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• W2012949542 abstract "Abnormal signaling by retinoids or n-3 polyunsaturated fatty acids has been implicated in clinical depression. The converging point in activities of these two classes of molecules is transcriptional activation of retinoid X receptors (Rxr). We show here that ablation of Rxrγ in mice leads to depressive-like behaviors including increased despair and anhedonia, which were accompanied by reduced expression of dopamine D2 receptor in the shell of nucleus accumbens (NAc) and altered serotonin signaling. While abnormal serotonin signaling is not sufficient to generate the depressive behaviors, increasing D2r expression by chronic fluoxetine (Prozac) treatment or adenoassociated virus type2 (AAV2) mediated expression of Rxrγ or D2r in the NAc of Rxrγ−/− mice normalizes depressive-like behaviors in Rxrγ−/− animals. Conversely, NAc infusion of raclopride, a D2r antagonist prevents AAV2-Rxrγ-mediated rescue of despair behaviors in Rxrγ−/− mice. Combined, our data argue that control of NAc D2r expression is critical for Rxrγ-mediated modulation of affective behaviors. Abnormal signaling by retinoids or n-3 polyunsaturated fatty acids has been implicated in clinical depression. The converging point in activities of these two classes of molecules is transcriptional activation of retinoid X receptors (Rxr). We show here that ablation of Rxrγ in mice leads to depressive-like behaviors including increased despair and anhedonia, which were accompanied by reduced expression of dopamine D2 receptor in the shell of nucleus accumbens (NAc) and altered serotonin signaling. While abnormal serotonin signaling is not sufficient to generate the depressive behaviors, increasing D2r expression by chronic fluoxetine (Prozac) treatment or adenoassociated virus type2 (AAV2) mediated expression of Rxrγ or D2r in the NAc of Rxrγ−/− mice normalizes depressive-like behaviors in Rxrγ−/− animals. Conversely, NAc infusion of raclopride, a D2r antagonist prevents AAV2-Rxrγ-mediated rescue of despair behaviors in Rxrγ−/− mice. Combined, our data argue that control of NAc D2r expression is critical for Rxrγ-mediated modulation of affective behaviors. Retinoid X receptor gamma (Rxrg) controls despair and hedonic behaviors in mice Nucleus accumbens shell is the key structure in Rxrg control of affective behaviors Rxrg control of affective behaviors involves dopamine D2 receptor functions in NAcSh Dopaminergic signaling and in particular its mesolimbic pathway plays an important, reinforcing role in regulation of motivated behaviors. Abnormally low dopaminergic signaling has been suggested to be involved in clinical depression (Millan, 2006Millan M.J. Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.Pharmacol. Ther. 2006; 110: 135-370Crossref PubMed Scopus (440) Google Scholar, Nestler and Carlezon, 2006Nestler E.J. Carlezon Jr., W.A. The mesolimbic dopamine reward circuit in depression.Biol. Psychiatry. 2006; 59: 1151-1159Abstract Full Text Full Text PDF PubMed Scopus (1396) Google Scholar). Classical antidepressant treatments increase dopaminergic tone and its signaling via different dopamine receptor subtypes, which suggests a direct implication of dopamine in the efficiency of such treatments (Renard et al., 2001Renard C.E. Fiocco A.J. Clenet F. Hascoet M. Bourin M. Is dopamine implicated in the antidepressant-like effects of selective serotonin reuptake inhibitors in the mouse forced swimming test?.Psychopharmacology (Berl.). 2001; 159: 42-50Crossref PubMed Scopus (83) Google Scholar, Valentini et al., 2004Valentini V. Frau R. Di Chiara G. Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine.J. Neurochem. 2004; 88: 917-927Crossref PubMed Scopus (76) Google Scholar, Willner et al., 2005Willner P. Hale A.S. Argyropoulos S. Dopaminergic mechanism of antidepressant action in depressed patients.J. Affect. Disord. 2005; 86: 37-45Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). The dopaminergic reuptake inhibitor, Bupropion, has been found effective as an antidepressant treatment (Foley et al., 2006Foley K.F. DeSanty K.P. Kast R.E. Bupropion: pharmacology and therapeutic applications.Expert Rev. Neurother. 2006; 6: 1249-1265Crossref PubMed Scopus (135) Google Scholar), although its actions also implicate noradrenergic transmission. Furthermore, some of the dopaminergic receptor ligands, such as bromocriptine and pergolide or pramipexole, are effective in the treatment of depression either as a monotherapy or as adjuvants (Corrigan et al., 2000Corrigan M.H. Denahan A.Q. Wright C.E. Ragual R.J. Evans D.L. Comparison of pramipexole, fluoxetine, and placebo in patients with major depression.Depress. Anxiety. 2000; 11: 58-65Crossref PubMed Scopus (341) Google Scholar, Mattes, 1997Mattes J.A. Pergolide to augment the effectiveness of antidepressants: clinical experience and a small double-blind study.Ann. Clin. Psychiatry. 1997; 9: 87-88Crossref PubMed Google Scholar, Theohar et al., 1982Theohar C. Fischer-Cornelssen K. Brosch H. Fischer E.K. Petrovic D. A comparative, multicenter trial between bromocriptine and amitriptyline in the treatment of endogenous depression.Arzneimittelforschung. 1982; 32: 783-787PubMed Google Scholar). Although the dopamine receptor specificity of these agents is variable, all of them act as agonists of dopamine D2 receptor (D2r), which suggests that this receptor plays a particular role in the regulation of affective behaviors. This possibility is further supported by preclinical studies in rodent models used for research on depression. Thus, chronic mild stress leads to a reduction of D2r expression in the nucleus accumbens (Willner, 1997Willner P. The mesolimbic dopamine system as a target for rapid antidepressant action.Int. Clin. Psychopharmacol. 1997; 12: S7-S14Crossref PubMed Scopus (206) Google Scholar), and activation of D2 receptors has an anti-depressant action in animal models of despair (Brocco et al., 2006Brocco M. Dekeyne A. Papp M. Millan M.J. Antidepressant-like properties of the anti-Parkinson agent, piribedil, in rodents: mediation by dopamine D2 receptors.Behav. Pharmacol. 2006; 17: 559-572Crossref PubMed Scopus (40) Google Scholar, Siuciak and Fujiwara, 2004Siuciak J.A. Fujiwara R.A. The activity of pramipexole in the mouse forced swim test is mediated by D2 rather than D3 receptors.Psychopharmacology (Berl.). 2004; 175: 163-169Crossref PubMed Scopus (55) Google Scholar). Moreover, chronic antidepressant treatments including selective serotonin reuptake inhibitors (SSRIs), which primarily modulate serotonergic transmission, can also increase D2r expression in humans and rodents (Ainsworth et al., 1998Ainsworth K. Smith S.E. Zetterström T.S. Pei Q. Franklin M. Sharp T. Effect of antidepressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat.Psychopharmacology (Berl.). 1998; 140: 470-477Crossref PubMed Scopus (94) Google Scholar, Dziedzicka-Wasylewska et al., 1997Dziedzicka-Wasylewska M. Rogoz R. Klimek V. Maj J. Repeated administration of antidepressant drugs affects the levels of mRNA coding for D1 and D2 dopamine receptors in the rat brain.J. Neural Transm. 1997; 104: 515-524Crossref PubMed Scopus (58) Google Scholar, Larisch et al., 1997Larisch R. Klimke A. Vosberg H. Löffler S. Gaebel W. Müller-Gärtner H.W. In vivo evidence for the involvement of dopamine-D2 receptors in striatum and anterior cingulate gyrus in major depression.Neuroimage. 1997; 5: 251-260Crossref PubMed Scopus (103) Google Scholar). In line with such findings, an inhibition of D2r in human and animal models prevents antidepressant activities of fluoxetine (Prozac) and/or other antidepressants (Willner et al., 2005Willner P. Hale A.S. Argyropoulos S. Dopaminergic mechanism of antidepressant action in depressed patients.J. Affect. Disord. 2005; 86: 37-45Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, and references therein). The expression of D2r is modulated at the transcriptional level by retinoic acid (RA), an active form of vitamin A (Krezel et al., 1998Krezel W. Ghyselinck N. Samad T.A. Dupé V. Kastner P. Borrelli E. Chambon P. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice.Science. 1998; 279: 863-867Crossref PubMed Scopus (290) Google Scholar, Samad et al., 1997Samad T.A. Krezel W. Chambon P. Borrelli E. Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family.Proc. Natl. Acad. Sci. USA. 1997; 94: 14349-14354Crossref PubMed Scopus (178) Google Scholar). Such control implicates activities of retinoic acid receptors (Rarα, Rarβ, Rarγ) and retinoid X receptors (Rxrα, Rxrβ, Rxrγ), which in the form of heterodimers act as transcription factors and mediate RA signaling in vivo (Kastner et al., 1997Kastner P. Mark M. Ghyselinck N. Krezel W. Dupé V. Grondona J.M. Chambon P. Genetic evidence that the retinoid signal is transduced by heterodimeric Rxr/Rar functional units during mouse development.Development. 1997; 124: 313-326Crossref PubMed Google Scholar). Rarβ and Rxrγ are the predominant retinoid receptors expressed in the striatum, including the nucleus accumbens (Krezel et al., 1999Krezel W. Kastner P. Chambon P. Differential expression of retinoid receptors in the adult mouse central nervous system.Neuroscience. 1999; 89: 1291-1300Crossref PubMed Scopus (186) Google Scholar, Zetterström et al., 1999Zetterström R.H. Lindqvist E. Mata de Urquiza A. Tomac A. Eriksson U. Perlmann T. Olson L. Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid.Eur. J. Neurosci. 1999; 11: 407-416Crossref PubMed Scopus (208) Google Scholar). Concomitant ablation of these receptors in Rarβ/Rxrγ double-knockout mice leads to strong reduction of D2r expression in the dorsal and ventral striatum and marked locomotor deficits (Krezel et al., 1998Krezel W. Ghyselinck N. Samad T.A. Dupé V. Kastner P. Borrelli E. Chambon P. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice.Science. 1998; 279: 863-867Crossref PubMed Scopus (290) Google Scholar). The involvement of murine retinoid receptors in the control of dopaminergic signaling in the striatum might suggest a potential role of the retinoid pathway in modulation of affective behaviors. Such modulation is further suggested by clinical data on depression associated with altered retinoid signaling in acne vulgaris patients treated with isotretinoin (Bremner and McCaffery, 2008Bremner J.D. McCaffery P. The neurobiology of retinoic acid in affective disorders.Prog. Neuropsychopharmacol. Biol. Psychiatry. 2008; 32: 315-331Crossref PubMed Scopus (121) Google Scholar). Rxr's were also proposed to mediate genomic actions of n-3 polyunsaturated fatty acids (n-3 PUFAs) (de Urquiza et al., 2000de Urquiza A.M. Liu S. Sjöberg M. Zetterström R.H. Griffiths W. Sjövall J. Perlmann T. Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain.Science. 2000; 290: 2140-2144Crossref PubMed Scopus (623) Google Scholar, Lengqvist et al., 2004Lengqvist J. Mata De Urquiza A. Bergman A.C. Willson T.M. Sjövall J. Perlmann T. Griffiths W.J. Polyunsaturated fatty acids including docosahexaenoic and arachidonic acid bind to the retinoid X receptor alpha ligand-binding domain.Mol. Cell. Proteomics. 2004; 3: 692-703Crossref PubMed Scopus (215) Google Scholar). Such functions of Rxrs could be directly relevant for the pathology of affective disorders, as decreased n-3 PUFA signaling has been suggested to be associated with depression and use of n-3 PUFAs such as docosahexaenoic acid or eicosapentaenoic acid were reported beneficial in clinical conditions (Logan, 2004Logan A.C. Omega-3 fatty acids and major depression: a primer for the mental health professional.Lipids Health Dis. 2004; 3: 25Crossref PubMed Scopus (103) Google Scholar, Peet and Stokes, 2005Peet M. Stokes C. Omega-3 fatty acids in the treatment of psychiatric disorders.Drugs. 2005; 65: 1051-1059Crossref PubMed Scopus (197) Google Scholar) and in animal models used in research on depression (Carlezon et al., 2005Carlezon Jr., W.A. Mague S.D. Parow A.M. Stoll A.L. Cohen B.M. Renshaw P.F. Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats.Biol. Psychiatry. 2005; 57: 343-350Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, Naliwaiko et al., 2004Naliwaiko K. Araújo R.L. da Fonseca R.V. Castilho J.C. Andreatini R. Bellissimo M.I. Oliveira B.H. Martins E.F. Curi R. Fernandes L.C. Ferraz A.C. Effects of fish oil on the central nervous system: a new potential antidepressant?.Nutr. Neurosci. 