TY - JOUR
T1 - Seizure sensitivity and GABAergic modulation of ethanol sensitivity in selectively bred FAST and SLOW mouse lines
AU - Shen, Elaine H.
AU - Dorow, Janet
AU - Harland, Richard
AU - Burkhart-Kasch, Sue
AU - Phillips, Tamara J.
PY - 1998
Y1 - 1998
N2 - 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(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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=0032470249&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032470249&partnerID=8YFLogxK
M3 - Article
C2 - 9808687
AN - SCOPUS:0032470249
SN - 0022-3565
VL - 287
SP - 606
EP - 615
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -