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Pii: s0893-133x(00)00226-8

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in RodentsRaz Yirmiya, Ph.D., Yehuda Pollak, M.A., Ohr Barak, M.A., Ronit Avitsur, Ph.D., Haim Ovadia, Ph.D., Michael Bette, Ph.D., Eberhard Weihe, M.D., and Joseph Weidenfeld, Ph.D. Antidepressants produce various immunomodulatory chronic treatment with fluoxetine completely abolished the effects, as well as an attenuation of the behavioral responses hypothermic response and facilitated and strengthened the to immune challenges, such as lipopolysaccharide (LPS). To hyperthermic response. The effects of antidepressants on the explore further the effects of antidepressants on responsiveness to LPS are probably not mediated by their neuroimmune interactions, rats were treated daily with effects on peripheral proinflammatory cytokine production, either fluoxetine (Prozac) or saline for 5 weeks, and various because LPS-induced expression of TNF␣ and IL-1␤ behavioral, neuroendocrine, and immune functions were mRNA in the spleen (assessed by semiquantitative in situ measured following administration of either LPS or saline. hybridization) was not altered following chronic treatment Chronic fluoxetine treatment significantly attenuated the with either fluoxetine or imipramine. The effects of anorexia and body weight loss, as well as the depletion of antidepressants on the acute phase response may have CRH-41 from the median eminence and the elevation in important clinical implications for the psychiatric and serum corticosterone levels induced by LPS. Chronic neuroendocrine disturbances that are commonly associated treatment with imipramine also attenuated LPS-induced with various medical conditions. adrenocortical activation. In rats and in mice, which [Neuropsychopharmacology 24:531–544, 2001]
normally display a biphasic body temperature response to 2001 American College of Neuropsychopharmacology. LPS (initial hypothermia followed by hyperthermia), Published by Elsevier Science Inc. KEY WORDS: Fluoxetine (Prozac); Imipramine; Several lines of evidence indicate that antidepressants Lipopolysaccharide (LPS); Tumor Necrosis Factor-␣ produce various immunomodulatory effects. In de- (TNF␣); Interleukin-1␤ (IL-1␤); Corticotrophin-releasing pressed patients, the effects of antidepressants are vari- hormone (CRH); Corticosterone; Fever; Depression able and seem to be related to the immune status of thepatients at the initiation of the treatment. When depres-sion was associated with immune activation, antide-pressants reduced immune function and cytokine secre- From the Department of Psychology (RY, YP, OB, RA), The tion. For example, the increased plasma levels of IL-6 Hebrew University of Jerusalem, Mount Scopus, Jerusalem, Israel;Department of Neurology (HO, JW), Hadassah-Hebrew University during acute depression were normalized by 8-week Medical Center, Ein-Kerem, Jerusalem, Israel; Institute of Anatomy treatment with fluoxetine (Sluzewska et al. 1995), the and Cell Biology, Department of Molecular Neuroimmunology increased monocyte counts in depressed patients were (MB, EW), University of Marburg, Marburg, Germany Address correspondence to: Raz Yirmiya, Ph.D., Department of reduced following 6-weeks treatment with tricyclic an- Psychology, The Hebrew University of Jerusalem, Mount Scopus, tidepressants (TCAs) (Seidel et al. 1996), and the in- Jerusalem 91905, Israel.
creased numbers of leukocytes and neutrophils were Received April 3, 2000; revised August 10, 2000; accepted Sep- tember 8, 2000.
also reduced by antidepressant treatment (Maes et al.
NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 2001 American College of NeuropsychopharmacologyPublished by Elsevier Science Inc.
0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00226-8 532 R. Yirmiya et al.
NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 1997). On the other hand, when immune functions were and LPS-induced secretion of IL-1␤, IL-6 and TNF␣ found to be normal, antidepressants had no immuno- from monocytes (Xia et al. 1996). Similarly, the antide- logical effects; for example, chronic moclobemide treat- pressant rolipram was found to suppress TNF␣ and (to ment had no effect on monocytes functions, TNF␣ pro- a lesser extent) also IFN␥ secretion by human and rat duction or IFN␥ levels (Landmann et al. 1997).
auto-reactive T-cells (Sommer et al. 1995). Finally, in a Moreover, in a study of depressed patients who exhib- recent study, exposure to antidepressants not only sup- ited immune suppression before treatment, the TCA pressed stimulated IFN␥ secretion, but also increased clomipramine increased the production of IL-1␤, IL-2, the secretion of IL-10, suggesting a general negative im- and IL-3 (Weizman et al. 1994).
munoregulatory effect (Maes et al. 1999). All of these In experimental animals, TCAs as well as selective studies were conducted using acute in vitro exposure to serotonin reuptake inhibitors (SSRIs) produce mainly antidepressants, and, therefore, their relevance to the immune suppression and anti-inflammatory effects.
effects of antidepressants on LPS-induced sickness be- For example, antidepressant treatment in vivo inhibited havior is questionable. As a first attempt to determine the increased acute phase response in olfactory bulbec- whether the effects of chronic antidepressant treatment tomized rats, a useful animal model of depression on the behavioral and neuroendocrine responses to LPS (Song and Leonard 1994), reduced the production of in- are mediated by suppression of LPS-induced activation terleukin-1 (IL-1) and IL-2 in a chronic mild stress of cytokine systems, we measured the effects of chronic model of depression (Kubera et al. 1996), inhibited im- treatment with both fluoxetine and imipramine on the mune activation in rats with experimental allergic neu- induction of TNF␣ and IL-1␤ mRNA following LPS ad- ritis (Zhu et al. 1994), and produced anti-inflammatory ministration in vivo.
effects in carrageenin- or brewer's yeast-induced in-flammation (Bianchi et al. 1994, 1995; Michelson et al.
1994).
