Targeting central melanocortin receptors: a promising novel approach for treating alcohol abuse disorders

Abstract

The melanocortin (MC) peptides are produced centrally by propiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus and act through five seven-transmembrane G-protein coupled melanocortin receptor (MCR) subtypes. The MC3R and MC4R subtypes, the most abundant central MCRs, are widely expressed in brain regions known to modulate neurobiological responses to ethanol, including regions of the hypothalamus and extended amygdala. Agouti-related protein (AgRP), also produced in the arcuate nucleus, is secreted in terminals expressing MCRs and functions as an endogenous MCR antagonist. This review highlights recent genetic and pharmacological findings that have implicated roles for the MC and AgRP systems in modulating ethanol consumption. Ethanol consumption is associated with significant alterations in the expression levels of various MC peptides/protein, which suggests that ethanol-induced perturbations of MC/AgRP signaling may modulate excessive ethanol intake. Consistently, MCR agonists decrease, and AgRP increases, ethanol consumption in mice. MCR agonists fail to blunt ethanol intake in mutant mice lacking the MC4R, suggesting that the protective effects of MCR agonists are modulated by the MC4R. Interestingly, recent evidence reveals that MCR agonists are more effective at blunting binge-like ethanol intake in mutant mice lacking the MC3R, suggesting that the MC3R has opposing effects on the MC4R. Finally, mutant mice lacking AgRP exhibit blunted voluntary and binge-like ethanol drinking, consistent with pharmacological studies. Collectively, these preclinical observations provide compelling evidence that compounds that target the MC system may provide therapeutic value for treating alcohol abuse disorders and that the utilization of currently available MC-targeting compounds- such as those being used to treat eating disorders- may be used as effective treatments to this end.

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…The final version may differ from this version. [Olney et al, 2014;Sprow et al, 2016]. In contrast, another recent report has found that MC4 receptor antagonists in the ventral tegmental area reduce alcohol self-administration in rats [Shelkar et al, 2015], suggesting that endogenous melanocortins and MC4 activation mediate the alcohol-reinforcing effect.…”

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…Clinical and basic research indicate that alcohol abuse and dependence are mediated in part by a number of neurobiological systems (c.f., Koob, Arends, & Le Moal, 2014; Koob, Buck, et al, 2014; Noronha, Cui, Harris, & Crabbe, 2014; Pierce & Kenny, 2013; Robbins, Everitt, & Nutt, 2010; Self & Staley, 2010; Sommer & Spanagel, 2013; Spanagel, 2009): acetylcholine (ACh: Chatterjee & Bartlett, 2010; Davis & de Fiebre, 2006; Rahman, Engleman, & Bell, 2015, 2016; Soderpalm, Ericson, Olausson, Blomqvist, & Engel, 2000), adenosine (Filip, Zaniewska, Frankowska, Wydra, & Fuxe, 2012; Nam, Bruner, & Choi, 2013), dopamine (DA: Bhaskar & Kumar, 2014; Engel & Jerlhag, 2014; Heinz, 2002; Nutt, Lingfor-Hughes, Erritzoe, & Stokes, 2015; Soderpalm & Ericson, 2013), endocannabinoid (Moreira, Jupp, Belin, & Dalley, 2015), gamma-aminobutyric-acid (GABA: Agabio & Colombo, 2014; Kumar et al, 2009; Liang & Olsen, 2014; Maccioni & Colombo, 2009), glutamate (Barron et al, 2012; Bell et al, 2016; Davis & Wu, 2001; Gass & Olive, 2008; Rao, Bell, Engleman, & Sari, 2015), purinergic (Franklin et al, 2014), serotonin (5-HT: Engleman, Rodd, Bell, & Murphy, 2008; Hauser et al, 2014; Lovinger, 1999), melanocortin (Olney, Navarro, & Thiele, 2014), opiate (Charbogne, Kieffer, Befort, 2014; Drews & Zimmer, 1997), orexin (Baimel et al, 2015), oxytocin (Buisman-Pijlman et al, 2014), neuropeptide-Y (NPY: Heilig & Thorsell, 2002), corticotropin releasing factor (CRF: Burke & Miczek, 2014; Koob, 2010), substance P (George et al, 2008), nociceptin/orphanin FQ (NOP, N/OFQ: Economidou et al, 2008; Witkin et al, 2014); ghrelin (Jerlhag, Egecioglu, Dickson, & Engel, 2011; Jerlhag et al, 2009; Jerlhag, Landgren, et al, 2011); neurotrophic factors such as BDNF (Logrip, Janak, & Ron, 2009), and hypothalamic-pituitary-adrenal (HPA) activity including corticosteroids, etc. (Gianoulakis, Guillaume, De Waele, & Angelogianni, 1995; Keith, Roberts, Wisen, & Crabbe, 1995; Kiefer, Jahn, Otte, Nakovics, & Wiedemann, 2006…”

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.…”

“…Accumulating anatomical, genetic, and pharmacological evidence has shown that the MC pathway in the hypothalamus and other brain areas is critical for developing dependency and addictive behaviors related to alcohol consumption (Olney et al, 2014). However, the molecular and cellular mechanisms behind these changes remain to be fully understood and this is particularly true for the initial stages of alcohol dependency in adolescents.…”

“…Numerous animal research has demonstrated that ethanol, the predominant alcohol in alcoholic beverages, disturbs the function of MC system depending on how this drug is administered (for review see Olney et al, 2014). For example, acute exposure to ethanol results in a drastic reduction of α-MSH-immunoreactivity in the PVN, Arc, and dorsomedial hypothalamic-dorsal (DMNd) and -ventral (DMNv) nuclei, as well as the central nucleus of amygdala (CeA) (Kokare et al, 2008).…”