Vol. 287, Issue 2, 606-615, November 1998

Seizure Sensitivity and GABAergic Modulation of Ethanol Sensitivity in Selectively Bred FAST and SLOW Mouse Lines¹

Elaine H. Shen, Janet Dorow, Richard Harland, Sue Burkhart-Kasch and Tamara J. Phillips

Veterans Affairs Medical Center, Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health Sciences University, Portland, Oregon

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 -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_B ligands on locomotor activity in the presence and absence of EtOH. FAST mice were more sensitive to the convulsant effects of GABA_A drugs, 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_B receptor involvement in ethanol-stimulated activity was strongly supported by results in the selected lines and an inbred strain.