Rationale: There is evidence that drugs that improve or impair learning can
facilitate or block ethanol tolerance, respectively. Since GABA(B) recepto
rs have been shown to be involved in processes related to learning, it is p
ossible that this system could play a role in the development of rapid tole
rance to ethanol. Objectives: The aim of this study was to verify the influ
ence 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 tra
ined on a continuously accelerating rota-rod device. Animals were pretreate
d with the GABA(B) agonist (-)-baclofen (3, 5, or 7 mg kg(-1)) or saline, 3
0 min before ethanol (1.75 g kg(-1)), and were tested 5, 10, and 15 min lat
er on the rota-rod. In another set of experiments, mice were pretreated wit
h 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 injecti
on, by injecting all animals with ethanol and retesting them on the rota-ro
d. Results: The results showed that (-)-baclofen (5 mg kg(-1)) significantl
y (ANOVA + Tukey's test) blocked rapid tolerance, whereas CGP36742 (3 and 1
0 mg kg(-1)) and CGP56433 (0.3, 1, and 3 mg kg(-1)) facilitated rapid toler
ance in a dose-dependent way. The blockade of rapid tolerance by (-)-baclof
en was antagonized by previous administration of CGP36742 or CGP56433. Conc
lusions: The current results suggest that rapid tolerance to ethanol is sub
jected to inhibition by a GABAergic GABA(B) receptor-mediated system in the
mouse.