In addition to their effects on immune functions, an- tidepressants were also found to attenuate the behav-ioral effects of immune activation. We have previously Subjects were Fischer 344 male rats or male SJL mice, reported that treatment with the TCA imipramine at- 10–12 weeks-old (Harlan–Sprague–Dawley, Jerusalem).
tenuated the depressive-like behavioral syndrome that The study was approved by the Hebrew University is induced in rats by administration of the immune acti- Committee for Experimentation on Laboratory Ani- vator lipopolysaccharide (LPS) (Yirmiya 1996, 1997).
mals. Rats and mice were housed three/cage and five/ Specifically, chronic (5 weeks of daily injections), but cage, respectively, in an air-conditioned room (23 ⫾ not acute administration of imipramine attenuated 1⬚C), with food and water ad libitum for several weeks LPS-induced decrease in the consumption of and pref- before the beginning of the experiment, as well as dur- erence for saccharine solution, which is considered as a ing the first 3–5 weeks of chronic drug administration good animal model of anhedonia (Willner 1997), as well (see below). Experimental manipulations (injections as other sickness behavior symptoms, including anor- and initial measurements) started at the beginning of exia, weight loss, and reduced social, locomotor, and the dark phase of a reversed 12-h light/dark cycle.
exploratory behavior (Yirmiya 1996). Similar findingswere recently reported using chronic treatment withthe TCA desipramine. However, in that study, treat- ment with paroxetine and venlafaxine (selective re- Experiment 1: Effects of Chronic Treatment with
uptake inhibitors of serotonin and norepinephrine, re- Fluoxetine on LPS-Induced Sickness Behavior
spectively) did not attenuate LPS-induced sicknessbehavior (Shen et al. 1999). One aim of the present At the beginning of the experiment, rats were divided study was to extend these findings by examining the ef- into two groups receiving a daily IP injection of either fects of the SSRI fluoxetine (Prozac) on LPS-induced saline or fluoxetine (Prozac; 10 mg/kg) (Eli Lilly and sickness behavior. Because LPS also produces marked Company, USA) for 5 weeks. This dose was chosen, be- changes in body temperature and activation of the hy- cause in several previous studies it was shown to atten- pothalamus-pituitary-adrenal (HPA) axis (Kluger 1991; uate the behavioral and neuroendocrine effects of acute Tilders et al. 1994), another aim of the present study challenges (e.g., Li et al. 1993; Zhang et al. 2000). Rats was to examine the effects of antidepressant treatment were weighed weekly. One week before the experi- on these thermoregulatory and neuroendocrine compo- ment, animals were separated into individual cages.
nents of the acute phase response.
Two days before the experiment, baseline food con- Some of the effects of antidepressants are probably sumption was measured by giving each rat 100.0 g of mediated by a direct action on immune cells. For exam- food pellets and weighing the remaining food 24 h ple, TCAs were found to inhibit spontaneous secretion later. Preliminary experiments showed that food spill- of IL-2 and IFN␥ from T-cells, as well as spontaneous age was negligible (less than 1% of the food consumed).
NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 Fluoxetine Attenuates Sickness Behavior One day before the experiment, rats within the saline The content of immunoreactive CRH-41 in the ME and fluoxetine groups were divided into two sub- was measured in tissue extracts by RIA, using a specific groups (n ⫽ 9–10), matched for mean food consump- anti-CRH-41 antiserum obtained from the Pasteur Insti- tion and body weight.
tute (Paris). The tissues were homogenized by ultra- On the morning of the behavioral experiment day, sonic disruption for 20 s. Following 15 min centrifuga- rats were weighed and injected with either saline or flu- tion at 10,000 rpm, at 4⬚C, duplicated 10-␮l aliquots oxetine, as before, followed immediately by an IP injec- were removed into plastic tubes containing 10 ␮l 0.5 M tion of either saline or LPS (100 ␮g/kg) (E. Coli 055, potassium phosphate buffer, pH 7.4, and 80 ␮l of assay Difco Laboratories, Detroit, MI). This dose of LPS in- buffer was then added. Assay tubes were incubated for duces robust sickness behavior, which was previously 72 h at 4⬚C with 0.1 ml of anti-CRH-41 (dilution found to be attenuated by chronic treatment with imi- 1:12,500). Tubes were then incubated for an additional pramine (Yirmiya 1996). Immediately following the sec- 72 h with 125I-labled Tyr-CRH-41. To stop the reaction, ond injection, food was replaced with 100.0 g of fresh 100 ␮l normal rabbit serum (diluted 1:80 in saline) was pellets for measurement of food consumption. Activity added, followed by 100 ␮l horse serum anti-rabbit glob- in the open field test was assessed 4 h after the injec- ulin (dilution 1:75) and 1 ml of 6% polyethylene glycol tions, in a dimly illuminated, quite room. Each rat was dissolved in water. Samples were vortexed and incu- placed in the corner of an open field (95 ⫻ 95 ⫻ 60 cm) bated for 45 min in an ice-cold water bath. Tubes were divided into 25 identical squares. The incidences of line then centrifuged at 4000 rpm, 4⬚C, for 20 min. The su- crossing with both hind paws and rearing were re- pernatant was aspirated, and the pellet was counted in corded by an observer blind to the treatment received a gamma counter. The sensitivity limit of this assay is 3 by the animal, over a period of 3 min. Body weight and pg/tube and the intra- and interassay coefficients of food consumption were measured 24 h after the injec- variation are 5.8% and 6.5%, respectively. The content tion. The results were analyzed by two-way analyses of of CRH-41 determined was directly proportional to dif- variance (ANOVAs), followed by post-hoc tests with ferent dilutions of volumes taken (2–10 ␮l) from the tis- the Fisher PLSD procedure (p ⬍ .05).
sue extracts. Serum corticosterone was determined byradioimmunoassay (RIA), as previously described(Weidenfeld and Yirmiya 1996). The sensitivity limit of Experiment 2: Effects of Chronic Antidepressant
the assay is 0.5 ␮g/100 ml, and the intra- and interassay Treatment on LPS-Induced Activation of the
coefficients of variation were 6.3 and 7%, respectively.
