Behavioral interactions between ethanol and GABA-mimetic and GABA antagonist drugs were evaluated by duration of narcosis and motor incoordination (inhibition of bar holding) in mice. Aminooxyacetic acid (AOAA), baclofen, and tetrahydroisoxazolopyridineol (THIP) (GABA mimetics) lengthened ethanol narcosis, while picrotoxin shortened ethanol narcosis. AOAA and baclofen also enhanced the incoordinating effects of ethanol, while picrotoxin and bicuculline (GABA antagonists) had the opposite effect. In addition, the incoordinating effects of AOAA and baclofen were potentiated by low doses of ethanol, while incoordination produced by bicuculline was antagonized by ethanol. Mice selected for genetic differences in neurosensitivity to ethanol (LS and SS strains) displayed corresponding differences in the incoordinating effects of baclofen and THIP. Furthermore, chronic ingestion of ethanol resulted in a decrease in the incoordinating effect of THIP. These results, together with electrophysiological, biochemical, and behavioral data from other laboratories, suggest that: (1) augmentation of GABA effects is involved in the incoordinating and soporific actions of ethanol; (2) one factor responsible for genetic differences in ethanol response is sensitivity to GABA; and (3) ethanol tolerance and dependence may be related to decreased sensitivity to GABA.