mGluR1 within the nucleus accumbens regulates alcohol intake in mice under limited-access conditions

Abstract

Idiopathic or alcohol-induced increases in the expression and function of the Group1 metabotropic glutamate receptor subtype 1 (mGluR1) within the extended amygdala are theorized to contribute to an individual’s propensity to consume excessive amounts of alcohol. In the past, the detailed study of the functional relevance of mGluR1 for alcoholism-related behaviors in animal models was hampered by the poor solubility and non-specific side effects of available inhibitors; however, the advent of the highly potent and soluble mGluR1 negative allosteric modulator JNJ-16259685 [(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone] has instigated a re-examination of the role for this mGluR subtype in mediating the behavioral effects of alcohol. In this regard, systemic pretreatment with JNJ-16259685 was proven effective at reducing alcohol reinforcement and motivation for the drug. mGluR1 is a Gαq/o-coupled receptor, the stimulation of which activates phospholipase C (PLC). Thus, the present study investigated potential neuroanatomical substrates and intracellular molecules involved in the ability of JNJ-16259685 to reduce alcohol intake. JNJ-16259685 (0–30 pg/side) was infused into the shell subregion of the nucleus accumbens (NAC) of C57BL/6J and Homer2 knock-out (KO) mice, either alone or in combination with the PLC inhibitor U-73122 (5.8 fg/side). Alcohol intake was then assessed under Drinking-in-the-Dark (DID) procedures. Intra-NAC JNJ-16259685 infusion dose-dependently reduced alcohol consumption by C57BL/6J mice; this effect was not additive with that produced by U-73122, nor was it present in Homer2 KO animals. These data provide novel evidence in support of a critical role for mGluR1-PLC signaling, scaffolded by Homer2, within the NAC shell, in maintaining alcohol consumption under limited access procedures. Such findings have relevance for both the pharmacotherapeutics and pharmacogenetics of risky alcohol drinking and alcoholism.

Homer2 within the nucleus accumbens core bidirectionally regulates alcohol intake by both P and Wistar rats

“…3 & 4). The negative findings regarding the effects of intra-NAc AAV-Homer2b infusion upon the intake of, and preference for, sweet solutions in rats are consistent with nearly a decade of evidence from studies of mice indicating that Homer2, or its associated mGluRs, do not contribute in any significant manner to regulating the rewarding/reinforcing properties of sweet solutions (e.g., Cozzoli et al, 2009, 2012; Lum, Campbell, Rostock, & Szumlinski, 2014; Szumlinski, Ary, Lominac, et al, 2008; Szumlinski et al, 2005). As such, the present drinking data provide the first cross-species evidence that NAc Homer2 actively regulates alcohol intake, without influencing the neural processes underpinning fluid consumption or the hedonic value of non-drug, highly palatable, positive reinforcers.…”

Intra-nucleus accumbens shell injections of R(+)- and S(−)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice

“…The 200 nl/side of fluid injected in the current study is less than what has been injected into the NACsh in previous studies [64, 65]. A built-in control for determining diffusion is histological misses.…”

Binge alcohol drinking elicits persistent negative affect in mice

“…Further, dysphoric states during withdrawal are mediated by changes in Acb neurotransmission, with alcohol-induced reductions in monoaminergic function theorized to contribute to the depressive effects of alcohol withdrawal. [23, 74, 75], Moreover, we know that a chronic history of binge drinking elevates indices of glutamatergic signaling within the Acb [15, 73]. Thus, we hypothesized at the outset of this study that a history of binge drinking would augment Acb cellular activity, particularly within the AchSh, and this increased activity would correlate with behavioral indices of negative affect.…”

“…The AcbSh and AcbC are both anatomically and functionally distinct [71], although both Acb subregions have been implicated in governing different aspects of alcohol reward and alcohol reward-related learning [72] and prior immunoblotting studies indicated changes in excitatory neurochemistry within these subregions in alcohol-experienced animals [15, 23, 63, 73, 74]. Further, dysphoric states during withdrawal are mediated by changes in Acb neurotransmission, with alcohol-induced reductions in monoaminergic function theorized to contribute to the depressive effects of alcohol withdrawal.…”