To further explore the generality of the effects of an- Following chronic treatment (daily IP injections for 5 tidepressants on the adrenocortical activation we con- weeks) with either fluoxetine (10 mg/kg) or saline, rats ducted a second study, examining the effects of both within each group were divided into two subgroups (n ⫽ fluoxetine and imipramine on corticosterone secretion 8–9), matched for mean body weight. Animals were following a higher dose of LPS (the dose used in the be- transferred to individual cages 24 h before the experi- havioral testing). Rats received a daily injection (IP) of ment, to avoid the acute stress associated with taking either saline, imipramine (10 mg/kg) or fluoxetine (10 out individual rats from a group cage during the sacri- mg/kg) for 5 weeks. On the experiment day, rats were fice procedure (in preliminary experiments, we found weighed and injected with either saline or fluoxetine, as that if animals are taken out, one by one, from a group before, followed immediately by an injection of either cage, the last animals have higher corticosterone levels saline or LPS (100 ␮g/kg). Two h later, rats were sacri- than the first ones). On the experiment day, rats re- ficed by decapitation, and trunk blood was collected for ceived either saline or fluoxetine, as before, followed by corticosterone determination. Serum corticosterone was an injection of either saline or LPS (50 ␮g/kg). We used determined as described above.
an LPS dose that was lower than the one used for the The results of both experiments were analyzed by behavioral studies, because the HPA axis is more sensi- two-way analyses of variance (ANOVAs), followed by tive to LPS than behavioral systems (e.g., Johnson et al.
post-hoc tests with the Fisher PLSD procedure (p ⬍.05).
1996), and the use of a higher dose could interfere withthe ability to demonstrate fluoxetine-induced attenua- Experiment 3: Effects of Acute Fluoxetine Treatment
tion of the HPA response. Two h later, rats were decap- on LPS-Induced Sickness Behavior and
itated, the brains were removed, and immediately placed on ice. The median eminence (ME) was uni-formly excised under a binocular and was placed in 500 To assess the effects of acute fluoxetine administration ␮l ice-cold 0.1 M HCl. The tissue was stored at ⫺80⬚C on sickness behavior, rats were divided into four groupsuntil assayed for immunoreactive CRH-41 ME content.
(n ⫽ 6–7), matched for mean baseline food consumption Trunk blood was collected, and serum samples were and body weight (see procedure for Experiment 1). On also stored at ⫺80⬚C for subsequent corticosterone de- the morning of the behavioral experiment day, rats were injected IP with either saline or fluoxetine (10 mg/kg), 534 R. Yirmiya et al.
NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 followed immediately by an IP injection of either saline We used a lower dose of LPS than the one used in rats, or LPS (100 ␮g/kg). Food consumption, changes in body because in preliminary experiments, we found that SJL weight, and open field activity were measured, as de- mice are more sensitive than rats to many of the behav- scribed in the procedure for Experiment 1.
ioral effects of LPS. Body temperature was recorded for To assess the effects of acute fluoxetine administration an additional 24 hr, at 30-min intervals.
on corticosterone secretion, a different group of rats was The results were analyzed by a two-way ANOVA, divided to four subgroups (n ⫽ 6–8), injected acutely with the group as a between- subjects factor and the with either saline or fluoxetine followed by either saline measurement times as within-subjects, repeated mea- or LPS, as described above. Two h after the injections, sure factor.
rats were sacrificed and serum corticosterone levels wereassessed as described in the procedure for Experiment 2.
Experiment 5: Effects of Chronic Antidepressant
The results of both experiments were analyzed by Treatment on LPS-Induced Splenic
two-way ANOVAs, followed by post-hoc tests with the Fisher PLSD procedure (p ⬍ .05).
Rats were divided into three groups, injected IP dailywith either saline, imipramine (10 mg/kg) or fluoxetine Experiment 4: Effects of Chronic Fluoxetine
(10 mg/kg) for 5 weeks. On the experiment day, rats Treatment on LPS-Induced Changes in
within each group were injected with their respective drug, and were then divided into subgroups, injected Rats were divided into two groups receiving a daily IP IP with either saline or LPS (100 ␮g/kg). Three hours injection of either saline or fluoxetine (10 mg/kg) for 5 following the injection, rats were sacrificed, and spleens weeks. Rats were weighed weekly. Two weeks follow- were rapidly removed and placed in temperature con- ing the initiation of this treatment, rats were implanted trolled isopentane (⫺30–⫺50⬚C) for 15–30 s. Tissues with biotelemetric transmitters (model VM-FH, Mini were then frozen in dry ice, wrapped in parafilm, and Mitter Co. Inc., Sunriver, OR) into the peritoneal cavity, transferred to a ⫺80⬚C freezer for storage.
as previously described (Yirmiya et al. 1997), and trans- For in situ hybridization, rat specific cDNA frag- ferred into individual cages. Following 5 weeks of the ments were generated by reverse transcription PCR of chronic treatment, each animal's cage was placed over a total RNA from rat lymph node. For IL-1␤ cDNA, a 589 receiver board (model RA-1010, Mini Mitter Co. Inc., bp fragment ranging from bp 206 to bp 795 of IL-1␤ Sunriver, OR), whose output was fed into a peripheral cRNA (Acc. M98820) and for TNF␣ cDNA a 291 bp processor (BCM100) connected to a personal computer.
fragment ranging from bp 4432 within Exon 1 to bp Baseline body temperature was recorded for 3 days. On 5348 within Exon 3 of TNF␣ DNA (Acc. L00981) were the morning of the experiment day, rats within the sa- amplified and inserted into a pGEM-T vector (Promega, line and fluoxetine groups were divided into two sub- Germany). IL-1␤ cDNA was linearized with Not I or groups (n ⫽ 6), injected IP with either saline or LPS (100 Nco I, TNF␣ cDNA was linearized with Apa I or Pst I ␮g/kg), and body temperature was recorded for an ad- restriction enzymes (Boehringer Mannheim, Germany).
ditional 24 h, at 30-min intervals.
