GABAB receptors play a role in the development of tolerance to ethanol in mice

Rationale: There is evidence that drugs that improve or impair learning can facilitate or block ethanol tolerance, respectively. Since GABA(B) receptors have been shown to be involved in processes related to learning, it is possible that this system could play a role in the development of rapid tolerance to ethanol. Objectives: The aim of this study was to verify the influence of one GABA(B) agonist and two GABA(B) antagonists on tolerance to the effect of ethanol on motor coordination. Methods: Male Swiss mice were trained on a continuously accelerating rota-rod device. Animals were pretreated with the GABA(B) agonist (-)-baclofen (3, 5, or 7 mg kg(-1)) or saline, 30 min before ethanol (1.75 g kg(-1)), and were tested 5, 10, and 15 min later on the rota-rod. In another set of experiments, mice were pretreated with the GABA(B) antagonists CGP36742 (1, 3, 10, or 30 mg kg(-1)) or CGP56433 (0.1, 0.3, 1.0, or 3.0 mg kg(-1)), or saline, 30 min before the test under ethanol. Rapid tolerance was evaluated 24 h after the first ethanol injection, by injecting all animals with ethanol and retesting them on the rota-rod. Results: The results showed that (-)-baclofen (5 mg kg(-1)) significantly (ANOVA + Tukey's test) blocked rapid tolerance, whereas CGP36742 (3 and 10 mg kg(-1)) and CGP56433 (0.3, 1, and 3 mg kg(-1)) facilitated rapid tolerance in a dose-dependent way. The blockade of rapid tolerance by (-)-baclofen was antagonized by previous administration of CGP36742 or CGP56433. Conclusions: The current results suggest that rapid tolerance to ethanol is subjected to inhibition by a GABAergic GABA(B) receptor-mediated system in the mouse.