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
Article first published online: 6 APR 2012
Copyright © 2012 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 36, Issue 10, pages 1748–1766, October 2012
How to Cite
Maccioni, P., Zaru, A., Loi, B., Lobina, C., Carai, M. A. M., Gessa, G. L., Capra, A., Mugnaini, C., Pasquini, S., Corelli, F., Hyytiä, P., Lumeng, L. and Colombo, G. (2012), 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. Alcoholism: Clinical and Experimental Research, 36: 1748–1766. doi: 10.1111/j.1530-0277.2012.01782.x
- Issue published online: 1 OCT 2012
- Article first published online: 6 APR 2012
- Manuscript Accepted: 2 FEB 2012
- Manuscript Received: 26 JUL 2011
- Compagnia di San Paolo—Programma Neuroscienze
- NIH-NIAAA. Grant Number: 2R24AA15512-06
- PO Sardegna FSE
- GABAB Receptor Agonist Baclofen;
- Positive Allosteric Modulator of the GABAB Receptor GS39783;
- Operant Oral Alcohol Self-Administration;
- Reinforcing and Motivational Properties of Alcohol;
- Alcohol-Preferring P Rats;
- Alcohol-Preferring sP Rats;
- Alcohol-Preferring A Rats
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).
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.
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.
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.