35S-labeled sense and antisense riboprobes were gener- The results were analyzed by a two-way ANOVA, with ated by in vitro transcription using SP6 or T7 poly- the chronic (saline vs. fluoxetine) and acute (saline vs.
merases (Boehringer Mannheim, Germany) as appro- LPS) treatments as between-group factors, and the time as priate in the presence of 35S-UTP (Amersham Life a within-subjects, repeated measures factor. Because LPS Science, Germany). All labeled cRNAs were purified produced a biphasic effect on body temperature (initial over NucTrap purification columns (Stratagene, Ger- hypothermia followed by prolonged hyperthermia) the many) and diluted in hybridization-buffer (100 mM results of each phase were analyzed separately.
Tris pH 7.5, 600 mM NaCl, 1 mM EDTA, 0.5 mg/ml To extend the findings with rats, we conducted a sec- t-RNA, 0.1 mg/ml sonicated salmon sperm DNA, 1x ond experiment on the effects of chronic fluoxetine Denhardt's, 10% dextrane sulfate, 50% formamide) to treatment on LPS-induced body temperature changes 50,000 cpm/␮l. Labeled cRNA was stored for no longer in mice. Male SJL mice were divided into two groups (n ⫽ than 3 weeks at ⫺75⬚C. In situ hybridization was per- 8), injected IP daily with either saline or fluoxetine (10 formed in nine serial cryostat sections (20 ␮m) from mg/kg in a volume of 10 ml/kg). Two weeks following each animal. Tissue sections were fixed in 4% paraform- the initiation of this treatment, mice were implanted aldehyde in PBS at 4⬚C for 1 h, washed three times in with biotelemetric transmitters, as described above.
PBS, penetrated by 0.4% Triton X-100 in PBS for 5 min Following 5 weeks of the chronic treatment, each ani- and acetylated for 10 min in 0.1 M triethanolamine pH mal's cage was placed over a receiver board, and base- 8.0 with 0.25% acetic anhydride. Tissues were washed line body temperature was recorded for 3 days. On the in 2x SSC, dehydrated in ethanol and stored at ⫺20⬚C morning of the experiment day, at the beginning of the until hybridization. Hybridization with cRNA, pre- light period, mice were injected IP with LPS (50 ␮g/kg).
pared by in vitro transcription, was performed by incu- NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 Fluoxetine Attenuates Sickness Behavior bation of 35 ␮l of cRNA on tissue sections for 16–18 h at ANOVAs, followed by post-hoc tests with the Fisher 56⬚C in a moist chamber. Sections were washed in 2x PLSD procedure (p ⬍ .05).
SSC and 1x SSC for 10 min each, and single strandedRNA was digested by 10 ␮g/ml RNAse and 1 U/ml T1RNAse (Boehringer Mannheim) in Tris/EDTA pH 8.0, 150 mM NaCl at 37⬚C for 1 h. Afterward, sections were Experiment 1: Effects of Chronic Treatment with
desalted by passing them through 1x SSC, 0.5x SSC, Fluoxetine on LPS-Induced Sickness Behavior
0.2x SSC for 10 min each and washed in 0.2x SSC at60⬚C for 1 h. Then the tissue sections were washed in Chronic treatment with fluoxetine was associated with a H2O for 10 min, dehydrated by ethanol and air dried.
reduction in food consumption and body weight. At Autoradiograms were taken by exposing the sections to baseline (i.e., following 5 weeks of fluoxetine administra- an autoradiography film (Hyperfilm-␤max, Amersham, tion), 24-h food consumption in saline- and fluoxetine- Dreieich, Germany) for 1–3 days. For quantification, ra- treated rats was 19.7 and 16.2 g, respectively [t(34) ⫽ 4.62, dioactive standards were exposed simultaneously to p ⬍ .001]. Body weight in saline- and fluoxetine-treated the autoradiograms. Digital image analysis of the auto- rats was 331 and 276 g, respectively [(34) ⫽5.62, p ⬍ .001].
radiograms was performed using the NIH Image pro- LPS produced a significant over-all reduction in food gram. The data from the sections for each animal was consumption [F(1,32) ⫽ 47.64, p ⬍ .0001] (Figure 1A). A averaged, and the results were analyzed by two-way significant interaction was found between the chronic Figure 1.
Effects of chronic treatment with fluoxetine on LPS-induced decrease in food consumption, body weight, and open field activity. Following chronic treatment with either saline or fluoxetine (10 mg/kg, injected IP daily for 5 weeks),
rats were injected acutely with either saline or LPS (100 ␮g/kg) (n⫽ 8–10 rats/group). A: Mean (⫾S.E.M.) food consumption
(g/24 h), measured 24 h following the acute injection. B: Mean (⫾SEM) body weight gain (g/24 h), 24 h following the acute
injection. C and D: Mean (⫾S.E.M.) line crossing and rearing in the open field test, measured 4 h after the administration of
either LPS or saline. *Significantly different from the corresponding acutely injected saline group (p ⬍ .05). †Significantly dif-
ferent from LPS-injected rats treated chronically with saline (p ⬍ .05).
