• Paola Maccioni, Daniela Vargiolu, Andrew W Thomas, Pari Malherbe, Claudia Mugnaini, Federico Corelli, Kimberly A Leite-Morris, Gian Luigi Gessa, and Giancarlo Colombo.
• Neuroscience Institute, National Research Council of Italy, Section of Cagliari, S.S. 554, km. 4,500, 09042, Monserrato, CA, Italy.
• Psychopharmacology (Berl.). 2015 May 1; 232 (10): 1831-41.

RationaleTreatment with positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs) inhibits several alcohol-motivated behaviors in rodents, including operant, oral alcohol self-administration.ObjectivesThe present study assessed the effects of (a) repeated administration of the GABAB PAMs, GS39783, and rac-BHFF and (b) a combination of an ineffective dose of either GS39783, or rac-BHFF, and an ineffective dose of the prototypic GABAB receptor agonist, baclofen, on operant, oral alcohol self-administration.MethodsStudies were conducted using selectively bred Sardinian alcohol-preferring (sP) rats exposed to a standard procedure of fixed ratio (FR) 4 (FR4) schedule of reinforcement for 15 % (v/v) alcohol.ResultsRepeated treatment with GS39783 (50 mg/kg, i.g.) or rac-BHFF (50 mg/kg, i.g.) produced an initial 40 % reduction in number of lever responses for alcohol and amount of self-administered alcohol that was maintained unaltered throughout the 10-day period of the GS39783 treatment and increased throughout the 5-day period of the rac-BHFF treatment. Combination of per se ineffective doses of GS39783 (5 mg/kg, i.g.), or rac-BHFF (5 mg/kg, i.g.), and baclofen (1 mg/kg, i.p.) reduced, by 35-45 %, both number of lever responses for alcohol and amount of self-administered alcohol.ConclusionsGS39783 and rac-BHFF (a) reduced alcohol reinforcing properties when given repeatedly, with no development of tolerance, and (b) potentiated baclofen effect. Both sets of data possess translational interest, as they suggest potential effectiveness of GABAB PAMs under chronic treatment and selective potentiation of baclofen effect.

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