2004; 7: 91-99Crossref PubMed Scopus (52) Google Scholar). We have combined pharmacological and genetic approaches to address the role of retinoid receptors in control of affective behaviors and implication of dopaminergic signaling in such control. To address the contribution of retinoid receptors in control of despair behaviors we have studied the effects of the loss of function of Rarβ and/or Rxrγ in mice on performance in the forced swim test. Concomitant ablation of Rarβ and Rxrγ in Rarβ−/−Rxrγ−/− double null mutant mice led to a marked increase of the immobility time, which attained 129 ± 4.3 s and was significantly longer (p < 0.001) than in wild-type (WT) control mice, which remained immobile for 71 ± 6.2 s (Figure 1A ). The increased immobility in the double-mutant mice was principally due to the loss of function of Rxrγ, since single Rxrγ−/− mutants displayed similar high immobility time of 117 ± 4 s, whereas inactivation of Rarβ did not affect immobility time in this task (64.9 ± 6.8 s; p > 0.05). An abnormal locomotor behavior is unlikely to account for the increased immobility time of Rxrγ−/− mice in the forced swim test, since Rxrγ−/− mice did not differ from their WT littermates with respect to spontaneous locomotion in actimetric cages, novelty-induced locomotion in the open field test, or locomotor coordination in the rotarod task (Krezel et al., 1998Krezel W. Ghyselinck N. Samad T.A. Dupé V. Kastner P. Borrelli E. Chambon P. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice.Science. 1998; 279: 863-867Crossref PubMed Scopus (290) Google Scholar; see Figure S1 available online). Since despair behaviors belong to the core symptoms of depression, we have explored whether antidepressant treatment could improve the performance of Rxrγ−/− mice. In agreement with previous reports of SSRI activities in C57BL6J and 129SV mouse strains (Dulawa et al., 2004Dulawa S.C. Holick K.A. Gundersen B. Hen R. Effects of chronic fluoxetine in animal models of anxiety and depression.Neuropsychopharmacology. 2004; 29: 1321-1330Crossref PubMed Scopus (466) Google Scholar), a 21 day chronic treatment with fluoxetine at the dose of 20 mg/kg/24hr did not affect performance of WT mice in the forced swim test, but such treatment reversed the despair behavior in Rxrγ−/− mice (Figure 1B), as illustrated by a significant genotype × fluoxetine treatment interaction (F[1,35] = 23.2, p < 0.001). Thus, high immobility of vehicle treated Rxrγ−/− mice was reduced in fluoxetine treated Rxrγ−/− animals, which behaved comparably to vehicle treated WT mice (Figure 1B). To better evaluate the involvement of retinoid receptors in the control of affective behaviors, we investigated hedonic behaviors in the sucrose preference test in Rarβ−/− and Rxrγ−/− single and compound mutant mice. During the active, night phase of the circadian cycle WT mice displayed clear preference for a 1% sucrose solution as compared to plain water, since sucrose represented 91.3% ± 2.7% of total liquid consumption. In compound Rarβ−/−Rxrγ−/− mutant mice, such a preference was absent as sucrose consumption reached 58.1% ± 10.6% of total liquid intake (Figure 2A ), which was significantly less than preference in WT mice (p < 0.05) and not different from a chance level of 50% (t = −0.1, ns, one-group t test). Such anhedonic behavior was due to ablation of Rxrγ, since Rxrγ single null mutants displayed similar loss of sucrose preference and consumed 57.8% ± 10.8% of sucrose solution, whereas Rarβ−/− mice consumed sucrose solution at 92% ± 2.1% and were indistinguishable from their WT controls. The total liquid intake during the sucrose preference test was not different between WT and mutant mice (4.6 ± 0.2 g for WT, 4.9 ± 0.3 for Rarβ−/−, 4.9 ± 0.2 for Rxrγ−/− and 5.2 ± 0.3 for Rarβ−/−Rxrγ−/− mutants). The absence of sucrose preference in Rarβ−/−Rxrγ−/− and Rxrγ−/− mice is unlikely to result from gustative deficits since all groups preferred water to 1% sucrose on the first presentation of sucrose drink. Thus, during 3 hr of the first testing session, in sucrose-naive WT mice sucrose solution constituted 43% ± 2.5% of total liquid consumption, as compared to 44% ± 2.1% for Rarβ−/−, 37% ± 5% for Rxrγ−/−, and 32.4% ± 7.3% for Rarβ−/−Rxrγ−/− mice, which for all groups was significantly less than the chance level of 50% (t > 3.5 for any of the comparisons, p < 0.05, one-group t test). Such avoidance of sucrose solution by sucrose-naive mice results from a natural tendency for reserved consumption of novel food/drink and provides evidence for recognition of 