536 R. Yirmiya et al.
NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 (fluoxetine/saline) and acute (LPS/saline) injections Body weight in the fluoxetine and imipramine treat- [F(1,32) ⫽ 4.16, p ⬍ .05], reflecting the greater decrease ment groups was 18% and 5%, respectively, lower than in food consumption in LPS-injected rats chronically in the control group. However, there was no correlation treated with saline compared to fluoxetine-treated rats.
between body weight and corticosterone secretion in ei- Post-hoc analysis showed that LPS produced significant ther the saline or the LPS groups (p ⬍ .2).
anorexia in both chronic treatment groups; however,LPS-induced reduction in food consumption was signif- Experiment 3: Effects of Acute Fluoxetine Treatment
icantly smaller in fluoxetine- than in saline-treated rats.
on LPS-Induced Sickness Behavior and
LPS produced a significant over-all reduction in body weight (bw) [F(1,32 ⫽ 58.21, p ⬍ .0001] (Figure 1B). A sig-nificant interaction was found between the chronic (flu- Acute injections with both fluoxetine and LPS pro- oxetine/saline) and acute (LPS/saline) injections [F(1,32) duced a significant reduction in food consumption ⫽ 4.15, p ⬍ .05], reflecting the greater decrease in bw in [F(1,22) ⫽ 31.25 and 29.11, respectively, p ⬍ .001] (Fig-LPS-injected rats chronically treated with saline as com- ure 4A). A significant interaction was found between pared to fluoxetine-treated rats. Post-hoc analysis the first (fluoxetine/saline) and second (LPS/saline) in- showed that LPS significantly reduced bw in both jection [F(1,22) ⫽ 8.38, p ⬍ .05]. Post-hoc analysis chronic treatment groups, however, LPS-induced reduc- showed that both LPS and fluoxetine produced signifi- tion in bw was significantly smaller in fluoxetine- than in cant anorexia. There was no significant difference be- saline-treated rats. Because the chronic fluoxetine and sa- tween the two LPS-injected groups.
line treatment groups differed markedly in baseline bw, Both fluoxetine and LPS produced a significant re- a similar analysis was conducted on the absolute values duction in body weight gain [F(1,32 ⫽ 5.43 and 32.8, re- (i.e., ANOVA with repeated measures on the values at spectively, p ⬍ .05] (Figure 4B); however, the interac- baseline and 24-h post sal/LPS injection). The same pat- tion between the first and second injection did not reach tern of results was obtained in this analysis.
statistical significance. Post-hoc analysis showed that LPS significantly decreased line crossing and rearing LPS significantly reduced body weight in rats injected in the open field test [F(1,33) ⫽ 22.36, and 8.60, respec- with either saline or fluoxetine. There was no signifi- tively, p ⬍ .005) (Figure 1C and D). There were no sig- cant difference between the two LPS-injected groups.
nificant interactions between the chronic (fluoxetine/ Both fluoxetine and LPS significantly decreased line saline) and the acute (LPS/saline) treatments.
crossing [F(1,22) ⫽ 35.02 and 33.08, respectively, p ⬍.001] and rearing [F(1,22) ⫽ 7.29 and 16.96, respectively,p ⬍ .01] (Figure 4C and D) in the open field test. In line Experiment 2: Effects of Chronic Fluoxetine
crossing, but not in rearing, a significant interaction Treatment on LPS-Induced Activation of the
was found between the first (fluoxetine/saline) and sec- ond (LPS/saline) injection [F(1,22) ⫽ 15.30, p ⬍ .005].
Administration of LPS produced a pronounced depletion Post-hoc analysis showed that both LPS and fluoxetine of CRH-41 ME content (40%) with a concomitant 4-fold produced a significant decrease in line crossing and increase in serum corticosterone in rats that were chroni- rearing. There were no significant differences between cally injected with saline (Figures 2A and B). Chronic the two LPS-injected groups.
treatment with fluoxetine completely abolished the neu- Both fluoxetine and LPS significantly elevated serum roendocrine effects of LPS. These findings were reflected corticosterone levels [F(1,23) ⫽ 13.88 and 10.02, respec- by significant interactions between the chronic (saline/ tively, p ⬍ .01] (Figure 4E). A significant interaction was fluoxetine) and the acute (saline/LPS) treatments, with found between the first (fluoxetine/saline) and second respect to both CRH-41 ME content and corticosterone se- (LPS/saline) injection [F(1,22) ⫽ 6.28, p ⬍ .05]. Post-hoc cretion [F(1,29) ⫽ 4.31 and 4.20, respectively, p ⬍ .05].
analysis showed that both LPS and fluoxetine produced a In the second experiment, treatment with both imi- significant increase in corticosterone levels. There was no pramine and fluoxetine were found to attenuate the ef- significant difference between the two LPS-injected groups.
fects of LPS on serum corticosterone levels, reflected bya significant interaction between the chronic (saline/ Experiment 4: Effects of Chronic Fluoxetine
fluoxetine/imipramine) and acute (saline/LPS) treat- Treatment on LPS-Induced Changes in
ments [F(2,24) ⫽ 9.3, p ⬍ .001] (Figure 3). Post-hoc tests revealed that LPS induced a significant elevation in cor-ticosterone levels in rats treated chronically with saline At baseline, there were no differences in body tempera- or imipramine, but not with fluoxetine. Furthermore, ture between rats that were treated chronically with flu- LPS-injected rats treated with either imipramine or flu- oxetine or saline. In rats that were chronically treated oxetine had significantly lower corticosterone levels with saline, LPS produced a biphasic change in body than LPS-injected rats treated chronically with saline.
temperature, with initial hypothermia at 2–6 h postinjec- NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 Fluoxetine Attenuates Sickness Behavior Figure 3.
Effects of chronic treatment with fluoxetine or imipramine on LPS-induced adrenocortical activation. Fol-lowing chronic treatment (daily IP injections for 5 weeks)with saline, imipramine (10 mg/kg) or fluoxetine (10 mg/kg), rats were injected acutely with either saline or LPS (100 ␮g/kg). Serum corticosterone levels (␮g/100 ml) were mea-sured 2 h following the acute injection. The results representthe mean (⫾S.E.M.) of 5–7 rats/group. *Significantly differ-ent from the corresponding acutely injected saline group (p ⬍ .05). †Significantly different from LPS-injected rats treatedchronically with saline (p ⬍ .05).
phase [F(1,19) ⫽ 8.56, p ⬍ .005], and a significant first in-jection by second injection by time interaction duringthe hyperthermic phase [F(33,627) ⫽ 2.96, p ⬍ .001].
In mice that were chronically treated with saline, LPS also produced a biphasic change in body tempera-ture, with initial hypothermia at 1.5–3.5 h postinjection, Figure 2.
