Suppressing effect of CMPPE, a new positive allosteric modulator of the GABAB receptor, on alcohol self-administration and reinstatement of alcohol seeking in rats

Positive allosteric modulators (PAMs) of the GABABreceptor constitute a class of pharmacological agentsgaining increasing attention in the alcohol researchfield because of their ability to suppress severalalcohol-related behaviors in rodents. CMPPE is a novel GABABPAM, still limitedly characterizedin vivo.Itwas therefore of interest to test its ability to affect operant, oral self-administration of alcohol and cue-induced reinstatement of alcohol seeking in alcohol-preferring rats. To this end, female Sardinianalcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under thefixed ratio (FR) 5(FR5) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions(under the FR5 [Experiment 1] and progressive ratio [PR; Experiment 2] schedules of reinforcement)preceded by treatment with CMPPE (0, 2.5, 5, and 10 mg/kg; intraperitoneally [i.p.]). In Experiment 3, oncelever-responding had stabilized, rats underwent an extinction responding phase and then a single rein-statement session during which lever-responding was resumed by the non-contingent presentation of acomplex of alcohol-associated cues; CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) was administered before thereinstatement session. Selectivity of CMPPE action was assessed by evaluating the effect of CMPPE (0, 2.5, 5,and 10 mg/kg; i.p.) on self-administration of a chocolate solution in male Wistar rats (Experiment 4). InExperiments 1 and 2, treatment with 5 and 10 mg/kg CMPPE reduced lever-responding and breakpoint foralcohol. In Experiment 3, treatment with 5 and 10 mg/kg CMPPE suppressed reinstatement of alcoholseeking. In Experiment 4, no dose of CMPPE affected lever-responding for the chocolate solution. Theseresults extend to CMPPE the ability of all previously tested GABABPAMs to affect alcohol-motivated be-haviors in rodents and confirm that these effects are a shared feature of the entire class of GABABPAMs.This conclusion is of relevance in view of the forthcoming transition of GABABPAMs to clinical testing.