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Noaín, Pe´rez-Milla´n et al. • Central D2Rs in Body Growth and Social Dominance J. Neurosci., March 27, 2013 • 33(13):5834 –5842 • 5837
lacDrd2KO mice of both genders, in con-trast to the effect observed in Drd2loxP/loxPcontrol mice, demonstrating the total ab-sence of functional D2Rs in lactotropes ofconditional lacDrd2KO mice ). Wealso found that haloperidol was equallyeffective lacDrd2KO and Drd2loxP/loxP control mice,in contrast to Drd2⫺/⫺ mice, which wereinsensitive to the D2R blocker's effect ), indicating that central D2R function isintact in lacDrd2KO mice. Therefore,lacDrd2KO mice are authentic lactotropeD2R-deficient mice. Body size and bodyweight curves of lacDrd2KO male micewere normal and identical to those observedin Drd2loxP/loxP male siblings ,G), aswell as GH axis parameters such as pituitaryGH and serum IGF-I levels, which were alsonormal in lacDrd2KO males ).
These results indicate that the absence ofD2Rs in pituitary lactotropes is not likely toaccount for the dwarfism found in Drd2⫺/⫺male mice.
NeuroDrd2KO mice have reduced body
weight and size
Transgenic mice expressing cre from a rat
nestin promoter were used in
combination with Drd2 loxP/loxP mice to
inactivate Drd2 alleles in neural progeni-
tors. As a result, neuroDrd2KO mice carry
null Drd2 alleles in cells of neural origin
and normally express Drd2 in other cell
types, as demonstrated at the molecular
and functional levels In situ
hybridization assays using a Drd2 exon 2
antisense riboprobe ) and [ 3H]-
nemonapride binding autoradiography
Figure 1.
LacDrd2KO mice display hyperprolactinemia and normal body growth. A, Cre-mediated td-tomato expression in
) revealed the absence of Drd2 various pituitary cell types. Immunofluorescence using primary antisera for PRL, GH, ACTH, and LH (green) performed on coronal mRNA and D2Rs, respectively, on coronal pituitary sections of Tg(Prl-cre) 1Mrub mice crossed with the cre inducible td-tomato line Ai14 (first column). Identical sections show brain sections taken from neuroDrd2KO td-tomato fluorescence (red, second column). Superimposed images show coexpression of cre and PRL but not GH (with a few
exceptions, see white arrow), ACTH or LH at lower (third column) and higher magnification (forth column). B, In situ hybridization
mice. NeuroDrd2KO mice failed to show using a Drd2 exon 2 antisense riboprobe in pituitary and brain sections of lacDrd2KO. Shown are whole pituitary sections and higher haloperidol-induced catatonia, in con- magnification of the anterior lobe and coronal brain sections (C) at the level of striatum and higher magnification. D, Serum PRL
trast to Drd2 loxP/loxP mice, but similar to levels in Drd2 loxP/loxP (n ⫽ 10) and lacDrd2KO (n ⫽ 11) females receiving saline (-) or haloperidol 3 mg/kg intraperitoneally (HAL, Drd2 ⫺/⫺ mice ), indicating the ⫹). Two-way ANOVA *p ⬍ 0.01 versus saline-treated Drd2loxP/loxP mice. E, Haloperidol (1.5 mg/kg, i.p.)-induced catatonia.
absence of functional central D2Rs. In ad- Latency to remove the front paws from an elevated horizontal bar was evaluated in Drd2 loxP/loxP (n ⫽ 4), lacDrd2KO (n ⫽ 5), and dition, D2R levels in the pituitary glands Drd2 ⫺/⫺ (n ⫽ 3) male mice. *p ⬍ 0.01 versus saline for each genotype. F, Nose to anus length of neuroDrd2KO and Drd2 loxP/loxP
of neuroDrd2KO mice appeared to be male littermates. G, Body weight curves of Drd2 loxP/loxP and lacDrd2KO male littermates. No significant differences were found
similar to those observed in Drd2 loxP/loxP between genotypes. H, Radioimmunoassay showed normal pituitary GH and serum IGF-I levels in lacDrd2KO mice relative to their
mice , B) and functionally nor- Drd2 loxP/loxP littermates. Bars and circles represent the mean ⫾ SEM.
