Attenuation of the stimulant response to ethanol is associated with enhanced ataxia for a GABA_A, but not a GABA_B, receptor agonist

Background: The γ-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol). Methods: In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABA_A receptor agonist muscimol, and the GABA _B receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined. Results: NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response. Conclusions: These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABA_A receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABA_B receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABA_B receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders.