Suppressing effect of COR659 on alcohol, sucrose, and chocolate self-administration in rats: involvement of the GABAB and cannabinoid CB1 receptors

Abstract

COR659 might exert its behavioral effects via a composite mechanism: (i) positive allosteric modulation of the GABA receptor, responsible for a large proportion of reduction of alcohol self-administration; (ii) an action at other receptor system(s), including the cannabinoid CB receptor, through which COR659 affects seeking and consumption of highly palatable foods.

The Novel Positive Allosteric Modulator of the GABAB Receptor, KK-92A, Suppresses Alcohol Self-Administration and Cue-Induced Reinstatement of Alcohol Seeking in Rats

“…sP rats meet all the fundamental requirements posed when defining an animal model of alcohol use disorder (AUD) (see Colombo et al, 2006;Bell et al, 2012). Notably, in relation to the aims of the present study, several previous studies indicated that alcohol self-administration and cue-induced reinstatement of alcohol seeking in sP rats were highly sensitive to positive allosteric modulation of the GABA B receptor (Maccioni et al, 2007(Maccioni et al, , 2008b(Maccioni et al, , 2009(Maccioni et al, , 2010(Maccioni et al, , 2012(Maccioni et al, , 2015(Maccioni et al, , 2017(Maccioni et al, , 2018(Maccioni et al, , 2019aLorrai et al, 2019;Ferlenghi et al, 2020).…”

“…The limited selectivity of KK-92A effect on alcohol selfadministration was somewhat unexpected for the following two main reasons. First, most of the GABA B PAMs tested to date have been reported to reduce alcohol self-administration with no effect on self-administration of highly palatable sucrose, saccharin, sweetened-milk, or chocolate solutions (e.g., Maccioni et al 2007Maccioni et al , 2008bMaccioni et al , 2009Maccioni et al , 2010Maccioni et al , 2012Maccioni et al , 2015Maccioni et al , 2019bLeite-Morris, 2013; see however Augier et al, 2017;Maccioni et al, 2017Maccioni et al, , 2019a. Second, treatment with the same doses of KK-92A tested in the present study resulted to be totally ineffective on operant self-administration of regular food pellets in rats (Li et al, 2017).…”

“…Positive allosteric modulation of the GABA B receptor has emerged as an important molecular mechanism to effectively control several alcohol-motivated behaviors. Accordingly, all positive allosteric modulators (PAMs) of the GABA B receptor (GABA B PAMs) tested to date (namely: CGP7930, GS39783, BHF177, rac-BHFF, ADX71441, COR659, CMPPE, ORM-27669, and ASP8062) have invariably been reported to reduce excessive alcohol drinking (Orrù et al, 2005;Loi et al, 2013;Hwa et al, 2014;Ferlenghi et al, 2020), binge-like drinking (Hwa et al, 2014;Linsenbardt and Boehm, 2014;Colombo et al, 2015;de Miguel et al, 2019), relapse-like drinking (Vengeliene et al, 2018), operant oral alcohol self-administration (Liang et al, 2006;Maccioni et al, 2007Maccioni et al, , 2008bMaccioni et al, , 2009Maccioni et al, , 2010Maccioni et al, , 2012Maccioni et al, , 2015Maccioni et al, , 2017Maccioni et al, , 2018Maccioni et al, , 2019aAugier et al, 2017;Lorrai et al, 2019;Ferlenghi et al, 2020;Haile et al, 2021), cue-and stress-induced reinstatement of alcohol seeking (Augier et al, 2017;Vengeliene et al, 2018;Maccioni et al, 2019a,b), alcohol-induced hyperlocomotion (Kruse et al, 2012), and alcohol-induced conditioned place preference (de Miguel et al, 2019) in rats and mice (for review, see Maccioni and Colombo, 2019;Holtyn and Weerts, 2020).…”

“…The pharmacological profile of GABA B PAMs possess numerous advantages, particularly when compared to that of the orthosteric agonist of the GABA B receptor, baclofen. Focusing on alcohol-motivated behaviors, the reducing effects of GABA B PAMs occurred at doses largely lower than those inducing sedation and muscle relaxation (Maccioni et al, 2010(Maccioni et al, , 2017Linsenbardt and Boehm, 2014;Vengeliene et al, 2018;de Miguel et al, 2019) and devoid of any effect on natural rewards (e.g., water, regular or palatable food) (Orrù et al, 2005;Maccioni et al, 2007Maccioni et al, , 2008bMaccioni et al, , 2009Maccioni et al, , 2010Maccioni et al, , 2012Maccioni et al, , 2015Maccioni et al, , 2019bLoi et al, 2013;Hwa et al, 2014;Colombo et al, 2015; see however Augier et al, 2017). Additionally, no tolerance developed on continuing treatment (Loi et al, 2013;Maccioni et al, 2015Maccioni et al, , 2019aVengeliene et al, 2018).…”

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

“…By binding to a different, non-competitive allosteric site on the GABA B receptor, PAMs allow endogenous GABA, binding at its original orthosteric site, to retain its potency and efficacy, reducing the risk of tolerance development and side effects [253,254]. A number of PAMs have been studied as potential pharmacotherapies for AUD, and have demonstrated reductions in alcohol-associated behaviors and ethanol self-administration in preclinical models [252,[255][256][257][258]. When directly contrasted against baclofen, a GABA B PAM had a better profile, with dose-dependent reduction of relapse-like alcohol drinking and with no signs of sedation [257].…”