Altered pharmacology of synaptic and extrasynaptic GABAA receptors on CA1 hippocampal neurons is consistent with subunit changes in a model of alcohol withdrawal and dependence

Previously, we reported (Cagetti, Liang, Spigelman, and Olsen, 2003) that chronic intermittent ethanol (CIE) treatment leads to signs of alcohol dependence, including anxiety and hyperactivity, accompanied by reduced synaptic gamma-aminobutyric acid ( A) receptor (GABA(A) R) function and altered sensitivity to its allosteric modulators consistent with a measured switch in subunit composition. In this study, we separated the synaptic and extrasynaptic components of GABA(A)R activation in recordings from pyramidal CA1 cells of hippocampal slices and demonstrated marked differences in the responsiveness of synaptic and extrasynaptic GABA(A)Rs to agonists and allosteric modulators in control rats, and in the way they are altered following CIE treatment. Notably, tonic inhibition mediated by extrasynaptic GABA(A)Rs was differentially sensitive to the partial agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; THIP) and the allosteric modulator zolpidem, compared with the miniature inhibitory synaptic currents (mIPSCs) in the same cells from saline-treated rats. After CIE treatment, potentiation of tonic currents by diazepam and zolpidem was lost, whereas potentiation by the alpha4 subunit-preferring benzodiazepine Ro15-4513 ( ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4] benzodiazepine-3- carboxylate) and THIP was only partially reduced. Potentiation of synaptic GABA(A) R currents by zolpidem was eliminated after CIE, whereas THIP slightly inhibited mIPSCs from control rats and greatly enhanced them after CIE treatment. These results are consistent with alpha1 subunit decreases at synaptic and extrasynaptic GABA(A)Rs, whereas alpha4 subunits are increased at synaptic and decreased at extrasynaptic GABA(A) Rs. Behaviorally, THIP was active as a hypnotic and anxiolytic but not as an anticonvulsant against pentylenetetrazol seizures in control rats. Only slight tolerance was observed to the sleep time, but not to the anxiolytic, effect of THIP after CIE. Thus, differential alterations in synaptic and extrasynaptic GABA(A) Rs appear to play an important role in the brain plasticity of alcohol dependence, and withdrawal signs may be profitably treated with GABAergic drugs such as THIP, which does not show cross-tolerance with ethanol.