RESUMEN
This study employs an oral operant conditioning paradigm to evaluate the effects of repeated social defeat during adolescence on the reinforcing and motivational actions of ethanol in adult OF1 mice. Social interaction, emotional and cognitive behavioral aspects were also analyzed, and real-time polymerase chain reaction (PCR) experiments were performed to study gene expression changes in the mesocorticolimbic and hypothalamus-hypophysis-adrenal (HHA) axis. Social defeat did not alter anxiety-like behavior in the elevated plus maze or cognitive performance in the passive avoidance and Hebb-Williams tests. A social interaction test revealed depression-like symptoms and social subordination behavior in defeated OF1 mice. Interestingly, social defeat in adolescence significantly increased the number of effective responses, ethanol consumption values and motivation to drink. Finally, real-time PCR analyses revealed that social defeat significantly increased tyrosine hydroxylase and corticotropin-releasing hormone in the ventral tegmental area and paraventricular nucleus, respectively. In contrast, mu-opioid receptor gene expression was decreased in the nucleus accumbens of socially defeated mice. In summary, these findings suggest that exposure to social defeat during adolescence increases vulnerability to the rewarding effects of ethanol without affecting emotional or cognitive performance. The gene expression alterations we have observed in the mesocorticolimbic and HHA axis systems of defeated mice could be related with their increased ethanol consumption. These results endorse future research into pharmacological strategies that modulate these systems for the treatment of social stress-related alcohol consumption problems.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Conducta Animal , Encéfalo/metabolismo , Condicionamiento Operante , Perfilación de la Expresión Génica , Conducta Social , Estrés Psicológico/genética , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/psicología , Animales , Ansiedad/genética , Ansiedad/metabolismo , Ansiedad/psicología , Reacción de Prevención , Depresores del Sistema Nervioso Central/administración & dosificación , Hormona Liberadora de Corticotropina/genética , Depresión/genética , Depresión/metabolismo , Depresión/psicología , Etanol/administración & dosificación , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Ratones , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Opioides mu/genética , Autoadministración , Estrés Psicológico/psicología , Tirosina 3-Monooxigenasa/genética , Área Tegmental Ventral/metabolismoRESUMEN
RATIONALE: Male CB1KO mice exhibit stronger aggressive responses than wild-type mice. OBJECTIVE: This study was designed to examine the role of cannabinoid CB2r in social and aggressive behavior. METHODS: The social interaction test and resident-intruder paradigm were performed in mice lacking CB2r (CB2KO) and in wild-type (WT) littermates. The effects of the CB2r selective agonist JWH133 (1 and 2 mg/kg) on aggression were also evaluated in Oncins France 1 (OF1) mice. Gene expression analyses of monoamine oxidase-A (MAO-A), catechol-o-methyltransferase (COMT), 5-hydroxytryptamine transporter (5-HTT), and 5-HT1B receptor (5HT1Br) in the dorsal raphe nuclei (DR) and the amygdala (AMY) were carried out using real-time PCR. RESULTS: Group-housed CB2KO mice exhibited higher levels of aggression in the social interaction test and displayed more aggression than resident WT mice. Isolation increased aggressive behavior in WT mice but did not affect CB2KO animals; however, the latter mice exhibited higher levels of social interaction with their WT counterparts. MAO-A and 5-HTT gene expression was significantly higher in grouped CB2KO mice. The expression of 5HT1Br, COMT, and MAO-A in the AMY was more pronounced in CB2KO mice than in WT counterparts. Acute administration of the CB2 agonist JWH133 significantly reduced the level of aggression in aggressive isolated OF1 mice, an effect that decreased after pretreatment with the CB2 receptor antagonist AM630. CONCLUSION: Our results suggest that CB2r is implicated in social interaction and aggressive behavior and deserves further consideration as a potential new target for the management of aggression.