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Vol. 63, Issue 1, 53-64, January 2003
Department of Molecular and Medical Pharmacology, School of
Medicine (E.C., J.L., R.W.O.), and Division of Oral Biology and
Medicine, School of Dentistry (J.L., I.S.), University of California
Los Angeles, Los Angeles, California
One of the pharmacological targets of ethanol is the GABAA
receptor (GABAR), whose function and expression are altered after chronic administration of ethanol. The details of the changes differ
between experimental models. In the chronic intermittent ethanol (CIE)
model for alcohol dependence, rats are exposed to intermittent episodes
of intoxicating ethanol and withdrawal, leading to a kindling-like
state of behavioral excitability. This is accompanied by presumably
causal changes in GABAR expression and physiology. The present study
investigates further the effect of CIE on GABAR function and
expression. CIE is validated as a model for human alcohol withdrawal
syndrome (AWS) by demonstrating increased level of anxiety; diazepam
improved performance in the test. In addition, CIE rats showed
remarkably reduced hypnotic response to a benzodiazepine and a steroid
anesthetic, reduced sensitivity to a barbiturate, but not propofol.
Immunoblotting revealed decrease in 
1 and 
expression and
increase in 
2 and 4 subunits in hippocampus of CIE rats,
confirmed by an increase in diazepam-insensitive binding for
ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-)(1,4)benzodiazepine-3-carboxylate (Ro15-4513). Elevated mRNA levels were shown for the 2S and
1 subunits. Recordings in hippocampal slices from CIE rats revealed that the decay time of GABAR-mediated miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal cells was decreased, and
potentiation of mIPCSs by positive modulators of GABAR was also reduced
compared with control rats. However, mIPSC potentiation by the
4-preferring benzodiazepine ligands bretazenil and Ro15-4513 was
maintained, and increased, respectively. These data suggest that
specific alterations in GABAR occur after CIE and may underlie the
development of hyperexcitability and ethanol dependence.
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