mal, as evidenced by the normal prolactinlevels observed in neuroDrd2KO mice lacDrd2KO mice lacked D2Rs in pituitary lactotropes while re- ) and the increase observed after receiving a 3 mg/kg taining normal Drd2 expression in pituitary melanotropes of the intraperitoneal haloperidol injection ). Therefore, intermediate lobe ) and in all brain areas examined neuroDrd2KO mice lack D2Rs in the CNS but retain normally ). To investigate whether ablation of D2R in lacDrd2KO mice functional D2Rs in the anterior pituitary. NeuroDrd2KO male was complete, we measured basal serum PRL levels and, more mice showed reduced body weight ) and length ) importantly, the acute effect of the D2R blocker haloperidol.
compared with their Drd2loxP/loxP male littermates. Body weight of LacDrd2KO mice displayed hyperprolactinemia that was par- neuroDrd2KO mice was 14.2% lower than Drd2loxP/loxP at 2 months ticularly significant in females ). The D2R antagonist halo- of age and this difference increased over time, being 21.7% lower at 6 peridol (3 mg/kg, i.p.) failed to increase serum PRL levels in months ). Body size of neuroDrd2KO mice at weaning was

5838 • J. Neurosci., March 27, 2013 • 33(13):5834 –5842
Noaín, Pe´rez-Milla´n et al. • Central D2Rs in Body Growth and Social Dominance Figure 2.
NeuroDrd2KO mice have reduced body weight and size. A, B, In situ hybridization
assay using a Drd2 exon 2 [ 35S]-UTP antisense riboprobe (A) and [ 3H]-nemonapride binding
autoradiography (B) in brain and pituitary coronal sections of Drd2 loxP/loxP and neuroDrd2KO
mice. Sections of Drd2 ⫺/⫺ mice were included as negative controls. C, Haloperidol (HAL, 1.5
mg/kg, i.p.)-induced catatonia. Latency to remove the front paws from an elevated horizontal
bar was evaluated in neuroDrd2KO mice and compared with Drd2 loxP/loxP (n ⫽ 6) and
Drd2 ⫺/⫺ (n ⫽ 6) mice. *p ⬍ 0.01 haloperidol versus saline for each genotype. D, Serum PRL
Figure 3.
NeuroDrd2KO mice display an impaired GH axis. A, Immunofluorescence using an
levels of female mice (n ⫽ 10 –12) receiving haloperidol (HAL, 3 mg/kg, i.p.) or saline. *p ⬍ anti-hGH primary antiserum performed on 4 ␮m pituitary slices of Drd2 loxP/loxP (n ⫽ 3) and 0.05 haloperidol versus saline for each genotype. E, Body weight curves of neuroDrd2KO and
neuroDrd2KO (n ⫽ 3) mice showed fewer pituitary somatotropes (green) in neuroDrd2KO mice Drd2 loxP/loxP male mice (n ⫽ 7–12). Repeated-measures ANOVA genotype: F relative to control mice. Cell nuclei were stained with propidium iodide (red). B, Right, Percent-
p ⬍ 0.005. *p ⬍ 0.01 neuroDrd2KO versus Drd2 loxP/loxP littermates, post hoc Fisher analysis. F,
age of GH-positive cells, one-way ANOVA (OWA): F ⫽ 18.01, *p ⬍ 0.02. Left, radioimmu- Nose to anus length of neuroDrd2KO and Drd2 loxP/loxP male mice (n ⫽ 9 –11) measured 3, 6, noassay of GH concentration in anterior pituitary glands of Drd2 loxP/loxP (n ⫽ 7) and and 9 weeks after birth. Repeated-measures ANOVA genotype: F ⫽ 21.35, p ⬍ 0.005.
