RT Journal Article
SR Electronic
T1 Seizure Sensitivity and GABAergic Modulation of Ethanol Sensitivity in Selectively Bred FAST and SLOW Mouse Lines
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 606
OP 615
VO 287
IS 2
A1 Elaine H. Shen
A1 Janet Dorow
A1 Richard Harland
A1 Sue Burkhart-Kasch
A1 Tamara J. Phillips
YR 1998
UL http://jpet.aspetjournals.org/content/287/2/606.abstract
AB 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 GABAA receptor ligands, and by assessing the effects of GABAA and GABABligands on locomotor activity in the presence and absence of EtOH. FAST mice were more sensitive to the convulsant effects of GABAAdrugs, 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 GABAA 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 GABAB agonist, baclofen. Ethanol-stimulated activity of FAST mice was inhibited by baclofen, and this effect was reversed by administration of the GABAB antagonist, CGP-35348. These GABAB 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 GABAA receptor complex were altered as a consequence of selection of FAST and SLOW mice, but found little support for GABAA mediation of EtOH-stimulated activity. In contrast, we found moderate evidence for differential alteration of GABAB receptor function; however, GABABreceptor involvement in ethanol-stimulated activity was strongly supported by results in the selected lines and an inbred strain. The American Society for Pharmacology and Experimental Therapeutics