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|Title:||Comparison of the effect of the positive allosteric modulator of the GABAb receptor, GS39783, on alcohol self-administration in three different lines of alcohol-preferring rats||Authors:||Maccioni, P.
Carai, M. A. M.
Gessa, G. L.
|Issue Date:||2012||Project:||None||Journal:||ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH||Abstract:||
Background: Administration of the GABAB receptor agonist, baclofen, and positive allosteric modulator,GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, includingoperant oral alcohol self-administration, in rats. This study was designed to compare the effect of baclofenand 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-minutesessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testingbaclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressiveratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783action, 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>AArats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy ofbaclofen and GS39783 in suppressing alcohol self-administration was P>sP>AA rats. Only the highestdose 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 propertiesof alcohol differ among P, sP, and AA rats; (ii) the reinforcing and motivational properties of alcoholin P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (iii) theheterogeneity in sensitivity to baclofen and GS39783 of alcohol self-administration in P, sP, and AArats may resemble the differential effectiveness of pharmacotherapies among the different typologies ofhuman alcoholics; and (iv) the GABAB receptor is part of the neural substrate mediating the reinforcingand motivational properties of alcohol.
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