Assessment of Voluntary Ethanol Consumption and the Effects of a Melanocortin (MC) Receptor Agonist on Ethanol Intake in Mutant C57BL/6J Mice Lacking the MC-4 Receptor: ETHANOL AND MC-4 RECEPTOR

The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). Recent evidence shows that chronic exposure to ethanol significantly blunts central MC peptide immunoreactivity and MC receptor (MCR) agonists protect against high ethanol intake characteristic of C57BL/6J mice. Here we assessed the role of the MC-4 receptor (MC4R) in voluntary ethanol intake and in modulating the effects of the non-selective MCR agonist melanotan-II (MTII) on ethanol consumption

MC4-R signaling within the nucleus accumbens shell, but not the lateral hypothalamus, modulates ethanol palatability in rats

The Melanocortin (MC) system is one of the crucial neuropeptidergic systems that modulate energy balance. The roles of endogenous MC and MC-4 receptor (MC4-R) signaling within the hypothalamus in the control of homeostatic aspects of feeding are well established. Additional evidence points to a key role for the central MC system in ethanol consumption. Recently, we have shown that nucleus accumbens (NAc), but not lateral hypothalamic (LH), infusion of a selective MC4-R agonist decreases ethanol consumption. Given that MC signaling might contribute to non-homeostatic aspects of feeding within limbic circuits, we assessed here whether MC4-R signaling within the NAc and the lateral hypothalamus (LH) alters normal ingestive hedonic and/or aversive responses to ethanol in rats as measured by a taste reactivity test. Adult male Sprague-Dawley rats were given NAc- or LH- bilateral infusion 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/0.5µl/site) and following 30 min, the animals received 1 ml of ethanol solution (6% w/v) intraoral for 1 minute and aversive and hedonic behaviors were recorded. We found that NAc-, but not LH-administration, of a selective MC4-R agonist decreased total duration of hedonic reactions and significantly increased aversive reactions relative to saline-infused animals which support the hypothesis that MC signaling within the NAc may contribute to ethanol consumption by modulating non-homeostatic aspects (palatability) of intake

Polymorphism in the corticotropin-releasing factor receptor 1 (CRF1-R) gene plays a role in shaping the high anxious phenotype of Marchigian Sardinian alcohol-preferring (msP) rats

Introduction: Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol along with anxious phenotype. In these animals, two single-nucleotide polymorphisms in position -1,836 and -2,097 from the first start codon of the CRF1-R transcript have been found. Materials and Methods: Here, we examined whether these point mutations account for the heightened anxiety-like behavior and stress responsiveness of msP rats. We rederived the msP rats to obtain two distinct lines carrying the wild-type (GG) and point mutations (AA), respectively. Results: CRF1-R gene expression analysis revealed significant dysregulation of the system in the extended amygdala of AA rats. At the behavioral level, using the elevated plus maze, we found that both AA and GG lines had higher basal anxiety compared to Wistar rats. In the defensive burying test, AA rats showed decreased burying behavior compared to the GG and the unselected Wistar lines. Freezing/immobility did not differ among AA and GG but was higher than that of Wistars. The selective CRF1-R antagonist antalarmin (0, 10, and 20 mg/kg) reduced burying behavior in Wistar animals. However, antalarmin (10 mg/kg) tended to increase rather than reducing this behavior when tested in the msP lines, an effect that appeared more marked in the GG as compared to the AA line. Conclusion: The present data suggest that rats with msP genetic background are more anxious and show different sensitivity to stress and CRF1-R blockade than Wistars. The point mutations occurring in the CRF1-R gene do not seem to influence basal anxiety while they appear to affect active responses to stress

Control of food intake by MC4-R signaling in the lateral hypothalamus, nucleus accumbens shell and ventral tegmental area: Interactions with ethanol

The Melanocortin system is involved in animal models of obesity and anorexia-cachexia and MC4 receptors (MC4-R) are currently a target system for the development of drugs aimed to treat obesity and eating disorders in humans. Previous evidence suggest that feeding peptides might lack their orexigenic activity while stimulate ethanol intake. The present study comparatively evaluated food intake (4-h interval) in Sprague-Dawley (SD) rats drinking ethanol (6% w/v, 2 bottle choice paradigm) (EE group) and ethanol-naïve (EN) rats in response to bilateral infusion of the selective MC4-R antagonist HS014 (0, 0.02 or 0.05 μg/0.5μl/site) or the selective MC4-R agonist cyclo(NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2 (0, 0.75 or 1.5 μg/0.5μl/site), into the lateral hypothalamus (LH), the nucleus accumbens (NAc), or the ventral tegmental area (VTA). The main findings in the study are: 1) LH-infusions of the MC4-R antagonist increased and the agonist reduced feeding and total calories consumed, while ethanol intake remained unaltered. 2) NAc- and VTA-infusions of the selective agonist reduced food, ethanol and total calories intake. 3) NAc- and VTA-infusions of the MC4-R antagonist increased feeding in EN rats, but not in EE animals which showed a mild increase in ethanol intake, while total calories consumed remained unaltered. Present data show that having ethanol available reduces feeding elicited by NAc and VTA-MC4-R blockade. Additionally, while MC4-R signalling in the LH appears to modulate homeostatic aspects of feeding, it may contribute to non-homeostatic aspects of ingestive behaviours in the VTA and the NAc