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

Abstract

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.

Adolescent binge-like ethanol exposure reduces basal α-MSH expression in the hypothalamus and the amygdala of adult rats

“…or CeA infusion of the MC3/MC4R agonist MTII has been shown to reduce alcohol consumption in mice (Navarro et al, 2003; 2005), alcohol-preferring AA rats (Ploj et al, 2002) and P rats (York et al, 2011). Additionally, administration of a selective MC4R antagonist into the nucleus accumbens reduces voluntary ethanol consumption (Lerma-Cabrera et al, 2012) and ethanol palatability (Lerma-Cabera et al, 2013). Similarly, in situ hybridization studies have shown increased ratios of POMC/AgRP mRNA in the Arc of alcohol-preferring AA rats (Lindblom et al, 2002).…”

“…Fourth, infusion of a selective MC4R agonist into the nucleus accumbens, but not into the lateral hypothalamus, reduces voluntary ethanol consumption, while infusion of the selective antagonist HS016 increases ethanol consumption without affecting caloric intake in adult Sprague-Dawley rats (Lerma-Cabrera et al, 2012). Moreover, stimulation of MC4R signaling in the accumbens shell region dramatically reduces ethanol palatability (Lerma-Cabrera et al, 2013), which suggests a key role for MC signaling in limbic regions in the hedonic responses to ethanol.…”

Hypothalamic neuropeptide signaling in alcohol addiction

“…In contrast, an MC4R antagonist enhances this anxiolytic effect and reduces the anxiety induced by alcohol withdrawal (Kokare et al, 2006). Moreover, an MC4R agonist in the NAc reduces hedonic reactions to alcohol while increasing aversive ones (Lerma-Cabrera et al, 2013). Therefore MCs, like CRF, may enhance the aversive aspects of alcohol drinking while simultaneously reducing the rewarding aspects.…”

New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

“…As mentioned in previous sections, alcohol consumption strongly reduces the expression of α-MSH in the limbic system and hypothalamus (Olney et al, 2014), whereas MC4R activation within the Nac suppress ethanol drinking (Navarro et al, 2011; Lerma-Cabrera et al, 2013b). In spite of this evidence, it is unknown whether alcohol addiction, in particular during the adolescence, occurs due to an imbalance in the inflammatory profile of glial cells caused by low signaling of the MC system.…”

“…In agreement with these data, infusion of a selective MC4R agonist (cyclo (NH-CH2-CH2-CO-His- D -Phe-Arg-Trp-Glu)-NH2) at the NAc and VTA, but not into the lateral hypothalamus (LH), diminish voluntary alcohol consumption in rats (Lerma-Cabrera et al, 2012). Follow-up work has demonstrated that MC signaling within the NAc contributes to alcohol consumption by modulating the non-homeostatic aspects (palatability) of intake (Lerma-Cabrera et al, 2013b), which bring to light the key role of MCs in limbic regions implicated in the hedonic response to alcohol.…”