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

Abstract.

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.