1% sucrose taste. A chronic, 19 day antidepressant treatment with 20 mg/kg/24hr of fluoxetine, reversed the sucrose preference deficits in Rxrγ−/− mice (Figure 2B), which is reflected by significant genotype × treatment interaction (F[1,64] = 7.9, p < 0.01). Thus, fluoxetine-treated Rxrγ−/− mice preferred sucrose solution to water similarly to WT control mice, and the percentage of sucrose solution consumed by fluoxetine-treated Rxrγ−/− mice was significantly higher than in vehicle-treated mutant animals (p < 0.001). Efficiency of fluoxetine to reverse affective abnormalities could suggest that altered serotonergic signaling is at the origin of depressive-like behaviors in Rxrγ−/− mice. To address this issue, we carried out global evaluation of serotonergic signaling focusing on hippocampus and striatum (including NAc), the two regions differentially innervated by dorsal and median raphe 5HT inputs suggested to play a role in control of affect (Lechin et al., 2006Lechin F. van der Dijs B. Hernandez-Adrian G. Dorsal raphe vs. median raphe serotonergic antagonism. Anatomical, physiological, behavioral, neuroendocrinological, neuropharmacological and clinical evidences: relevance for neuropharmacological therapy.Prog. Neuropsychopharmacol. Biol. Psychiatry. 2006; 30: 565-585Crossref PubMed Scopus (80) Google Scholar). HPLC measurements of 5HT and its metabolite 5HIAA in tissue homogenates revealed a significant increase of 5HT levels in the striatum of Rxrγ−/− mice (2.01 ± 0.18 ng/g for Rxrγ−/− and 1.46 ± 0.17 for WT mice; t = 2.2, p = 0.05), which was not accompanied by altered metabolism of serotonin (Figure 3A ). Although there was no significant difference in 5HT levels in the hippocampus, Rxrγ−/− displayed strong tendency (t = 1.92, p = 0.08) for increased metabolism of 5HT in this region (Figure 3B). Such abnormalities in the distribution of 5HT did not correlate with abnormal expression of 5HT1a receptor, prominently involved in control of 5HT tone and proposed to play a role in control of affective behaviors and in actions of SSRI antidepressants (Blier et al., 1998Blier P. Piñeyro G. el Mansari M. Bergeron R. de Montigny C. Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission.Ann. N Y Acad. Sci. 1998; 861: 204-216Crossref PubMed Scopus (191) Google Scholar, Blier and Ward, 2003Blier P. Ward N.M. Is there a role for 5-HT1A agonists in the treatment of depression?.Biol. Psychiatry. 2003; 53: 193-203Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar). Indeed, the relative 5HT1a mRNA levels (standardized with respect to expression of the house keeping gene 36B4) were comparable between Rxrγ−/− and their WT controls in the NAc (2.2 ± 0.4 for Rxrγ−/− and 2.7 ± 0.3 for WT; t = −1, ns) and hippocampus (1.4 ± 0.2 for Rxrγ−/− and 1.9 ± 0.3 for WT mice; t = −1.5, ns). To investigate functional relevance of abnormal serotonergic signaling for depressive-like behaviors in Rxrγ−/− mice we have tested whether acute fluoxetine treatment can reverse increased despair in the forced swim test. In contrast to chronic treatment, acute administration of fluoxetine at 20 mg/kg (IP, 30min prior to the forced swim test) did not alter increased immobility of Rxrγ−/− mice as there was no significant interaction for genotype × fluoxetine treatment (F[1,28] = 3E-4, ns) and the main effect of genotype (F[1,28] = 19.4, p < 0.001) remained significant despite of the treatment (Figure 3C). To control for the efficiency of acute fluoxetine treatment we used wild-type BALBcByJ (BALBc) mice, the strain susceptible to reveal antidepressant activities of fluoxetine (Lucki et al., 2001Lucki I. Dalvi A. Mayorga A.J. Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice.Psychopharmacology. 