Effects of Melanocortin Receptor Activation and Blockade on Ethanol Intake: A Possible Role for the Melanocortin-4 Receptor

Abstract

Background-The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin. A growing body of literature suggests that the MC system modulates neurobiological responses to drugs of abuse. Because ethanol has direct effects on central proopiomelanocortin activity, it is possible that MC neuropeptides participate in the control of voluntary ethanol consumption. Here we assessed the possibility that MC receptor (MCR) agonists modulate ethanol intake via the MC3 receptor (MC3R) and/or the MC4 receptor (MC4R) and whether the MCR antagonist AgRP-(83-132) controls ethanol consumption.

Repeated Binge-Like Ethanol Administration During Adolescence cause Decreased C-Fos Immunoreactivity in Amygdala and Arcuate Nucleus in Adult Sprague-Dawley Rats

“…MC neuropeptides, in the brain, act through at MC3 receptor (MC3R) and MC4R (Cone). Central administration of potent non-selective MCR agonist melanotan-II (MTII) and a selective MC4R agonist significantly reduced voluntary ethanol in adult mice and rats (Navarro et al, 2005(Navarro et al, , 2011Lerma-Cabrera et al, 2012), but not MTII administration in Mc4r-/-mice (Navarro et al, 2011). Central AgRP and HS014, MC4R antagonist administration increases voluntary ethanol consumption in mice and rats (Navarro et al, 2005;Lerma-Cabrera et al, 2012).…”

Orexigenic Peptides and Alcohol Intake: Differential Effects of Orexin, Galanin, and Ghrelin

“…At least 28 peptides are known to be involved in food and water intake, and several of these have also been implicated in ethanol consumption. These include galanin, neuropeptide Y (NPY), melanin concentrating hormone, the opioids, and a-melanocyte stimulating hormone (Bodnar and Klein, 2005;Duncan et al, 2005;Gilpin et al, 2004;Haddad, 2004;Kokare et al, 2006;Lewis et al, 2005;Navarro et al, 2005;Rada et al, 2004;Thiele et al, 2004). In addition to replicating the effects of galanin, the present report expands this area of research to include 2 other orexigenic peptides of current interest, orexin-A and ghrelin.…”

Regulation of the mesocorticolimbic and mesostriatal dopamine systems by α-melanocyte stimulating hormone and agouti-related protein

“…Injection of an MC4R selective agonist into the VTA and nucleus accumbens decreased ethanol intake (Lerma-Cabrera et al, 2012), and both MTII and an MC4R-selective agonist continued to decrease ethanol intake in MC3R knockout mice (Navarro et al, 2005), whereas MTII had no effect on ethanol intake in MC4R knockout mice (Navarro et al, 2011). Thus, it appears that ␣MSH can activate MC4Rs in multiple corticolimbic regions to decrease alcohol intake, whereas AgRP antagonism of MC4R activity leads to increased alcohol intake.…”

“…Icv injection of MTII decreased ethanol intake (Navarro et al, 2005(Navarro et al, , 2003Ploj et al, 2002), while icv injection of AgRP increased ethanol intake (Navarro et al, 2005), although this effect has not been observed in all studies (Navarro et al, 2003;Ploj et al, 2002). Furthermore, AgRP knockout mice show decreased ethanol intake, decreased ethanol self-administration, and decreased binge-like intake of ethanol (Navarro et al, 2009).…”

“…icv MTII Decreased ethanol intake Navarro et al (2005Navarro et al ( , 2003 and Ploj et al (2002) Liu et al (2013) SHU9119 to medial amygdala Blocked stress-induced decreases in feeding Liu et al (2013) MTII to VTA Decreased food intake Decreased sucrose and saccharin intake Roseberry (2013) and Yen and Roseberry (2015) SHU9119 to VTA Increased food intake Increased body weight Roseberry (2013) icv AgRP Increased oil self-administration No effect on sucrose self-administration Tracy et al (2008) icv AgRP Lippert et al (2014) preference and selectively decreases fat intake (Samama et al, 2003), which could possibly be due to alterations in the rewarding qualities of the appetizing and rewarding fat foods used in these studies, although this possibility has not been tested. In addition, icv injection of ACTH, ␣MSH, or MTII increases grooming and rearing behavior (Torre and Celis, 1986;Van Wimersma Greidanus et al, 1989) through a process that has been reported to be dependent on activation of dopamine D1 receptors (D1R) (Van Wimersma Greidanus et al, 1989).…”