual variation.
Progress in Brain Research, 79, 289-302.
Russell, M.A.
1990b The nicotine addiction trap: a 40-year sentence for four cigarettes. British Journal of Addiction,85(2), 293-300.
Russell, M.A.H.
1990a Nicotine intake and its control over smoking. In S.Wonnacott, M.A.H.Russell, & I.P.Stolerman(Eds.), Nicotine psychopharmacology: Molecular, cellular and behavioural aspects (pp. 374-418).
Oxford: Oxford University Press.
Rusted, J., Graupner, L., & Warburton, D.M.
1995 Effects of post-trial administration of nicotine on human memory: Evaluating the conditions forimproving memory. Psychopharmacology, 119, 405-413.
Rusted, J.M., Mackee, A., Williams, R., Willner, P.
1998 Deprivation state but not nicotine content of the cigarette affects responding by smokers on aprogressive ratio task. Psychopharmacology, 140(4), 411-417.
Rusted, J.M., & Warburton, D.M.
1995 Nicotinic receptors and information processing. In T.W.Stone (Ed.). CNS Neurotransmitters andneuromodulators (pp. 185-195). Boca Raton, FL: CRC Press.
Ruxton, C.H.S., & Kirk, T.R.
1997 Breakfast: A review of associations with measures of dietary intake, physiology and biochemistry.
British Journal of Nutrition, 78(2), 199-213.
Sabol, K.E., Richards, J.B., & Freed, C.R.
1990 In vivo dialysis measurements of dopamine and DOPAC in rats trained to turn on a circulartreadmill. Pharmacology Biochemistry and Behavior, 36(1), 21-28.
Salamone, J.D., Cousins, M.S., & Snyder, B.J.
file:///C /Library Downloads/jdi.htm (49 of 58) [09-Jun-2001 07:02:07] 1997 Behavioral functions of nucleus accumbens dopamine: Empirical and conceptual problems with theanhedonia hypothesis. Neuroscience & Biobehavioral Reviews, 21(3), 341-359.
Satel, S.L., Kosten, T.R., Schuckit, M.A., & Fischman, M.W.
1993 Should protracted withdrawal from drugs be included in DSM-IV? American Journal of Psychiatry,93(5), 695-704.
Schachter, S.
1977 Studies of the interaction of psychological and pharmacological determinants of smoking: I.
Nicotine regulation in heavy and light smokers. Journal of Experimental Psychology: General, 106(1),5-12.
Schachter, S.
1982 Recidivism and self-cure of smoking and obesity. American Psychologist, 37(4), 436-444.
Schachter, S.
1983 More on recidivism. American Psychologist, 38(7), 854-855.
Schachter, S.
1990 "Debunking myths about self-quitting: Evidence from 10 prospective studies of persons whoattempt to quit smoking by themselves": Reply. American Psychologist, 45(12), 1389-1390.
Schachter, S., Silverstein, B., & Perlick, D.
1977 Studies of the interaction of psychological and pharmacological determinants of smoking: V.
Psychological and pharmacological explanations of smoking under stress. Journal of ExperimentalPsychology: General, 106(1), 31-40.
Schaler, J.A.,2000 Addiction is a choice. Chicago, IL: Open Court.
Schelling, T.C.
1992 Addictive drugs: The cigarette experience. Science, 255(5043), 430-433.
Schneider, N.G., Olmstead, R., Nilsson, F., Mody, F.V., Franzon, M., & Doan, K.
1996 Efficacy of a nicotine inhaler in smoking cessation: A double-blind, placebo-controlled trial.
Addiction, 91(9), 1293-1306.
Schneider, N.G., Olmstead, R.E., Steinberg, C., Sloan, K., Daims, R.M., & Brown, H.V.
1996 Efficacy of buspirone in smoking cessation: a placebo-controlled trial. Clinical Pharmacology &Therapeutics, 60(5), 568-575.
Schoberberger, R., Kunze, U., & Schmeiser-Rieder, A.
1997 [Diagnosis and therapy of nicotine dependence]. [German]. Versicherungsmedizin, 49(1), 25-29.
Scholte, R.H., & Breteler, M.H.
1997 Withdrawal symptoms and previous attempts to quit smoking: Associations with self-efficacy.
Substance Use & Misuse, 32(2), 133-148.
Schwartz, J.L.
