Role of melanin-concentrating hormone in the control of ethanol consumption: Region-specific effects revealed by expression and injection studies

Abstract

The peptide melanin-concentrating hormone (MCH), produced mainly by cells in the lateral hypothalamus (LH), perifornical area (PF) and zona incerta (ZI), is suggested to have a role in the consumption of rewarding substances, such as ethanol, sucrose and palatable food. However, there is limited information on the specific brain sites where MCH acts to stimulate intake of these rewarding substances and on the feedback effects that their consumption has on the expression of endogenous MCH. The current study investigated MCH in relation to ethanol consumption, in Sprague-Dawley rats. In Experiment 1, chronic consumption of ethanol (from 0.70 to 2.7 g/kg/ day) dose-dependently reduced MCH gene expression in the LH. In Experiments 2-4, the opposite effect was observed with acute oral ethanol, which stimulated MCH expression specifically in the LH but not the ZI. In Experiment 5, the effect of MCH injection in brain-cannulated rats on ethanol consumption was examined. Compared to saline, MCH injected in the paraventricular nucleus (PVN) and nucleus accumbens (NAc) selectively stimulated ethanol consumption without affecting food or water intake. In contrast, it reduced ethanol intake when administered into the LH, while having no effect in the ZI. These results demonstrate that voluntary, chronic consumption of ethanol leads to local negative feedback control of MCH expression in the LH. However, with a brief exposure, ethanol stimulates MCH-expressing neurons in this region, which through projections to the feeding-related PVN and reward-related NAc can promote further drinking behavior.

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

“…We hypothesize that these adaptations persist during protracted abstinence, which could explain the effect of GW803430 on escalated self-administration during protracted abstinence. In support of our findings, local injection of MCH into the NAc or the PVN increases alcohol-intake (332). This raises the possibility that alteration of the circuits that regulate both foodintake and reward underlie the escalation of alcohol consumption.…”

Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli

“…MCH/GABAergic neurons in the LH project to the VTA and NAc (Bittencourt et al, 1992;DallvechiaAdams et al, 2002;Saito et al, 2001;Sears et al, 2010) and modulate consumption of natural and drug rewards (Morganstern et al, 2010;Parker and Bloom, 2012). However, as we used the same vGat-ires-cre mice used by Jennings et al (2015) and the same DREADD constructs, MCH/GABAergic neurons are unlikely to be involved as cre is not present in MCH neurons of the current vGat-ires-cre mice (Jennings et al, 2015).…”

Differential Role of D1 and D2 Receptors in the Perifornical Lateral Hypothalamus in Controlling Ethanol Drinking and Food Intake: Possible Interaction with Local Orexin Neurons

“…To encourage animals to drink and adapt to the unsweetened ethanol, the concentration of ethanol was gradually increased every 4 days, from 1, 2, 4, to 7% (v/v). Animals had access to ethanol solutions for 12 h per day, starting 3 h into the dark period, as described in recent publications (Chen et al, 2013; Morganstern et al, 2010b). Chow was also provided along with ethanol for 12 h per day during most of the dark period when a majority of consumption normally occurs, as shown by our preliminary observations (12 h: 78 ± 5 kcal vs 24 h: 82 ± 7 kcal) and published findings (Agabio et al, 1996).…”

“…It also increases ethanol drinking when administered directly into the PF/LH (Schneider et al, 2007), and its endogenous expression is stimulated by ethanol exposure and ethanol-paired cues (Dayas et al, 2008; Morganstern et al, 2010a). The possibility that the DA receptor subtypes in the PF/LH act with distinct effects on the local OX system is suggested by the finding that stimulation of the D1 or D2 receptors differentially affect the excitability of nearby neurons expressing MCH (Conductier et al, 2011), which in the LH and zona incerta (ZI) have also been implicated in controlling ethanol consumption (Morganstern et al, 2010b). In contrast to the clear relationship between OX and ethanol, mixed results have been obtained in studies of MCH, with ethanol intake increased by cerebroventricular injection of this peptide (Duncan et al, 2005) but also by deletion of the MCH receptor gene (Duncan et al, 2007), suggesting a more complex relationship between ethanol and this peptide system.…”