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Comparison of the Effect of the GABAB Receptor Agonist, Baclofen, and the Positive Allosteric Modulator of the GABAB Receptor, GS39783, on Alcohol Self-Administration in 3 Different Lines of Alcohol-Preferring Rats

Authors


Reprint requests: Giancarlo Colombo, Section of Cagliari, Neuroscience Institute, National Research Council of Italy, S.S. 554, km. 4,500, I-09042 Monserrato, CA, Italy; Tel.: +39 070 675 4342; Fax: +39 070 675 4320; E-mail: colomb@unica.it

Abstract

Background

Administration of the GABAB receptor agonist, baclofen, and positive allosteric modulator, GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self-administration, in rats. This study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in 3 lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcohol-preferring (sP), and Alko Alcohol (AA).

Methods

Rats of each line were initially trained to respond on a lever, on a fixed ratio (FR) 4 (FR4) schedule of reinforcement, to orally self-administer alcohol (15%, v/v) in daily 30-minute sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressive ratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783 action, rats were slightly food-deprived and trained to lever-respond for food pellets.

Results

The rank of order of the reinforcing and motivational properties of alcohol was P>sP>AA rats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy of baclofen and GS39783 in suppressing alcohol self-administration was P>sP>AA rats. Only the highest dose of baclofen reduced lever-responding for food pellets; this effect was common to all 3 rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line.

Conclusions

These results suggest that: (i) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (ii) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (iii) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol self-administration in P, sP, and AA rats may resemble the differential effectiveness of pharmacotherapies among the different typologies of human alcoholics; and (iv) the GABAB receptor is part of the neural substrate mediating the reinforcing and motivational properties of alcohol.

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