1992 Methods of smoking cessation. Medical Clinics of North America, 76(2), 451-476.
file:///C /Library Downloads/jdi.htm (50 of 58) [09-Jun-2001 07:02:07] Sekita, K., Ochiai, T., Ohno, K., Murakami, O., Wakasa, Y., Uzawa, K., Furuya, T., & Kurokawa, Y.
1992 [Studies on reinforcing effects of methylephedrine, caffeine and their mixture with intravenous-selfadministration in rhesus monkeys]. [Japanese]. Eisei Shikenjo Hokoku - Bulletin of National Institute ofHygienic Sciences, (110), 15-22.
Self, D.W., McClenahan, A.W., Beitner-Johnson, D., Terwilliger, R.Z., & Nestler, E.J.
1995 Biochemical adaptations in the mesolimbic dopamine system in response to heroinself-administration. Synapse, 21(4), 312-318.
Self, D.W., & Nestler, E.J.
1995 Molecular mechanisms of drug reinforcement and addiction. Annual Review of Neuroscience, 18,463-495.
Seltzer, C.C.
1997 "Conflicts of interest" and "political science." Journal of Clinical Epidemiology, 50(5), 627-629.
Sepkovic, D.W., Marshall, M.V., Rogers, W.R., Cronin, P.A., Colosimo, S.G., & Haley, N.J.
1988 Thyroid hormone levels and cigarette smoking in baboons. Proceedings of the Society forExperimental Biology & Medicine, 187(2), 223-228.
Sershen, H., Toth, E., Lajtha, A., & Vizi, E.S.
1995 Nicotine effects on presynaptic receptor interactions. Annals of the New York Academy of Sciences,757, 238-244.
Shiffman, S.
1989 Tobacco "chippers"--individual differences in tobacco dependence. Psychopharmacology, 97(4),539-547.
Shiffman, S.
1991 Refining models of dependence: Variations across persons and situations. British Journal ofAddiction, 86(5), 611-615.
Shiffman, S., Paty, J.A., Gnys, M., Kassel, J.D., & Elash, C.
1995 Nicotine withdrawal in chippers and regular smokers: subjective and cognitive effects. HealthPsychology, 14(4), 301-309.
Shiffman, S., Paty, J.A., Kassel, J.D., Gnys, M., Zettler-Segal, M.
1994 Smoking behavior and smoking history of tobacco chippers. Experimental & ClinicalPsychopharmacology, 2(2), 126-142.
Shiffman, S., Zettler-Segal, M., Kassel, J., Paty, J., Benowitz, N.L., O'Brien, G.
1992 Nicotine elimination and tolerance in non-dependent cigarette smokers. Psychopharmacology,109(4), 449-456.
Shoaib, M., Schindler, C.W., & Goldberg, S.R.
1997 Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition.
Psychopharmacology, 129(1), 35-43.
Shoaib, M., & Shippenberg, T.S.
1996 Adrenalectomy attenuates nicotine-induced dopamine release and locomotor activity in rats.
file:///C /Library Downloads/jdi.htm (51 of 58) [09-Jun-2001 07:02:07] Psychopharmacology, 128(4), 343-350.
Shoaib, M., Stolerman, I.P., & Kumar, R.C.
1994 Nicotine-induced place preferences following prior nicotine exposure in rats. Psychopharmacology,94(3-4), 445-452.
Shytle, R.D., Silver, A.A., & Sanberg, P.R.
1996 Nicotine, tobacco and addiction. Nature, 384(6604), 18-19.
Siegel, R.K.
1985 Treatment of cocaine abuse: Historical and contemporary perspectives. Journal of PsychoactiveDrugs, 17(1), 1-9.
Silagy, C., Mant, D., Fowler, G., & Lodge, M.
1994a Meta-analysis on efficacy of nicotine replacement therapies in smoking cessation. Lancet,343(8890), 139-142.
Silagy, C., Mant, D., Fowler, G., & Lodge, M.
1994b The effectiveness of nicotine replacement therapies in smoking cessation. Online Journal ofCurrent Clinical Trials, 1137906 words; 110 paragraphs.
Silverstein, B., Kozlowski, L.T., & Schachter, S.
1977 Studies of the interaction of psychological and pharmacological determinants of smoking: III.
Social life, cigarette smoking, and urinary pH. Journal of Experimental Psychology: General, 106(1),20-23.
Singer, G., & Wallace, M.
1984 Schedule-induced self-injection of drugs: An animal model of addiction. In N.W.Bond (Ed.),Animal models of psychopathology (pp. 211-225). Sydney: Academic Press.
Slotkin, T.A.