Effects of chronic treatment with fluoxetine on LPS-induced activation of the HPA axis. Following chronic followed by hyperthermia, at 4.5–9 h postinjection (Fig- treatment with either saline or fluoxetine (10 mg/kg, ure 5B). Chronic fluoxetine treatment completely abol- injected IP daily for 5 weeks), rats were injected acutely with ished the hypothermic response to LPS. Thus, fluoxet- either saline or LPS (50 ␮g/kg) (n ⫽ 8–9 rats/group). Two h ine-treated mice displayed only LPS-induced later, rats were sacrificed, the ME was uniformly excised for hyperthermia, which began 3 h postinjection and sub- later determination of the content of immunoreactive CRH- sided by 9 h postinjection. These effects were reflected 41, and blood was collected for subsequent corticosterone by a significant effect of fluoxetine during the hypother- determination. A: Mean (⫾S.E.M.) levels of CRH-41 (pg/
mic phase [F(1,14) ⫽ 5.44, p ⬍ .05], and a similar trend, Median Eminence). B: Mean (⫾S.E.M.) serum corticosterone
which did not reach statistical significance, during the levels (␮g/100 ml). *Significantly different from the corre- hyperthermic phase [F(1,14) ⫽ 3.69, p ⫽ .07].
sponding acutely injected saline group (p ⬍ .05).
Experiment 5: Effects of Chronic Antidepressant
tion, followed by prolonged hyperthermia, at 12–23 h Treatment on LPS-Induced Splenic
postinjection (Figure 5A). Chronic fluoxetine treatment completely abolished the hypothermic response to LPSand altered the kinetics of the hyperthermic response.
LPS produced a marked increase in the expression of Thus, fluoxetine-treated rats displayed only LPS-in- TNF␣ and IL-1␤ mRNA [F(1,35) ⫽ 82.2 and 90.4, re- duced hyperthermia, which began at 3 h postinjection spectively, p ⬍ .0001], which was not influenced by the and continued throughout the measurement period, antidepressant treatment (Figures 6 and 7). Post-hoc with a slight reduction below the control levels at 17–23 analysis revealed that the difference between the LPS h postinjection. These effects were reflected by a signifi- and saline subgroups was significant in all chronic cant interaction between the first (fluoxetine/saline) and treatment groups. Neither fluoxetine nor imipramine had second (LPS/saline) injection during the hypothermic any effect on LPS-induced TNF␣ or IL-1␤ expression.
538 R. Yirmiya et al.
NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 Figure 4.
Effects of acute treatment with fluoxetine on LPS-induced changes in food consumption, body weight, open field activity, and corticosterone secretion. Following acute IP injection with either saline or fluoxetine (10 mg/kg), rats were
injected with either saline or LPS (100 ␮g/kg) (n ⫽ 6–7 rats/group in the behavioral experiment and 6–8 rats/group in the
corticosterone experiment). A. Mean (⫾S.E.M.) food consumption (g/24 h), measured 24 h following the injections. B. Mean
(⫾SEM) body-weight gain (g/24 h), 24 h following the injections. C and D. Mean (⫾S.E.M.) line crossing and rearing in the
open field test, measured 4 h after the injections. E. Mean (⫾S.E.M.) plasma corticosterone levels, measured in a separate
sample of rats, 2 h after the injections. *Significantly different from the corresponding acutely injected saline group (p ⬍ .05).
†Significantly different from the corresponding chronically treated saline group (p ⬍ .05).
findings replicate the results of many previous studies,which demonstrated that activation of the immune sys- In the present study, administration of LPS was found tem by LPS, as well as other immune challenges, in- to induce several sickness behavior symptoms. These duces a reduction in appetite and body weight, suppres- NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 Fluoxetine Attenuates Sickness Behavior Figure 5.
Effects of chronic fluoxetine administration on LPS-induced changes in body temperature in rats and mice. A.
Two groups of rats received chronic treatment with either saline or fluoxetine (10 mg/kg, injected IP daily for 5 weeks).
Baseline body temperature was recorded for 3 days before the experiment day, using a biotelemetric system, and did not dif-
fer between the groups. On the experiment day (at the beginning of the dark phase of the circadian cycle), rats within each
chronic treatment group were injected with either saline or LPS (100 ␮g/kg) (n ⫽ 6/group). Body temperature was recorded
for an additional 23 h, at 30-min intervals. B. Two groups of mice (n ⫽ 8/group) received chronic treatment with either
saline or fluoxetine (10 mg/kg, injected IP daily for 5 weeks). Baseline body temperature was recorded for 3 days, using a
biotelemetric system, and did not differ between the groups. On the experiment day (at the beginning of the light phase of
the circadian cycle), all mice were injected with LPS (50 ␮g/kg) and body temperature was recorded for an additional 23 h,
at 30-min intervals.
sion of locomotor, exploratory, and social activity, levels. This result is also consistent with many previous fatigue and malaise, impairment in cognitive abilities, studies, which reported that LPS produces marked al- reduced libido and sexual behavior, and anhedonia (An- terations in all components of the HPA axis, including isman and Merali 1999; Dantzer et al. 1999; Maier and the secretion of CRH, ACTH, and glucocorticoids (Til- Watkins 1998; Yirmiya 1996; Yirmiya et al. 1994, 1999).
ders et al. 1994), as well as an impairment in the gluco- Our results also demonstrate that LPS produced a corticoid negative feedback regulation of adrenocortical marked depletion of CRH-41 ME content, which reflects responses (Weidenfeld and Yirmiya 1996). Taken to- its release into the portal vessels (Chappell et al. 1986), gether, these behavioral and neuroendocrine symptoms with a concomitant elevation in plasma corticosterone resemble the characteristics of depression; therefore, we 540 R. Yirmiya et al.
NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 Figure 6.
Effects of fluoxetine on LPS-induced splenic TNF␣ (Top) and IL-1␤ (Bottom) mRNA expression. Follow- Figure 7.
