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

Abstract 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-naive (EN) rats in response to bilateral infusion of the selective MC4-R antagonist HS014 (0, 0.02 or 0.05 μg/0.5 μl/site) or the selective MC4-R agonist cyclo(NH-CH 2 -CH 2 -CO-His- d -Phe-Arg-Trp-Glu)-NH 2 (0, 0.75 or 1.5 μg/0.5 μl/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 signaling in the LH appears to modulate homeostatic aspects of feeding, it may contribute to non-homeostatic aspects of ingestive behaviors in the VTA and the NAc.