1983 Preclinical perinatal and developmental effects of methadone: Behavioral and biochemical aspects:Critique. (National Institute on Drug Abuse Treatment Research Monograph 1281).
Smart, R.G.
1994 Dependence and the correlates of change: A review of the literature. In G. Edwards & M. Lader(Eds.), Addiction: Processes of change. (Oxford Medical Publications and Society for the Study ofAddiction Monograph No. 3), 79-94. Oxford, England: Oxford University Press.
Smith, A., & Roberts, D.C.S.
1995 Oral self-administration of sweetened nicotine solutions by rats. Psychopharmacology, 120(3),341-346.
Smith, J.K., Neill, J.C., & Costall, B.
1997 Bidirectional effects of dopamine D2 receptor antagonists on responding for a conditionedreinforcer. Pharmacology Biochemistry and Behavior, 57(4), 843-849.
Smith, T.A., House, R.F.J., Croghan, I.T., Gauvin, T.R., Colligan, R.C., Offord, K.P., Gomez-Dahl, L.C.,& Hurt, R.D.
1996 Nicotine patch therapy in adolescent smokers. Pediatrics, 98(4 Pt 1), 659-667.
file:///C /Library Downloads/jdi.htm (52 of 58) [09-Jun-2001 07:02:07] Solursh, L.P.
1989 Combat addiction: Overview of implications in symptom maintenance and treatment planning.
Journal of Traumatic Stress, 2(4), 451-462.
Sonderskov, J., Olsen, J., Sabroe, S., Meillier, L., & Overvad, K.
1997 Nicotine patches in smoking cessation: A randomized trial among over-the-counter customers inDenmark. American Journal of Epidemiology, 145(4), 309-318.
Spealman, R.D.
1983 Maintenance of behavior by postponement of scheduled injections of nicotine in squirrel monkeys.
Journal of Pharmacology & Experimental Therapeutics, 227(1), 154-159.
Stassen, H.H., Bridler, R., Hägele, S., Hergersberg, M., Mehmann, B., Schinzel, A., Weisbrod, M., &Scharfetter. C.
2000 Schizophrenia and smoking: Evidence for a common neurobiological basis? American Journal ofMedical Genetics, 96(2), 173-177.
Stephens, M.L.
1986 Maternal deprivation experiments in psychology: A critique of animal models. Jenkinstown, PA:American Anti-Vivisection Society.
Stephenson, J.
1996 Clues found to tobacco addiction. Journal of the American Medical Association, 275(16),1217-1218.
Stepney, R.
1996 The concept of addiction: Its use and abuse in the media and science. Human Psychopharmacology,11(Suppl. 1), S15-S20.
Stewart, M.J., Gillis, A., Brosky, G., Johnston, G., Kirkland, S., Leigh, G., Persaud, V., Rootman, I.,Jackson, S., & Pawliw-Fry, B.A.
1996 Smoking among disadvantaged women: causes and cessation. Canadian Journal of NursingResearch, 28(1), 41-60.
Stolerman, I.P.
1991 Behavioural pharmacology of nicotine: Multiple mechanisms. British Journal of Addiction, 86(5),533-536.
Stolerman, I.P.
1992 Drugs of abuse: Behavioral principles, methods and terms. Trends in Pharmacological Sciences,13, 170-176.
Stolerman, I.P.
1993 Components of drug dependence: reinforcement, discrimination and adaptation. BiochemicalSociety Symposia, 59, 1-12.
Stolerman, I.P., & Jarvis, M.J.
1995 The scientific case that nicotine is addictive. Psychopharmacology, 117(1), 2-10.
Stolerman, I.P., & Shoaib, M.
file:///C /Library Downloads/jdi.htm (53 of 58) [09-Jun-2001 07:02:07] 1991 The neurobiology of tobacco addiction. Trends in Pharmacological Sciences, 91(12), 467-473.
Sullum, J.
1996 Smoke alarm: This weed will make you stupid, unemployable, and lethargic. Now it's pot. It usedto be tobacco. Reason, Oct., 87-81.
Sullum, J.
1998 For your own good: The anti-smoking crusade and the tyranny of public health. New York: FreePress.
Swedberg, M.D., Henningfield, J.E., & Goldberg, S.R.
1990 Nicotine dependency: Animal studies. In S. Wonnacott, M.A.H. Russell, & I.P.Stolerman (Eds.),Nicotine psychopharmacology: Molecular, cellular and behavioural aspects (pp. 38-76). Oxford: OxfordUniversity Press.