neuroDrd2KO (n ⫽ 10) siblings (OWA: F ⫽ 7.54, *p ⬍ 0.05). C, Right, relative hypotha-
*p ⬍ 0.05 for neuroDrd2KO versus age-matched Drd2 loxP/loxP littermates, post hoc Fisher anal- lamic mRNA levels of Ghrh in Drd2 loxP/loxP (n ⫽ 9) and neuroDrd2KO (n ⫽ 9) mice determined ysis. G, Food consumption was measured for 7 consecutive days in adult neuroDrd2KO and
by semiquantitative real-time PCR (OWA: F ⫽ 6.32, *p ⬍ 0.05). Left, relative hypotha- Drd2 loxP/loxP (n ⫽ 5–10) mice. Averaged food intake (left) and food intake relative to animal lamic mRNA levels of Sst from Drd2 loxP/loxP and neuroDrd2KO mice (n ⫽ 13). Samples were weight (right) is plotted. Bars and circles represent the mean ⫾ SEM.
normalized to cyclophilin mRNA. Bars denote the mean ⫾ SEM. All mice were 6 –9 months old.
the nervous system develop an immature GH axis that limits the already significantly lower (10.2%) than control littermates and the body growth program.
difference persisted until reaching adulthood ). The de-creased growth exhibited by neuroDrd2KO male mice was not NeuroDrd2KO mice have low levels of the GH-dependent
due to reduced feeding, because the daily food intakes of liver proteins IGF-I and MUP
neuroDrd2KO and Drd2loxP/loxP siblings were similar ).
To determine whether the impaired GH axis found in Therefore, these results demonstrate that the sole absence of D2Rs in neuroDrd2KO mice has downstream consequences in GH- the nervous system impairs normal growth rates and produces dependent liver hormones, we measured IGF-I and MUP levels.
smaller mice.
Serum IGF-I levels were 18.7% lower in neuroDrd2KO malemice compared with those found in their control siblings NeuroDrd2KO mice have an impaired GH axis
), whereas MUP levels were markedly reduced (45.6%) in the We analyzed the relative number of somatotropes and GH con- urine of neuroDrd2KO male mice ). Interestingly, MUP tent in pituitaries from neuroDrd2KO and control male mice.
levels of the male mutants were similar to those found in the urine Immunofluorescence performed on pituitary slices taken from of their Drd2 loxP/loxP female littermates ). In contrast, neuroDrd2KO male mice showed a 28.1% shortfall of GH- serum testosterone levels in neuroDrd2KO male mice were sim- positive cells compared with control male mice , B). In ilar to those found in control male littermates, in clear contrast to agreement, a great reduction (63.2%) in GH content was deter- testosterone levels measured in adult wild-type females and cas- mined by radioimmunoassay in pituitaries from neuroDrd2KO trated wild-type males ). These results suggest that the mice ). Analysis of the hypothalamic content of Ghrh and reduced MUP levels were primarily the consequence of an im- Sst mRNAs using a semiquantitative RT-PCR assay showed that paired GH axis.
neuroDrd2KO males had 30% lower Ghrh mRNA levels com-pared with their Drd2 loxP/loxP littermates ), whereas hy- Central D2Rs, social dominance, and territorial behavior
pothalamic Sst mRNA levels were not significantly altered The higher MUP content typically found in the urine of adult ). These results demonstrate that male mice lacking D2Rs in males is thought to promote a variety of male-specific behaviors

Noaín, Pe´rez-Milla´n et al. • Central D2Rs in Body Growth and Social Dominance J. Neurosci., March 27, 2013 • 33(13):5834 –5842 • 5839
Figure 4.
NeuroDrd2KOmice have reduced IGF-I and MUPs and normal testostene levels. A,
Radioimmunoassay of serum IGF-I levels in neuroDrd2KO (n ⫽ 14) and Drd2 loxP/loxP (n ⫽ 20)mice (one-way ANOVA [OWA]: F from male Drd2 loxP/loxP (n ⫽ 17) and neuroDrd2KO (n ⫽ 12) adult mice and from theirDrd2 loxP/loxP (n ⫽ 16) and neuroDrd2KO (n ⫽ 9) female littermates. Two-way ANOVA showedsignificant main effects both for sex and genotype (sex effect: F ⫽ 26.68, *p ⬍ 0.00001 and genotype effect: (1,50) ⫽ 17.84, *p ⬍ 0.0005). C, Serum testosterone levels determined
by radioimmunoassay in neuroDrd2KO male mice (n ⫽ 9) compared with their Drd2 loxP/loxP
male littermates (n ⫽ 9). Castrated wild-type adult male mice (n ⫽ 4) and wild-type adult
females (n ⫽ 5) were included as negative controls (OWA: F
⫽ 5.0673, p ⬍ 0.008). *p ⬍ 0.05 for wild-type castrated males and wild-type females versus Drd2 loxP/loxP and neuroDrd2KOmale mice, post hoc Fisher's LSD. Bars represent the mean ⫾ SEM.
