Comparison of the effect of the GABAΒ 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

Abstract

Background: Administration of the GABA(B) 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 GABA(B) receptor is part of the neural substrate mediating the reinforcing and motivational properties of alcohol.

Figure 1

Effect of treatment with the GABA_B receptor agonist, baclofen, on total number of responses on the alcohol lever (panels A–C), amount of self-administered alcohol (panels D–F), latency to the first response on the alcohol lever (panels G–I), and cumulative response patterns of alcohol self-administration (panels J–L) in selectively bred, Indiana alcohol-preferring (P) (panels A, D, G, and J), Sardinian alcohol-preferring (sP) (panels B, E, H, and K), and Alko Alcohol (AA) (panels C, F, I, and L) rats. Rats were initially trained to lever-press for oral alcohol (15% v/v, in water) [fixed ratio (FR) 4 (FR4)] and water (FR1) in daily 30-min sessions; once self-administration behavior had stabilized, rats were tested with baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) under the same FR schedule of reinforcement. All doses of baclofen were tested in each rat under a Latin-square design. In panels J–L, the first 15 min of the sessions were divided into 30 time intervals of 30 s each. Each bar or point is the mean ± SEM of n=12 rats. +: P<0.05, ++: P<0.001, and +++: P<0.0001 with respect to vehicle-treated P rats (LSD test); §: P<0.001 with respect to vehicle-treated sP rats (LSD test); *: P<0.01,**: P<0.005, and ***: P<0.0001 with respect to vehicle-treated rats of the same line (LSD test); #: P<0.05, ##: P<0.001, and ###: P<0.0001 with respect to rats of the same line treated with 1 mg/kg baclofen (LSD test); ¥: P<0.05, ¥¥: P<0.001, and ¥¥¥: P<0.0001 with respect to rats of the same line treated with 1.7 mg/kg baclofen (LSD test).

Figure 2

Effect of treatment with the GABA_B receptor agonist, baclofen, on total number of responses on the alcohol lever (panels A–C), breakpoint for alcohol (panels D–F), latency to the first response on the alcohol lever (panels G–I), and cumulative response patterns of alcohol self-administration (panels J–L) in selectively bred, Indiana alcohol-preferring (P) (panels A, D, G, and J), Sardinian alcohol-preferring (sP) (panels B, E, H, and K), and Alko Alcohol (AA) (panels C, F, I, and L) rats. Rats were initially trained to lever-press for oral alcohol (15% v/v, in water) [fixed ratio (FR) 4 (FR4)] and water (FR1) in daily 30-min sessions; once self-administration behavior had stabilized, rats were tested with baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) under a progressive ratio (PR) schedule of reinforcement, in which the response requirement was increased progressively over a 60-min session. Breakpoint was defined as the lowest response requirement not achieved by the rat. All doses of baclofen were tested in each rat under a Latin-square design. In panels J–L, the first 15 min of the sessions were divided into 30 time intervals of 30 s each. Each bar or point is the mean ± SEM of n=12 rats. +: P<0.005, ++: P<0.001, and +++: P<0.0001 with respect to vehicle-treated P rats (LSD test); *: P<0.05 and **: P<0.0001 with respect to vehicle-treated rats of the same line (LSD test); #: P<0.001 and ##: P<0.0001 with respect to rats of the same line treated with 1 mg/kg baclofen (LSD test); ¥: P<0.05, ¥¥: P<0.001, and ¥¥¥: P<0.0001 with respect to rats of the same line treated with 1.7 mg/kg baclofen (LSD test).

Figure 3

Effect of treatment with the positive allosteric modulator of the GABA_B receptor, GS39783, on total number of responses on the alcohol lever (panels A–C), amount of self-administered alcohol (panels D–F), latency to the first response on the alcohol lever (panels G–I), and cumulative response patterns of alcohol self-administration (panels J–L) in selectively bred, Indiana alcohol-preferring (P) (panels A, D, G, and J), Sardinian alcohol-preferring (sP) (panels B, E, H, and K), and Alko Alcohol (AA) (panels C, F, I, and L) rats. Rats were initially trained to lever-press for oral alcohol (15% v/v, in water) [fixed ratio (FR) 4 (FR4)] and water (FR1) in daily 30-min sessions; once self-administration behavior had stabilized, rats were tested with GS39783 (0, 25, 50, and 100 mg/kg; i.g.) under the same FR schedule of reinforcement. All doses of GS39783 were tested in each rat under a Latin-square design. In panels J–L, the first 15 min of the sessions were divided into 30 time intervals of 30 s each. Each bar or point is the mean ± SEM of n=12 rats. +: P<0.01 and ++: P<0.0001 with respect to vehicle-treated P rats (LSD test); §: P<0.001 with respect to vehicle-treated sP rats (LSD test); *: P<0.05, **: P<0.01, ***: P<0.001, and ****: P<0.0001 with respect to vehicle-treated rats of the same line (LSD test); #: P<0.05 and ##: P<0.0005 with respect to rats of the same line treated with 25 mg/kg GS39783 (LSD test); ¥: P<0.05, ¥¥: P<0.01, and ¥¥¥: P<0.0005 with respect to rats of the same line treated with 50 mg/kg GS39783 (LSD test).

Figure 4

Effect of treatment with the positive allosteric modulator of the GABA_B receptor, GS39783, on total number of responses on the alcohol lever (panels A–C), breakpoint for alcohol (panels D–F), latency to the first response on the alcohol lever (panels G–I), and cumulative response patterns of alcohol self-administration (panels J–L) in selectively bred, Indiana alcohol-preferring (P) (panels A, D, G, and J), Sardinian alcohol-preferring (sP) (panels B, E, H, and K), and Alko Alcohol (AA) (panels C, F, I, and L) rats. Rats were initially trained to lever-press for oral alcohol (15% v/v, in water) [fixed ratio (FR) 4 (FR4)] and water (FR1) in daily 30-min sessions; once self-administration behavior had stabilized, rats were tested with GS39783 (0, 25, 50, and 100 mg/kg; i.g.) under a progressive ratio (PR) schedule of reinforcement, in which the response requirement was increased progressively over a 60-min session. Breakpoint was defined as the lowest response requirement not achieved by the rat. All doses of GS39783 were tested in each rat under a Latin-square design. In panels J–L, the first 15 min of the sessions were divided into 30 time intervals of 30 s each. Each bar or point is the mean ± SEM of n=12 rats. +: P<0.05, ++: P<0.01, and +++: P<0.0001 with respect to vehicle-treated P rats (LSD test); §: P<0.05 and §§: P<0.01 with respect to vehicle-treated sP rats (LSD test); *: P<0.05 and **: P<0.0001 with respect to vehicle-treated rats of the same line (LSD test); #: P<0.05 and ##: P<0.01 with respect to rats of the same line treated with 25 mg/kg GS39783 (LSD test).