Tanda, G., Pontieri, F.E., & Di Chiara, G.
1997 Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common m1 opioidreceptor mechanism. Science, 276(5321), 2048-2050.
Tanskanen, A., Tuomilehto, J., Viinamaki, H., Vartiainen, E., Lehtonen, J., & Puska, P.
2000 Smoking and the risk of suicide. Acta Psychiatrica Scandinavica, 101(3), 243-245.
Taylor, P.
1984 Smoke ring: The politics of tobacco. London: The Bodley Head.
Tella, S.R., Ladenheim, B., Andrews, A.M., Goldberg, S.R., & Cadet, J.L.
1996 Differential reinforcing effects of cocaine and GBR-12909: Biochemical evidence for divergentneuroadaptive changes in the mesolimbic dopaminergic system. Journal of Neuroscience, 16(23),7416-7427.
Tella, S.R., Ladenheim, B., & Cadet, J.L.
1997 Differential regulation of dopamine transporter after chronic self-administration of bupropion andnomifensine. Journal of Pharmacology & Experimental Therapeutics, 281(1), 508-513.
Ter, R.G., Kleijnen, J., & Knipschild, P.
1990 A meta-analysis of studies into the effect of acupuncture on addiction. British Journal of GeneralPractice, 40(338), 379-382.
Terry, A.V.J., Buccafusco, J.J., Jackson, W.J., Zagrodnik, S., Evans-Martin, F.F., & Decker, M.W.
1996 Effects of stimulation or blockade of central nicotinic-cholinergic receptors on performance of anovel version of the rat stimulus discrimination task. Psychopharmacology, 123(2), 172-181.
Tessari, M., Valerio, E., Chiamulera, C., & Beardsley, P.M.
1995 Nicotine reinforcement in rats with histories of cocaine self- administration. Psychopharmacology,121(2), 282-283.
Tiffany, S.T.
1991 The application of 1980s psychology to 1990s smoking research. British Journal of Addiction,86(5), 617-620.
file:///C /Library Downloads/jdi.htm (54 of 58) [09-Jun-2001 07:02:07] Tonnesen, P., Mikkelsen, K., Norregaard, J., & Jorgensen, S.
1996 Recycling of hard-core smokers with nicotine nasal spray. European Respiratory Journal, 9(8),1619-1623.
Trichopoulos, D., Li, F.P., & Hunter, D.J.
1996 What causes cancer? Scientific American, 275(3), 80-87.
Turenne, S.D., Miles, C., Parker, L.A., & Siegel, S.
1996 Individual differences in reactivity to the rewarding/aversive properties of drugs: Assessment bytaste and place conditioning. Pharmacology Biochemistry and Behavior, 53(3), 511-516.
United States Department of Health and Human Services1988 The health consequences of smoking: Nicotine addiction. A report of the Surgeon General.
Rockville, MD: US Departments of Health and Human Services, Office of the Assistant Secretary forHealth. Office on Smoking and Health.
United States Government Office of Technology Assessment1994 Ethnographic drug studies. In Technologies for understanding and preventing substance abuse andaddiction. Washington DC: US Government Office of Technology Assessment.
Vallin, J.
1984 Politiques de santé et mortalité dans les pays industrialisés. Espace populations et société, 13-31.
Villanueva, H.F., James, J.R., & Rosecrans, J.A.
1989 Evidence of pharmacological tolerance to nicotine. (National Institute on Drug Abuse ResearchMonograph 95), 349-350.
Vizi, E.S., & Lendvai, B.
1999 Modulatory role of presynaptic nicotinic receptors in synaptic and non-synaptic chemicalcommunication in the central nervous system. Brain Research Reviews, 30(3), 219-235.
Volkow, N.D., Wang, G.J., Fowler, J.S., Logan, J., Gatley, S.J., Hitzemann, R., Chen, A.D., Dewey,S.L., & Pappas, N.
1997 Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature,386(6627), 830-833.
Wakasa, Y., Takada, K., & Yanagita, T.
1995 Reinforcing effect as a function of infusion speed in intravenous self-administration of nicotine inrhesus monkeys. Nihon Shinkei Seishin Yakurigaku Zasshi, 15(1), 53-59.
Waldum, H.L., Nilsen, O.G., Nilsen, T., Rorvik, H., Syversen, U., Sandvik, A.K., Haugen, O.A., Torp,S.H., & Brenna, E.
1996 Long-term effects of inhaled nicotine. Life Sciences, 58(16), 1339-1346.
Warburton, D.M.