2001; 155: 315-322Crossref PubMed Scopus (417) Google Scholar), and we found that 20 mg/kg of fluoxetine was sufficient to significantly reduce despair behaviors in this strain (Figure 3D). We concluded that inefficiency of acute fluoxetine treatment to modulate despair behaviors suggests that abnormal serotonergic signal is not sufficient to generate depressive behaviors and adaptive changes associated with chronic fluoxetine treatments might be at the origin of affective abnormalities in Rxrγ−/− mice. The despair behavior and anhedonia and their reversal by chronic antidepressant treatment in Rxrγ−/− mice, indicates that null mutation of Rxrγ leads to deficits resembling some of the core symptoms of depression. We hypothesized that abnormal function of the nucleus accumbens (NAc), the key structure implicated in the control of motivated behaviors and one of the primary sites of Rxrγ expression (Krezel et al., 1999Krezel W. Kastner P. Chambon P. Differential expression of retinoid receptors in the adult mouse central nervous system.Neuroscience. 1999; 89: 1291-1300Crossref PubMed Scopus (186) Google Scholar) might be at the origin of the behavioral abnormalities in Rxrγ−/− mice. As dopaminergic signaling in the NAc is critically involved in the modulation of motivated behaviors and in the mechanisms of antidepressant activities including fluoxetine, we examined the expression of dopaminergic D1 and D2 receptors in Rxrγ−/− mice. Using real-time quantitative RT-PCR, we found a significant 32% reduction of D2r expression in the NAc of Rxrγ−/− mice (t = −3.16, p < 0.01; Figure 4A ). Interestingly, no such reduction (t = −0.22, ns) was observed in the dorsal caudate putamen (CPu). The inactivation of Rxrγ did not affect expression of D1r as D1r RNA levels were not significantly different between WT and Rxrγ−/− mice in the NAc (11.7 ± 1.0 versus 10.6 ± 1.0 units; t = −0.76, ns) and dorsal striatum (37.2 ± 2.2 versus 39.9 ± 0.8 units; t = 1.35, ns), as measured by RT-PCR and calculated relative to expression of a reference housekeeping gene (Figure S2). In order to further investigate the regionalization and the origin of reduced levels of D2r mRNA in the NAc we carried out in situ hybridization (ISH) studies (Figure 4B). Comparisons of Rxrγ−/− mice and their WT controls revealed that the number of neurons expressing D2r was significantly reduced in the shell of the NAc (152 ± 4 versus 206 ± 6; t = −8, p < 0.001) and the core of the NAc (294 ± 6 versus 338 ± 16; t = −2.44; p < 0.05), but not in the dorsal striatum (798 ± 17 versus 841 ± 34; t = −1.1, ns). To minimize cell counting errors related to differences in the signal intensity between different sections, which may account for more discrete changes, we took advantage of expression of D2r in the dorsal striatum (CPu), which was not affected by ablation of Rxrγ−/− and we used this region as our internal (intra-section) control to calculate relative changes in D2r cell numbers. To this end we divided cell counts in the NAcSh or NAcCo by those obtained for the adjacent region of CPu on the same section. We found a strong (36%) reduction in relative cell number only in the NAcSh (0.16 ± 0.01 for Rxrγ−/− as compared to 0.25 ± 0.02 for WT; t = −4.7, p = 0.001), but not in the NAcCo (0.37 ± 0.01 for Rxrγ−/− versus 0.40 ± 0.02 for WT; t = −1.5, ns), of Rxrγ−/− mice (Figure 4C). The difference in the magnitude of changes in D2r expression might be related to much weaker expression of Rxrγ in the NAcCo as compared to shell region (Krezel et al., 1999Krezel W. Kastner P. Chambon P. Differential expression of retinoid receptors in the adult mouse central nervous system.Neuroscience. 1999; 89: 1291-1300Crossref PubMed Scopus (186) Google Scholar). Reduction of D2r in the NAcSh might be functionally relevant as chronic fluoxetine treatment, in addition to reversing depressive-like behaviors, increased also the relative number of D2r positive cells in the NAcSh of behaviorally naive Rxrγ−/− mutants (0.15 ± 0.02 for nontreated Rxrγ−/− versus 0.23 ± 0.01 for fluoxetine treated Rxrγ−/− mice; t = −3.4, p < 0.01), but not WT mice (0.24 ± 0.01 for nontreated WT versus 0.27 ± 0.02 for fluoxetine treated mice; t = −1.2, ns; Figure 4D). A decrease of D2r-positive cell number in the NAcSh of Rxrγ−/− mice is most probably related to reduced transcription of D2r, rather than to the loss of a subpopulation of D2r expressing neurons. Supporting this hypothesis, the number of cells expressing mRNA coding for enkephaline, a neuropeptide found predominantly in D2r expressing neurons, was not significantly reduced (124.3 ± 2.8 enkephaline-positive cells in the NAc shell of Rxrγ−/− mice, as compared to 133.6 ± 3 cells in WT animals; t = −2.34, ns). Thus, the reduced number of D2r-expressing