that are critical for reproductive fitness, such as social recogni-tion, territorial scent-marking, and aggression To evaluate whether the feminized lowerMUP levels found in the urine of neuroDrd2KO male mice mod-ify these evolutionarily conserved behaviors, we designed a seriesof behavioral tests. First, we examined how adult male C57BL/6JWT mice reacted when confronted with either Drd2 loxP/loxP orneuroDrd2KO male adults in a social dominance experimentalparadigm called the double entrance tube test Normally in this test, when two adult male mice are placed at theopposite extremes of a cylindrical tube, they both gain access tothe center and, after close mutual inspection, one moves forward,forcing the other to walk backwards until stepping down from the Figure 5.
Urine from adult neuroDrd2KO males fails to promote social and territorial behav- end of the tube , right). However, when confronting fe- iors. A, Left, C57BL/6J adult females, Drd2 loxP/loxP adult males and neuroDrd2KO adult males
males, adult male mice do not show this behavior and back out were challenged with C57BL/6J adult males in a social-dominance tube test. Fifteen trials were spontaneously without showing signs of social dominance. When performed for each genotype. The behavior of C57BL/6J males was significantly different when we challenged C57BL/6J adult males with sex- and age-matched confronting C57BL/6J females compared with Drd2 loxP/loxP males (one-tailed ␹ 2 *p ⬍ 0.05).
Drd2 loxP/loxP mice, we observed a similar number of retreats in C57BL/6J males confronting neuroDrd2KO males showed an intermediate phenotype because mice of each genotype: C57BL/6J males backed out from the tube their behavior was not different from that observed when confronting either C57BL/6J females in seven of 15 trials, whereas Drd2 loxP/loxP males backed out in the or Drd2 loxP/loxP males (one-tailed ␹ 2 p ⬎ 0.05). Right, Representative images of a typical test:(1) two mice approaching the center of the tube, (2) mutual inspection, and (3) the mouse on other eight ). Conversely, when challenged with WT fe- the right pushes the other out. B, Intruder-resident test. Isolated C57BL/6J adult male residents
males, C57BL/6J adult males backed out of the tube in 12 of 15 (n ⫽ 18) were challenged with C57BL/6J castrated males swabbed on their backs and genital encounters without showing social dominance behavior areas with saline (n ⫽ 6), urine from Drd2 loxP/loxP adult male mice (n ⫽ 6), or urine from ). Interestingly, C57BL/6J adult male mice challenged against neuroDrd2KO adult males (n ⫽ 6). Left, latency to the first resident's attack (one-way ANOVA sex- and age-matched neuroDrd2KO mice exhibited behavioral ⫽ 4.55, p ⬍ 0.05). *p ⬍ 0.05 compared with saline, post hoc Fisher analysis.
responses similar to those shown when challenged against Right, total time spent attacking (Kruskal-Wallis OWA on ranks: H ⫽ 6.65 with 2 degrees of C57BL/6J females. In this case, C57BL/6J males backed out of the freedom, p ⬍ 0.05). *p ⬍ 0.05 compared with saline, post hoc Dunnett's comparison. C, Scent
tube spontaneously in 10 of 15 encounters and moved forward marking test. Left, C57BL/6J adult male mice were challenged in a cage previously occupied by neuroDrd2KO males in only five trials ). The different a Drd2flox/flox (n ⫽ 5) or a neuroDrd2KO (n ⫽ 8) adult male mouse. Urine marks made by the reaction of C57BL/6J adult males toward neuroDrd2KO adult visitor during 5 min were counted under UV light (OWA: F 14.66, *p ⬍ 0.005). Right, two representative examples of spotted urine are shown. Bars represent the mean ⫾ SEM.