1985 Addiction, dependence and habitual substance use. Bulletin of the British Psychological Society,38, 285-288.
Warburton, D.M.
1990a Psychopharmacological aspects of nicotine. In S. Wonnacott, M.A.H. Russell, & I.P. Stolerman file:///C /Library Downloads/jdi.htm (55 of 58) [09-Jun-2001 07:02:07] (Eds.), Nicotine psychopharmacology: Molecular, cellular and behavioural aspects (pp. 77-111).
Oxford: Oxford University Press.
Warburton, D.M.
1990b Heroin, cocaine and now nicotine. In D.M.Warburton (Ed.), Addiction controversies (pp. 21-35).
London, England: Harwood Academic Publishers.
Warburton, D.M.
1994a The appetite for nicotine. In C.R.Legg & D.A. Booth (Eds.), European Brain & Behaviour SocietyPublications: Series 1. Appetite: Neural and behavioural bases (pp. 264-284). Oxford, England: OxfordUniversity Press.
Warburton, D.M.
1994b Pleasure: The politics and the reality. Chichester U.K.: Wiley.
Warburton, D.M.
1994c The reality of the beneficial effects of nicotine. Addiction, 89(2), 138-143.
Warburton, D.M.
1994d Psychological resources from nicotine. Journal of smoking-related disorders, 5(Suppl. 1),149-155.
Warburton, D.M.
1995 The functional conception of nicotine use. In P.B.S.Clark, Effects of nicotine on biological systemsII (pp. 257-264). Boston: Birkhauser Verlag.
Warburton, D.M., & Arnall, C.
1994 Improvements in performance without nicotine withdrawal. Psychopharmacology, 115(4),539-542.
Ward, A.S., Li, D.H., Luedtke, R.R., & Emmett-Oglesby, M.W.
1996 Variations in cocaine self administration by inbred rat strains under a progressive-ratio schedule.
Psychopharmacology, 127(3), 204-212.
Weaver, M.F., Jarvis, M.A.E., & Schnoll, S.H.
1999 Role of the primary care physician in problems of substance abuse. Archives of Internal Medicine,159(9), 913-924.
Weerts, E.M., & Griffiths, R.R.
1999 Evaluation of the intravenous reinforcing effects of clonidine in baboons. Drug and AlcoholDependence, 53(3), 207-214.
West, R.J.
1984 Psychology and pharmacology in cigarette withdrawal. Journal of Psychosomatic Research, 28(5),379-386.
West, R.J., Russell, M.A., Jarvis, M.J., & Feyerabend, C.
1984 Does switching to an ultra-low nicotine cigarette induce nicotine withdrawal effects?Psychopharmacology, 84(1), 120-123.
file:///C /Library Downloads/jdi.htm (56 of 58) [09-Jun-2001 07:02:07] Westman, E.C., Behm, F.M., & Rose, J.E.
1995 Airway sensory replacement combined with nicotine replacement for smoking cessation. Arandomized, placebo-controlled trial using a citric acid inhaler. Chest, 107(5), 1358-1364.
Westman, E.C., Behm, F.M., & Rose, J.E.
1996 Dissociating the nicotine and airway sensory effects of smoking. Pharmacology Biochemistry andBehavior, 53(2), 309-315.
Whitebread, C.
1995 The history of the non-medical use of drugs in the United States. Address to the California Judge'sAssociation Conference [On-line]. Available: http://www.druglibrary.org/schaffer/History/whiteb1.htm.
Whitebread, C., & Bonnie, R.
1970 The forbidden fruit and the tree of knowledge: The legal history of marihuana in the united states.
Virginia Law Review (October), 1-450.
White, N.M.
1996 Addictive drugs as reinforcers: multiple partial actions on memory systems. Addiction, 91(7),921-949.
Willner, P.
1991a Methods for assessing the validity of animal models of human psychopathology. In A.A. Boulton,G.B. Baker, & M. Thomas Martin-Iverson (Eds.), Animal models in psychiatry, I. Neuromethods, 18 (pp.
1-23). Clifton, NJ: Humana Press.
Willner, P.
1991b Animal models of depression. In P.Willner (Ed.), Behavioral models in psychopharmacology:Theoretical, industrial and clinical perspectives (pp. 91-125). Cambridge, England: CambridgeUniversity Press.
Wilson, C., Nomikos, G.G., Collu, M., & Fibiger, H.C.
