The regulation of alcohol intake by melanin-concentrating hormone in rats

Abstract

Given into the brain, melanin-concentrating hormone (MCH) increases alcohol consumption, but the mechanism and physiological relevance of this effect are unclear. We hypothesized that endogenous MCH will enhance alcohol drinking and that MCH increases alcohol's reinforcing properties. An MCH receptor 1 (MCHR1) antagonist, or saline was administered centrally alone, or preceding MCH or saline to rats trained to drink 10% alcohol using sucrose fading. Blocking MCHR1 neither reduced alcohol intake (saline = 0.4 ± 0.1g, 30 μg MCHR1 antagonist = 0.4 ± 0.1 g/kg alcohol), nor attenuated MCH-induced alcohol drinking (MCHR1 antagonist/saline = 0.7 ± 0.1 g/kg, MCHR1 antagonist/MCH = 0.9 ± 0.1 g/kg alcohol). Another cohort of rats was trained to lever press for alcohol on a progressive ratio schedule. MCH or saline was administered centrally and lever presses were measured. MCH had no effect prior to the break point, but increased total responding during the session (saline = 87.2 ± 32.0, MCH = 315.4 ± 61.0 presses). In conclusion, these data suggest that MCH augments alcohol drinking partly by enhancing the drug's reinforcing value. Further, endogenous MCH does not seem to regulate alcohol drinking, however because the antagonist failed to attenuate MCH-induced alcohol intake this conclusion is tentative.

Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats

“…Central administration of this antagonist failed to impact the intake of alcohol and also left the intake of an isocaloric sucrose solution unaffected. The antagonist did suppress 2 h chow intake but failed to attenuate MCH-induced alcohol drinking (Duncan et al 2006). While the first of these observations may be supportive of in vivo antagonist activity, it is not conclusive, and the lack of efficacy to block effects of exogenous MCH on alcohol drinking suggests that such activity may, at a minimum, be limited, for instance due to limited tissue penetration into some brain areas.…”

“…However, in a follow-up study, the same 10 µg intracerebroventricular (i.c.v.) MCH dose robustly increased the breakpoints for self-administration of sucrose, while leaving breakpoints for alcohol unaffected (Duncan et al 2006). The latter study also probed the role of MCH signaling in the control of alcohol intake using a peptide MCH analog with selective antagonistic properties at MCH1-Rs in vitro (Bednarek et al 2002).…”

“…MCH, acting through the MCH1-R in the Nc AccS, was shown to increase dopamine responses in vitro and in vivo, whereas MCH1-R antagonists suppressed cocaine self-administration, as well as reinstatement of cocaine-seeking induced by priming doses of the drug, or drug-associated cues (Chung et al 2009). It has also been shown that central administration of MCH increases alcohol intake (Duncan et al 2005(Duncan et al , 2006. These observations lead us to hypothesize that antagonism of the MCH1-R may modulate rewarding properties of alcohol and the susceptibility to relapse-like behavior.…”

Hypothalamic neuropeptide signaling in alcohol addiction

“…Injection of MCH into the PVN, adjacent third ventricle, or NAc has been shown to promote moderate alcohol drinking and stimulate operant responding for alcohol as well as sucrose (Duncan et al, 2005; Duncan et al, 2006; Morganstern et al, 2010b), just as these injections increase the intake of laboratory chow (Georgescu et al, 2005; Guesdon et al, 2009; Rossi et al, 1999). However, injection of an MCHR1 antagonist into the third ventricle failed to affect alcohol drinking or block MCH-induced drinking (Duncan et al, 2006), and MCHR1 knockout paradoxically led male mice to consume more alcohol than wild-type mice (Duncan et al, 2007). Evidence supporting a role for endogenous MCH in stimulating alcohol intake comes from a study showing peripheral administration of an MCHR1 antagonist to suppress alcohol self-administration and cue-induced reinstatement of alcohol-seeking (Cippitelli et al, 2010).…”

Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues

“…Transgenic overexpression of MCH also leads to hyperphagia and weight gain [23], whereas deletion or antagonism of MCH-1R suppresses intake [24,25]. With respect to reward learning, MCH influences both food-seeking and cocaine-seeking [26][27][28], and deletion of MCH-1R disrupts conditioning of incentive motivation to a reward-paired auditory cue, leading to reductions in its ability to promote novel instrumental nose-poke responding [29].…”