The Melanocortin (MC) system has been extensively studied for its role in energy balance. This system possesses an endogenous agonist, α-melanocyte stimulating hormone (α-MSH) and an inverse agonist, Agouti-related peptide (AgRP), which are downstream factors of leptin [1
] and show opposing actions on the same MC receptors [2
]. There is an established role for the MC signaling within the hypothalamus in modulating feeding behaviour, body weight regulation [4
] and food selection [8
] by homeostatic mechanisms [1
], and more recently it has been suggested that MC signaling in limbic structures might regulate non-homeostatic aspects of feeding [1
The MC system, with a special emphasis on MC4 receptor (MC4-R), is clearly involved in animal models of obesity and anorexia-cachexia [11
]. Moreover, MC receptors (MC-R) are currently a promising target system for the development of drugs aimed to treat obesity and eating disorders in humans [8
]. MC peptides that might be employed to treat feeding disorders also have other biological activities that involve MC4-R signaling. In this regard, recent pharmacological and genetic studies have provided additional evidence that MC play a role in ethanol consumption in ethanol preferring strains. Thus, intracerebroventricular (i.c.v.) infusion of the non-selective MC3-R/MC4-R agonist Melanotan-II (MTII) decreases ethanol consumption in C57BL/6J mice [20
] and AA rats [21
]. I.c.v. infusion of the non-selective MC3-R/MC4-R inverse agonist Agouti-related protein (AgRP)-(83–132) disrupts MTII-induced reduction of ethanol consumption [20
] and increases voluntary ethanol consumption in C57BL/6J mice [22
]. Consistent with pharmacological studies, genetic deletion of AgRP blunts ethanol self-administration and binge-like ethanol drinking [23
]. Furthermore, i.c.v. infusion of MTII reduces ethanol consumption in MC3-R knockout (Mc3r-/-
) mice and i.c.v. administration of the highly selective MC4-R agonist cyclo(NH-CH2
significantly decreases voluntary ethanol consumption and feeding in C57BL/6J mice [22
], supporting a role for the MC4-R.
A growing body of experimental evidence suggests the existence of overlapped neurobiological systems for food and ethanol intake [24
]. In this regard, there is pharmacological evidence showing that some feeding peptides might lack their orexigenic activity while selectively stimulate ethanol intake in Sprague-Dawley (SD) rats [25
], a strain which shows low voluntary ethanol intake on average and spontaneous drinking patterns commensurate with a model of social drinking. Thus, administration of the orexigenic peptides orexin or galanin, but not ghrelin, into the appropriate locus in the hypothalamus increased ethanol intake while food consumption remained unaltered in ethanol drinking rats [25
]. These data raise the possibility that having ethanol available might modify the anorectic/orexigenic activity of centrally administered feeding compounds in low-ethanol drinkers.
Taking into account that low/moderate ethanol drinking is widely extended in our society some important questions remain unaddressed from the perspective of using specific MC-R as drug targets with a focus on the treatment of anorexia/cachexia and other eating disorders in humans. First, whether having ethanol available alters the anorectic/orexigenic activity of MC4-R compounds; second, whether a MC4-R antagonist triggering feeding may also induce ethanol drinking in animals showing low ethanol consumption baseline; third, the anatomical sites and mechanisms that mediate these effects.
The present study evaluates food intake in SD rats while drinking ethanol in response to a selective MC4-R antagonist and agonist infused into the lateral hypothalamus (LH), the nucleus accumbens shell (NAc) or the ventral tegmental area (VTA), which are brain regions in which MC signaling might be involved in the homeostatic (LH) and non-homeostatic (NAc, VTA) [1
] aspects of food intake. We compare here feeding in response to site-directed MC4-R compounds in ethanol-naïve (EN) and ethanol exposed (EE) SD rats, which show low ethanol drinking baseline. Additionally, we test here if centrally-infused MC4-R compounds do significantly alter voluntary ethanol consumption.