1995 Dopaminergic correlates of motivated behavior: Importance of drive. Journal of Neuroscience,15(7 Pt 2), 5169-5178.
Winefield, A.H., & Glow, P.H.
1980 Active versus passive control in sensory contingent bar pressing in rats. Journal of GeneralPsychology, 80(1st Half), 27-40.
Wise, R.A.
1994 Cocaine reward and cocaine craving: the role of dopamine in perspective. (National Institute onDrug Abuse Research Monograph 145), 191-206.
Wise, R.A.
1996a Addictive drugs and brain stimulation reward. Annual Review of Neuroscience, 19, 319-340.
Wise, R.A.
1996b Neurobiology of addiction. Current Opinion in Neurobiology, 6(2), 243-251.
Wise, R.A.
1997 Drug self-administration viewed as ingestive behavior. Appetite, 28(1), 1-5.
file:///C /Library Downloads/jdi.htm (57 of 58) [09-Jun-2001 07:02:07] Wise, R.A., & Leeb, K.
1993 Psychomotor-stimulant sensitization: A unitary phenomenon. Behavioral Pharmacology, 4,339-349.
Wise, R.A., & Munn, E.
1993 Effects of repeated amphetamine injections on lateral hypothalamic brain stimulation reward andsubsequent locomotion. Behavioral Brain Research, 55(2), 195-201.
Wood, R.W.
1990 Animal models of drug self-administration by smoking. (National Institute on Drug Abuse ResearchMonograph 99), 159-171.
Woolverton, W.L.
1992 Cocaine self-administration: pharmacology and behavior. (National Institute on Drug AbuseResearch Monograph 124), 189-202.
World Health Organization1974 Twentieth report on the expert committeee on addiction-producing drugs. Geneva: World HealthOrganization.
World Health Organization1978 Mental disorders: Glossary to their classification in accordance with the ninth revision of theinternational classification of diseases, Geneva. Geneva: World Health Organisation.
Wu, A.H., Yu, M.C., & Mack, T.M.
1997 Smoking, alcohol use, dietary factors and risk of small intestinal adenocarcinoma. InternationalJournal of Cancer, 70(5), 512-517.
Yanagita, T., Ando, K., Kato, S., & Takada, K.
1983 Psychopharmacological studies on nicotine and tobacco smoking in rhesus monkeys.
Psychopharmacology Bulletin, 19(3), 409-412.
Yoshida, M., Yokoo, H., Mizoguchi, K., Kawahara, H., Tsuda, A., Nishikawa, T., & Tanaka, M.
1992 Eating and drinking cause increased dopamine release in the nucleus accumbens and ventraltegmental area in the rat: Measurement by in vivo microdialysis. Neuroscience Letters, 139(1), 73-76.
Young, A.M., Joseph, M.H., & Gray, J.A.
1992 Increased dopamine release in vivo in nucleus accumbens and caudate nucleus of the rat duringdrinking: a microdialysis study. Neuroscience, 48(4), 871-876.
Young, A.M., Joseph, M.H., & Gray, J.A.
1993 Latent inhibition of conditioned dopamine release in rat nucleus accumbens. Neuroscience, 54(1),5-9.
file:///C /Library Downloads/jdi.htm (58 of 58) [09-Jun-2001 07:02:07]

Source: http://www.clarewatererhypnotherapy.co.uk/nicotine_addiction.pdf

Microsoft word - coumarin - the real story update.doc

Coumarin: The Real Story (Updated Jan. 2008). Copyright © Tony Burfield 2006-2008 What is it? Coumarin (2H-1-benzopyran-2-one) CAS No 91-64-5, is a crystalline white solid when seen pure, with a hay-like, sweet aromatic creamy odour with certain nutty shadings, much used in synthetic form as a fragrance chemical for perfumes and for fragranced soaps and detergents. Coumarin has a widespread occurrence in natural products too (see separate section below), and is a representative of the lactones (where a lactone is an ester group integrated into a carbon ring system).

propuestaciudadana.org.pe

© Defensoría del Pueblo Jr. Azángaro N° 430 Lima 01-PerúCentral Telefónica (511) 311-0300 Fax (511) 426-7889 Línea gratuita: 0800-15170 Primera edición, Lima, Perú, abril de 2013. Este documento ha sido elaborado por el Programa de Ética Pública, Prevención de la Corrupción y Políticas Públicas adscrito a la Adjuntía para la Prevención de Conflictos Sociales y la Gobernabilidad de la Defensoría del Pueblo.