Nucleus Accumbens MC4-R Stimulation Reduces Food and Ethanol Intake in Adult Rats Regardless of Binge-Like Ethanol Exposure during Adolescence.

The melanocortin (MC) system regulates feeding and ethanol consumption. Recent evidence shows that melanocortin 4 receptor (MC4-R) stimulation within the nucleus accumbens (NAc) elicits anorectic responses and reduces ethanol consumption and ethanol palatability in adult rats. Ethanol exposure during adolescence causes long-lasting changes in neural pathways critically involved in neurobehavioral responses to ethanol. In this regard, binge-like ethanol exposure during adolescence reduces basal alpha-melanocyte-stimulating hormone (α-MSH) and alters the levels of agouti-related peptide (AgRP) in hypothalamic and limbic areas. Given the protective role of MC against excessive ethanol consumption, disturbances in the MC system induced by binge-like ethanol exposure during adolescence might contribute to excessive ethanol consumption during adulthood. In the present study, we evaluated whether binge-like ethanol exposure during adolescence leads to elevated ethanol intake and/or eating disturbance during adulthood. Toward that aim, Sprague-Dawley rats were treated with ethanol (3 g/kg i.p.; BEP group) or saline (SP group) for 14 days (PND 25 to PND 38). On PND73, all the groups were given access to 20% ethanol on an intermittent schedule. Our results showed that adult rats given intermittent access (IAE) to 20% ethanol achieved high spontaneous ethanol intake that was not significantly enhanced by binge-like ethanol pretreatment during adolescence. However, BEP group exhibited an increase in food intake without a parallel increase in body weight (BW) relative to SP group suggesting caloric efficiency disturbance. Additionally, we evaluated whether binge-like ethanol exposure during adolescence alters the expected reduction in feeding and ethanol consumption following NAc shell administration of a selective MC4-R agonist in adult rats showing high rates of ethanol consumption. For that, animals in each pretreatment condition (SP and BEP) were divided into three subgroups and given bilateral NAc infusions of the selective MC4-R agonist cyclo(NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2 (0, 0.75 or 1.5 µg). Results revealed that MC4-R stimulation within the NAc reduced feeding and ethanol intake in high ethanol-drinking adult rats, regardless of previous binge-like ethanol exposure during adolescence, which adds new evidence regarding the dual ability of MC compounds to control excessive ethanol and food intake.

Orexin receptor 1 signaling contributes to ethanol binge-like drinking: Pharmacological and molecular evidence.

Orexins (OX) have been recently implicated in ethanol seeking and self-administration. A few recent studies have provided additional evidence that OX receptor antagonists effectively reduce voluntary ethanol consumption in subjects spontaneously showing high levels of ethanol intake. The present study further evaluates the contribution of OXR1 to excessive binge-like drinking of ethanol in ad libitum-fed C57BL/6J mice from a pharmacological and molecular approach. The main findings in the study are: (1) Icv administration of SB-334867 (3 µg/µl) blunted ethanol (20% v/v), but not saccharin (0.15% w/v) binge-like drinking in a drinking in the dark procedure, without any alteration of chow consumption or total calories ingested; (2) Icv administration of SB-334867 (3 µg/µl) increased the latency to recover the righting reflex after a sedative dose of ethanol without any significant alteration in ethanol peripheral metabolism; (3) four repetitive, 2-h daily episodes of saccharin, but not ethanol binge-like drinking blunted OXR1 mRNA expression in the lateral hypothalamus. Present findings extend the current knowledge pointing to a role for OX signaling in ethanol sedation, which might partially explain the inhibitory effect of OXR1 antagonists on ethanol consumption. Combined pharmacological and molecular data suggesting the contribution of OXR1 in ethanol binge-drinking leading us to propose the idea that targeting OXR1 could represent a novel pharmacological approach to control binge-consumption episodes of ethanol in vulnerable organisms failing to spontaneously reduce OX activity.

Repeated binge-like ethanol administration during adolescence cause decreased C-Fos immunoreactivity in amygdala and arcuate nucleus in adult Sprague-Dawley rats / La administración repetida de etanol, tipo atracón, durante la adolescencia provoca descenso en la expresión de C-Fos en la amígdala y núcleo arqueado de ratas Sprague-Dawley adultas

Binge alcohol drinking during adolescence has been associated with neurotoxicity and increased risk for the development of alcohol use disorders. There is evidence that acute and chronic ethanol administration alters c-fos expression, an indirect index of cellular activity, in different brain regions in adult rats. We evaluate here if a binge-like pattern of ethanol exposure during adolescence has a relevant impact on basal and/or ethanol-stimulated regional c-fos activity during adulthood. For that aim, Sprague-Dawley rats PND 25 were saline pre-treated, (SP group) or binge-ethanol pre-treated (BEP group) for two­consecutive days, at 48-h intervals, over a 14-day period (PND 25 to PND 38). At adult stage (PND 63) and following 25 ethanol-free days, we evaluated c-fos immunoreactivity in response to saline or acute ethanol (1.5 or 3.0 g/kg) in the hypothalamus and amygdala. We found that acute ethanol administration dose-dependently increased c-fos activity in the the Paraventricular nucleus of the hypothalamus (PVN). Interestingly, binge-ethanol exposure during adolescence significantly reduced basal c-fos activity during adulthood in the Central nucleus of the amygdala (CeA) and the Arcuate nucleus of hypothalamus (Arc). We conclude that binge-like ethanol administration during adolescence causes long-term disturbances in basal neural activity in brain areas critically involved with ethanol consumption.

El consumo en atracón durante la adolescencia está asociado con neurotoxicidad y con el riesgo de desarrollar un trastorno en el uso de alcohol. Diversos estudios muestran que la administración aguda y crónica de alcohol en ratas adultas altera la expresión de c-fos, un marcador indirecto de actividad celular, en diferentes áreas cerebrales. Nosotros evaluamos si el patrón de consumo de alcohol en atracón durante la adolescencia tiene un impacto en la actividad basal de c-fos en esas regiones activadas por el alcohol. Utilizamos ratas Sprague-Dawley en su día post-natal 25 (PND25) tratadas con suero salino (grupo SP) o con etanol tipo atracón (grupo BEP) durante dos días consecutivos, en intervalos de 48 h, durante 14 días (PND25- PND38). En la edad adulta (PND63) y después de 25 días sin etanol, evaluamos la inmunorreactividad para c-fos en respuesta a una administración aguda de suero salino o etanol (1,5 ó 3,0 g/kg) en diferentes regiones cerebrales. La administración de alcohol incrementó de manera dosis-dependiente la actividad de c-fos en el núcleo paraventricular del hipotálamo. Además la exposición a etanol tipo atracón durante la adolescencia disminuyó la actividad basal de c-fos en la adultez en el núcleo central de la amígdala y en el núcleo arqueado del hipotálamo. Concluimos que el consumo de alcohol en atracón durante la adolescencia causa problemas a largo plazo en la actividad basal de regiones cerebrales implicadas en el consumo de alcohol.