Abstract

FAST and SLOW selected mouse lines were bred for differences in locomotor response to low-dose ethanol. FAST mice exhibit an extreme stimulant response and SLOW mice exhibit locomotor depression at the same ethanol dose. We tested the hypothesis that γ-aminobutyric acid (GABA) systems modulate ethanol’s stimulant effects by examining convulsant responses to GABA_A receptor ligands, and by assessing the effects of GABA_A and GABA_Bligands on locomotor activity in the presence and absence of EtOH. FAST mice were more sensitive to the convulsant effects of GABA_Adrugs, and to one of two non-GABAergic drugs also tested. FAST and SLOW mice differed in locomotor responses to two benzodiazepines, but not to other GABA_A receptor ligands. Ethanol’s stimulant effects were not selectively altered by bicuculline or picrotoxin. The selected lines differed in sensitivity to the locomotor depressant effects of the GABA_B agonist, baclofen. Ethanol-stimulated activity of FAST mice was inhibited by baclofen, and this effect was reversed by administration of the GABA_B antagonist, CGP-35348. These GABA_B receptor mediated effects were replicated in DBA/2J inbred mice that exhibit extreme sensitivity to ethanol’s stimulant effects. In summary, we found moderate to strong evidence that some sites on the GABA_A receptor complex were altered as a consequence of selection of FAST and SLOW mice, but found little support for GABA_A mediation of EtOH-stimulated activity. In contrast, we found moderate evidence for differential alteration of GABA_B receptor function; however, GABA_Breceptor involvement in ethanol-stimulated activity was strongly supported by results in the selected lines and an inbred strain.