Present address: University of California, San Francisco, Department of Cell Biology, Genentech Hall, Room N316, 600 16th Street, San Francisco, CA 94107, USA.
Selected line difference in sensitivity to a GABAergic neurosteroid during ethanol withdrawal
Article first published online: 2 JUN 2005
Genes, Brain and Behavior
Volume 5, Issue 1, pages 53–63, February 2006
How to Cite
Finn, D. A., Douglass, A. D., Beadles-Bohling, A. S., Tanchuck, M. A., Long, S. L. and Crabbe, J. C. (2006), Selected line difference in sensitivity to a GABAergic neurosteroid during ethanol withdrawal. Genes, Brain and Behavior, 5: 53–63. doi: 10.1111/j.1601-183X.2005.00137.x
- Issue published online: 25 JUL 2005
- Article first published online: 2 JUN 2005
- Received 13 December 2004, revised 18 February 2005, accepted 19 February 2005
- GABA-stimulated chloride uptake;
- Withdrawal Seizure-Prone mice;
- Withdrawal Seizure-Resistant mice
The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA (GABAA) receptors. Earlier work indicates that sensitivity to the anticonvulsant effect of ALLO was enhanced during ethanol (EtOH) withdrawal in rats and in C57BL/6 mice, an inbred strain with mild EtOH withdrawal. In contrast, ALLO sensitivity was reduced during EtOH withdrawal in DBA/2 mice, an inbred strain with severe EtOH withdrawal. Thus, the present studies examined ALLO sensitivity during EtOH withdrawal in another animal model of EtOH withdrawal severity, the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines. Male mice were exposed to EtOH vapor or air for 72 h. During peak withdrawal, animals were injected with ALLO [0, 3.2, 5, 10 or 17 mg/kg, intraperitoneally (i.p.)] and tested for their sensitivity to the anticonvulsant effect. In separate studies, potentiation of GABA-stimulated chloride uptake by ALLO (10 nm to 10 µm) was assessed in microsacs prepared from mouse brain mice during peak withdrawal. Notably, WSP mice were cross-tolerant to the anticonvulsant effect of ALLO during EtOH withdrawal (i.e. significant decrease in the efficacy of ALLO) when compared with values in air-exposed mice. In contrast, sensitivity to the anticonvulsant effect of ALLO was unchanged during EtOH withdrawal in the WSR line. Functional sensitivity of GABAA receptors to ALLO was significantly decreased during EtOH withdrawal in WSP mice in a manner consistent with the change in behavioral sensitivity to ALLO. These findings suggest that mice selectively bred for differences in EtOH withdrawal severity are differentially sensitive to ALLO during EtOH withdrawal.