males compared with that observed when confronting theirDrd2 loxP/loxP littermates could be due, at least in part, to the rel-atively smaller size of neuroDrd2KO mice and/or to their lower of the intruder, resident mice exhibited aggressive behavior that concentration of urinary MUP. To further investigate this lat- varied in latency and intensity depending on the nature of the ter hypothesis, we tested the ability of the urine taken from liquid swabbed on the intruder. Latency to the first attack was Drd2 loxP/loxP and neuroDrd2KO male adults to promote territo- 65 ⫾ 17 s when castrated mice received urine from Drd2loxP/loxP rial male-to-male aggression in an adapted version of the mice, and this value increased significantly when mice were intruder-resident aggression test To swabbed with either saline or urine taken from neuroDrd2KO this end, each C57BL/6J adult male resident mouse reared in male adult mice , left). Moreover, 3 of 6 intruders isolation for 1 month was challenged with a castrated adult WT swabbed with saline and 3 of 6 intruders swabbed with male intruder mouse placed into the resident's cage. Each cas- neuroDrd2KO male mice urine received no attacks from the res- trated mouse was swabbed on its back and genital area with ident males during the 3 min test. Therefore, when resident males saline or freshly collected urine taken from Drd2 loxP/loxP or were confronted with castrated males swabbed with urine taken neuroDrd2KO adult male mice. Upon close olfactory inspection from neuroDrd2KO mice, the latency to the first attack increased 5840 • J. Neurosci., March 27, 2013 • 33(13):5834 –5842
Noaín, Pe´rez-Milla´n et al. • Central D2Rs in Body Growth and Social Dominance markedly and the time spent attacking decreased compared with neurons of the indirect extrapyramidal pathway castrated intruders swabbed with urine taken from Drd2 loxP/loxP because these two conditional Drd2 knock-out models male adults , right). Finally, we performed a third exper- exhibited normal growth curves. Because D2Rs couple to inhib- iment to investigate whether C57BL/6J adult male mice displayed itory signals that diminish neuron activity, a candidate neuronal different scent-marking behavior when placed in a cage where a type is a group of periventricular SST neurons that make synaptic sex- and age-matched Drd2 loxP/loxP or a neuroDrd2KO mouse contacts with GHRH arcuate neurons to exert a tonic inhibition was previously housed. A stereotyped behavior commonly ob- of Ghrh expression and GHRH release served when a male mouse detects odorant cues from another and control the rhyth- adult conspecific male is the induction of widespread urine de- mic oscillations of GHRH neuronal firing that establish the male positions that are interpreted as increased scent-marking activity pattern of GH release to cover the area with its own scent This However, a semiquantitative RT-PCR determination only behavior is greatly reduced when the adult male is placed in a found a tendency for increased hypothalamic Sst mRNA levels location previously visited only by a castrated or a subordinate in neuroDrd2KO mice that never reached statistical signifi- male By measuring the number of urinary spots, we determined that C57BL/6J adult male mice The present study demonstrates that central D2Rs regulate a reared in isolation displayed greater scent-marking activity when neuroendocrine/exocrine cascade that controls body growth and placed in a cage previously occupied by a Drd2 loxP/loxP mouse participates in male-to-male territorial behavior. This multistep rather than by a neuroDrd2KO male adult littermate ).
signaling cascade initiates in brain centers that regulate the hypo- These results indicate that wild-type male adults do not exhibit thalamic level Ghrh expression and GHRH release, which then typical male-to-male social and territorial behavior when ex- relays to the pituitary to control the pattern of GH release. GH posed to neuroDrd2KO males or to their urine. Therefore, cen- surges from the pituitary of male rodents are characterized by tral D2Rs are necessary for the masculinization of the GH axis high-amplitude and low-frequency pulses intercalated among and, therefore, for the production of higher levels of pheromones long nadir periods, which permit the resensitization of GH recep- typically found in the urine of normal males.
