Abstract
Rationale
Treatment with positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs) inhibits several alcohol-motivated behaviors in rodents, including operant, oral alcohol self-administration.
Objectives
The 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.
Methods
Studies 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.
Results
Repeated 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.
Conclusions
GS39783 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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Acknowledgments
The authors are grateful to Mrs. Carla Acciaro for animal breeding and care, and Ms. Anne Farmer for language editing of the manuscript. This work has been supported by the following grants: CRP-17596 from Regione Autonoma della Sardegna (L.R. 7 agosto 2007, n. 7); EA 13 20 from European Foundation for Alcohol Research (ERAB).
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Maccioni, P., Vargiolu, D., Thomas, A.W. et al. Inhibition of alcohol self-administration by positive allosteric modulators of the GABAB receptor in rats: lack of tolerance and potentiation of baclofen. Psychopharmacology 232, 1831–1841 (2015). https://doi.org/10.1007/s00213-014-3815-8
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DOI: https://doi.org/10.1007/s00213-014-3815-8