Effects of chronic treatment with fluoxetine, imi- ing chronic treatment with either saline or fluoxetine (10 pramine or saline on LPS-induced expression of TNF␣ and mg/kg injected IP daily for 5 weeks), rats were injected IL-1␤. The figure summarizes the quantitative results of acutely with either saline or LPS (100 ␮g/kg). Spleens were individual sections (such as those presented in Figure 6).
removed 3 h postinjection and mRNA levels assessed by in Nine sections were quantified for each animal for each situ hybridization. Presented are representative spleen sec- cytokine. The results represent the mean (⫾S.E.M.) of seven tions taken from one animal from each of the following rats/group. *Significantly different from the corresponding groups: chronic saline treatment/acute saline injection (A),
acutely injected saline group (p ⬍ .05).
chronic fluoxetine treatment/acute saline injection (B),
chronic saline treatment/acute LPS injection (C), chronic
fluoxetine treatment/acute LPS injection (D).
the selective norepinephrine reuptake inhibitor venlafax-ine (Shen et al. 1999). The results of the present study in-dicate that chronic treatment with the SSRI fluoxetinecan attenuate LPS-induced anorexia and body-weight have recently argued that LPS (and probably other im- loss. However, in contrast with our previous findings mune challenges) produces a depressive-like episode in with imipramine, fluoxetine had no effect on LPS-induced animals, which is similar to the syndrome of "depres- suppression of open field activity. The results also indi- sion due to a general medical condition" in humans cate that LPS-induced adrenocortical activation was at- (Yirmiya 1996, 1997; Yirmiya et al. 1999).
tenuated to about the same degree by chronic treatment In support of this hypothesis, we have previously with either fluoxetine or imipramine. Taken together, demonstrated that chronic, but not acute, treatment with these findings suggest that whereas chronic treatment imipramine attenuated LPS-induced reduction in food with TCAs can effectively attenuate LPS-induced sick- consumption, body weight, social exploration, open field ness behavior symptoms, SSRIs have more limited and activity, and saccharin preference (Yirmiya 1996). A sim- variable effects on sickness behavior, but can be at least ilar attenuation of LPS-induced sickness behavior has as effective as TCAs in attenuating the effects of LPS on been recently reported following chronic administration the HPA axis.
of the TCA desipramine, but not the SSRI paroxetine or LPS induces many changes within the brain, includ- NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 Fluoxetine Attenuates Sickness Behavior ing alterations in monoaminergic systems (e.g., secre- itself produced marked sickness behavior and elevation tion of norepinephrine and serotonin) and CRH levels, of corticosterone levels. These findings are consistent which are considered as the main targets for antide- with the results of previous studies, in which marked pressants' therapeutic actions. With respect to their ef- reduction of food intake, body weight, and motor activ- fects on behavioral parameters, the fact that TCAs seem ity (McGuirk et al. 1992; Heisler et al. 1999), as well as to be superior to SSRIs (Shen et al. 1999; Yirmiya 1996, elevated corticosterone levels (Bianchi et al. 1994; Dun- and the results of the present study) suggests that anti- can et al. 1998) were found following acute fluoxetine depressant-induced changes in the noradrenergic sys- administration. In the present study, animals that were tem may be more important. However, the lack of in- acutely injected with fluoxetine did not exhibit further formation on the neurochemistry of LPS-induced changes in sickness behavior and corticosterone secre- sickness behavior does not allow speculation on the tion following LPS (with the exception of LPS-induced specific role of each monoamine. For the HPA activa- decrease of body weight in fluoxetine-treated rats).
tion, which seemed to be equally affected by fluoxetine However, these findings may represent the fact that for and imipramine, serotonergic mechanisms are proba- most parameters the effects of fluoxetine were so large bly critical (although noradrenergic mechanisms may that further alterations by LPS were not possible. This still play a role) for the following reasons. First, seroton- situation is different from the experiments with chronic ergic mechanisms are critically involved in LPS-in- treatment, in which fluoxetine by itself had only mini- duced pituitary adrenal activation (Givalois et al. 1999; mal effects, and LPS produced less anorexia, body- Guo et al. 1996). Second, chronic fluoxetine induces de- weight loss, and corticosterone secretion in fluoxetine- sensitization of hypothalamic 5-HT-1A receptors and than in saline-treated rats. Thus, any direct comparison attenuates the pituitary–adrenal response to an acute between the effects of acute and chronic fluoxetine serotonergic agonist (Raap et al. 1999). Thus, following treatments is problematic. It should be noted that al- chronic antidepressant treatment, LPS-induced seroto- though the effects of acute fluoxetine are similar to nin secretion probably results in less HPA activation.
those of other acute stressors, the effects of chronic flu- Another system that is markedly altered following oxetine treatment on the responsiveness to LPS cannot chronic antidepressant treatment is the HPA axis. For be attributed to chronic stress; whereas, exposure to example, following long (8 weeks), but not short (2 chronic stress facilitates the adrenocortical response to a weeks) treatment with either fluoxetine or imipramine, novel acute stressor (e.g., Marti et al. 1994), such as LPS, CRH mRNA was decreased by 30–48% in the hypotha- chronic fluoxetine treatment attenuated this response.