tor signaling by a Janus kinase/signal transducer and activation oftranscription (JAK-STAT) complex that specifically involves STAT5a and STAT5b In this study, we conducted a differential cell-specific ablation Only when long interpulse strategy to eliminate D2Rs selectively from pituitary lactotropes nadirs of GH levels are attained in puberal males are high tran- and, independently, from brain neurons. Whereas lacDrd2KO scriptional rates of Igf1 and other somatomedins that promote mice displayed normal body growth, neuroDrd2KO mice body growth observed in the liver and extrahepatic sites showed deficits in the GH axis that led to reduced body weight The lower serum levels of IGF-I observed in and length, recapitulating the dwarf phenotype observed in neuroDrd2KO mice are consistent with their smaller body size Drd2 ⫺/⫺ mutants. Based on the analysis of lacDrd2KO mice, we and weight, a phenotype that in the wild could be detrimental for concluded that the absence of lactotrope D2R is not responsible reproductive fitness due to reduced competitiveness among for the altered lactotrope/somatotrope ratio previously observed males. The sexually dimorphic liver proteins that depend on the in Drd2 ⫺/⫺ mice, ruling out its participation in the termi- male pattern of GH release is manifold and include MUPs nal differentiation of these two cell types. Furthermore, This group of pheromones se- neuroDrd2KO mice showed fewer somatotropes, diminished pi- creted into the blood and then excreted in the urine are known to tuitary GH content, and lower levels of hypothalamic Ghrh ex- promote social recognition and territorial dominance between pression. Therefore, central D2Rs are essential for the normal males Therefore, an maturation of the GH axis and full development of the body emerging downstream finding disclosed by this study is that the growth plan. Selective ablation of D2Rs in the brain while main- urine of mice lacking D2Rs in the nervous system showed a lower taining normal Drd2 expression in the pituitary was achieved by content of MUP and, therefore, lost the signaling cues that trigger using a strain of transgenic mice expressing cre from a nestin territorial behavior in other males. Typically, MUP levels in males promoter. A similar strategy has been used previously to elimi- are much higher than in females and this nate the transcription factor CREB from the CNS difference not only depends on the sexually dimorphic pattern because the nestin gene (Nes) is expressed in of GH pulsatility, but also on testosterone concentration, be- embryonic dividing cells derived from the neuroectoderm but cause castrated males have feminized MUP levels and females not from the oral ectoderm treated with testosterone display male MUP levels and is particularly absent from progenitors and differ- Because testosterone concentration was normal in entiated cells of all anterior pituitary cell lineages neuroDrd2KO mice, the reduced MUP levels are likely to be the In fact, neuroDrd2KO mice sole consequence of an impaired GH axis resulting from lack of showed normal Drd2 expression in the intermediate and anterior Drd2 expression in the CNS. MUPs are encoded by ⬎30 genes, lobe of the pituitary but complete absence of expression in the mainly synthetic, in a locus of mouse chromosome 4 CNS. The differential response to haloperidol-induced hyperp- The large allelic variation at this rolactinemia and catatonia observed in lacDrd2KO and locus and the relative amount of each MUP in the mouse urine neuroDrd2KO mice confirmed, at the functional level, our suc- contributes to generate a great combinatorial diversity of individ- cessful attempt to inactivate Drd2 expression selectively in the ual patterns that are believed to provide, in the wild, a unique pituitary or in the brain.
biological identity card for each conspecific Identifying the Drd2-expressing neurons in the CNS control- In fact, male mice use MUPs to scent-mark and counter- ling the maturation of the GH axis is still pending, although our mark territories The ability of MUPs own studies ruled out the participation of DA neurons expressing to create a chemical barrier for territorial defense and to promote D2 autoreceptors and striatal medium spiny territorial protection adds to the adaptive behavioral inventory Noaín, Pe´rez-Milla´n et al. • Central D2Rs in Body Growth and Social Dominance J. Neurosci., March 27, 2013 • 33(13):5834 –5842 • 5841
that males use to gain access to receptive females. Therefore, this García-Tornadu I, Díaz-Torga G, Risso GS, Silveyra P, Cataldi N, Ramirez study shows that central D2R regulate a neuroendocrine- MC, Low MJ, Libertun C, Becu´-Villalobos D (2009) Hypothalamic exocrine cascade that controls the maturation of the GH axis and orexin, OX1, alphaMSH, NPY and MCRs expression in dopaminergicD2R knockout mice. Neuropeptides 43:267–274. downstream signals that play important roles in territorial behav- Gleiberman AS, Michurina T, Encinas JM, Roig JL, Krasnov P, Balordi F, ior and competition between adult males.
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