neurons could reflect a general decrease of D2r transcription in the NAc shell, with a reduction below the detection threshold level in neurons expressing low levels of D2r. Alternatively, it might be related to reduced transcriptional control of D2r restricted to a selected neuronal population. To address this issue, we quantified the intensity of D2r expression in the ISH experiments, using the ImageJ software (see Experimental Procedures). We found that the mean intensity of the D2r signal in the NAc shell was not different between WT and Rxrγ−/− mice when comparing absolute mean values (122.9 ± 2.2 for WT and 125.1 ± 2 for Rxrγ−/− mice; t = 0.7, ns) or when such measures were normalized with respect to the intensity of D2r expression in the dorsal striatum within the same brain section, where D2r expression was not affected by ablation of Rxrγ (1.05 ± 0.01 for WT and 1.08 ± 0.02 for Rxrγ−/− mice; t = 1, ns). These data suggest that Rxrγ might control expression of D2r in a selected subpopulation of D2r neurons. Finally, to assess whether cell- and regional-specific reduction of D2r mRNA expression leads to abnormal D2r activities, we investigated neuronal activation in Rxrγ−/− mice in response to haloperidol, a D2 preferential antagonist. To this end, we studied the induction of c-fos protein expression, a molecular marker related to neuronal activity and plasticity. An acute treatment with haloperidol (1 mg/kg) increased the number of c-fos positive cells in various regions of the striatum, including the shell and core of the NAc and CPu in all tested mice (Figures 5A and 5B ). However, in the shell of the NAc the magnitude of this increase was significantly lower in the in Rxrγ−/− than in WT mice as reflected by the significant interaction between genotype and treatment (F[1,14] = 5.6, p < 0.05) and PLSD Fischer post hoc analysis (p < 0.01). Such difference was not observed in the core of the NAc or in the dorsal CPu in the same sections (compare NAc-Sh with NAc-Co and CPu for WT-Hal and KO-Hal in Figure 5C). To study whether such a decrease reflects the action of haloperidol or is related to the stress inflicted during drug injection, we also evaluated the numbers of c-fos positive cells in saline-injected mice and found that these numbers were not significantly different between WT and Rxrγ−/− mice (compare WT-veh and KO-veh in Figure 5C). Thus, the haloperidol-specific induction of c-fos in the shell of the NAc, calculated as the ratio of c-fos positive cells in the haloperidol-treated mice with respect to saline-treated mice, was lower by 48% in Rxrγ−/− mice as compared to their WT controls (Figure 5D). To validate these findings functionally we tested the locomotor effects of low, non-cataleptic doses of haloperidol, which have been proposed to involve post-synaptic dopamine D2 receptors in the nucleus accumbens (Messier et al., 1992Messier C. Mrabet O. Destrade C. Locomotor bias produced by intra-accumbens injection of dopamine agonists and antagonists.Pharmacol. Biochem. Behav. 1992; 41: 177-182Crossref PubMed Scopus (18) Google Scholar, Millan et al., 2004Millan M.J. Seguin L. Gobert A. Cussac D. Brocco M. The role of dopamine D3 compared with D2 receptors in the control of locomotor activity: a combined behavioural and neurochemical analysis with novel, selective antagonists in rats.Psychopharmacology (Berl.). 2004; 174: 341-357Crossref PubMed Google Scholar, Pijnenburg et al., 1976Pijnenburg A.J. Honig W.M. Van der Heyden J.A. Van Rossum J.M. Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity.Eur. J. Pharmacol. 1976; 35: 45-58Crossref PubMed Scopus (467) Google Scholar). All mice treated with haloperidol displayed reduction of locomotor activity in" @default.
• W2012949542 created "2016-06-24" @default.
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• W2012949542 creator A5050131030 @default.
• W2012949542 creator A5067673882 @default.
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• W2012949542 date "2010-06-01" @default.
• W2012949542 modified "2023-10-14" @default.
• W2012949542 title "Retinoid X Receptor Gamma Control of Affective Behaviors Involves Dopaminergic Signaling in Mice" @default.
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