lamic PVN (Brady et al. 1991, 1992). Moreover, chronic In agreement with previous reports on the effects of treatment with fluoxetine, as well as other antidepres- LPS on body temperature in rodents (Leon et al. 1999; sants, significantly elevated the levels of glucocorticoid Paul et al. 1999; Saper 1998; Wang et al. 1997; Yirmiya et receptors in the hippocampus (Brady et al. 1991, 1992), al. 1994), we report here that in control rats and mice, which normally mediate the negative feedback re- LPS produced a biphasic effect on body temperature, sponse to stress-induced activation of the HPA axis (Sa- with an initial hypothermia, followed by a febrile polsky et al. 1984). Finally, our results are in agreement phase. In both strains, chronic treatment with fluoxet- with previous studies in experimental animals (Reul et ine completely abolished the hypothermic phase. In flu- al. 1993) and in healthy humans (Michelson et al. 1997), oxetine-treated rats, and to a lesser extent also in mice, which reported that chronic treatment with antidepres- the hyperthermic response was facilitated in time and sants markedly attenuated the pituitary-adrenal re- larger than in controls. It is possible that this effect on sponse to stressful or pharmacological challenges. Al- hyperthermia is secondary to the blockade of the hypo- though the role of CRH in mediating the anorexic thermic response; that is, without the balancing effect of effects of LPS has not been studied directly, there are in- hypothermic mechanisms, the hyperthermia is facili- dications that CRH mediates the anorexic effects of IL-1 tated in time and more pronounced. This interpretation (Bluthe et al. 1992; Uehara et al. 1989). Moreover, ample is supported by the finding that in fluoxetine-treated evidence indicates that CRH mediates LPS-induced rats, LPS-induced hyperthermia was facilitated in time adrenocortical activation (Tilders et al. 1994). Thus, it and more pronounced during the initial few hours, may be suggested that fluoxetine-induced attenuation but not at the later time points. LPS-induced hypother- of CRH neuronal activation is involved in the reduction mia involves reduced thermogenesis by macrophage- of LPS-induced anorexia and adrenocortical activation.
dependent (Derijk et al. 1994), nonvagal (Romanovsky We have previously reported that, in contrast to et al. 1997) peripheral (Saper 1998) mechanisms. Several the suppressive effect of chronic imipramine on LPS- mediators have been proposed to be involved in LPS- induced sickness behavior, acute administration of imi- induced hypothermia, including prostaglandins (Derijk pramine had no effect (Yirmiya 1996). It is difficult to et al. 1994; Wang et al. 1997), leukotriens (Paul et al.
reach a similar conclusion with respect to fluoxetine, 1999), IL-10 (Leon et al. 1999), TNF␣ and vasopressin because, in contrast to imipramine, acute fluoxetine by (Derijk and Berkenbosch 1994; Saper 1998). There is 542 R. Yirmiya et al.
NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 5 very little information on effects of antidepressants in there is evidence for differential regulation of periph- general and fluoxetine in particular on these media- eral and central cytokine production following LPS ad- tors. The results of the present study demonstrate that ministration (Sacoccio et al. 1998). Thus, in future re- chronic fluoxetine treatment did not affect splenic search, the effects of antidepressants on LPS-induced TNF␣ production. This finding is not consistent with an production of brain cytokines should be assessed.
involvement of TNF␣ in fluoxetine's effect, although it Many medical conditions are associated with a high does not rule out an effect of fluoxetine on LPS-induced prevalence of depression (Evans et al. 1996; Laghrissi- TNF␣ production in other peripheral and central tis- Tode et al. 1996), and a high incidence of antidepressant sues, which could still modulate the changes in body drug use (Egberts et al. 1997). Chronic treatment with temperature. In previous research, chronic fluoxetine antidepressants, including fluoxetine, has been found treatment resulted in reduced CSF concentrations of to be effective in alleviating the depression associated vasopressin in depressed patients (De-Bellis et al. 1993), with multiple sclerosis (Schiffer and Wineman 1990), as well as a reduction in hypothalamic vasopressin se- stroke (Lauritzen et al. 1994), HIV infection (Rabkin et cretion in rats (Altemus et al. 1992). Together, these find- al. 1994), cancer (Razavi et al. 1996), and neurodegener- ings suggest that a reduction in vasopressin secretion ative diseases (Alexopoulos 1996). Because these medi- is a possible mechanism for the effects of fluoxetine on cal conditions are also associated with dramatic im- the hypothermic response to LPS. To gain better under- mune activation and cytokine secretion (Dinarello and standing, future research should examine the effects of an- Wolff 1993; Rothwell et al. 1996; Yirmiya et al. 1999), it tidepressants on other mediators of LPS-induced changes may be suggested that at least part of the effects of flu- in body temperature.
oxetine (and possibly other antidepressants) in these The effects of antidepressants on the responsiveness conditions is in attenuating sickness behavior symptoms.
to LPS may be mediated by changes in immune re-sponse to LPS (particularly reduced production of cy-tokines), and/or by alterations in neurochemical sys- tems that mediate the effects of LPS (and the cytokinesthat are secreted following its administration) within The authors thank Edna Cohen, Roee Canaan, Inbal Goshen, the brain. As a first step in elucidating these mecha- and Anna Itzik for their help in running the experiments. This nisms, we examined the effects of fluoxetine and imi- work was supported by Grant 94-204 from the United-States- pramine on the induction of splenic cytokines following Israel Binational Science Foundation, by a grant from the Mil- LPS administration. Our findings indicate that neither ton Rosenbaum Foundation for Psychiatric Research, and bythe Center for Research on Pain, The Hebrew University of antidepressant attenuated LPS-induced expression of Jerusalem. RY is a member of the Eric Roland Center for Neu- TNF␣ and IL-1␤ mRNA in the spleen. These findings demonstrate that in contrast with the suppressive ef-fects of antidepressants on cytokine production in vitro(Sommer et al. 1995; Xia et al. 1996), chronic treatmentwith antidepressants in vivo has no effect on LPS- induced production of cytokines in the spleen. Obvi-ously, this finding does not preclude the possibility that Alexopoulos GS (1996): The treatment of depressed antidepressants produce some of their effects by modu- demented patients. J Clin Psychiat 57:14–20 lating the cytokine response for the following reasons.
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268_273_pscherer 7.8.15 8:56 Stránka 268 268/ ACTA CHIR. ORTHOP. TRAUM. ČECH., 82, 2015, Delayed Fracture Healing in Diabetics with Distal Radius Fractures Opožděné hojení zlomenin u diabetiků se zlomeninou distálního radia S. PSCHERER1, G. H. SANDMANN2, S. EHNERT3, A. K. NUSSLER3, U. STÖCKLE3, T. FREUDE3