Alteration in the sensitivity of GABA(A) receptors to allosteric modulatory drugs in rat hippocampus after chronic intermittent ethanol treatment.

Chronic intermittent ethanol (CIE)-treated rats exhibited a kindling-like persistent increase in withdrawal hyperexcitability. The alteration of GABA(A) receptor (GABA(A)R) function in the hippocampus was suggested as a possible mechanism underlying the hyperexcitability observed in CIE rats, because (1) GABA(A)R agonist (muscimol)-evoked 36Cl- efflux was decreased; (2) paired-pulse inhibition in the CA1 area, predominantly due to GABA(A)R-mediated recurrent inhibition, was persistently decreased; and (3) GABA(A)R subunit expression was altered in the hippocampus from CIE rats. To further characterize the functional alteration of GABA(A)R after CIE treatment, their sensitivity to acute ethanol, a steroid anesthetic (alphaxalone), and a benzodiazepine inverse agonist (DMCM; methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) were studied using either synaptically evoked GABA(A)R responses or exogenously applied muscimol-evoked responses in hippocampal slices. Bath application of ethanol (60 mM) enhanced the area of GABA(A)R-mediated inhibitory postsynaptic potentials in the hippocampal CA1 region from control and CIE rats, and this potentiation was significantly (p = 0.027) greater in CIE rats (98%) than in control rats (53%). The positive modulatory effect of alphaxalone (1 microM) on GABA(A)R-inhibitory postsynaptic potentials was not significantly different between control and CIE rats (p = 0.375), whereas alphaxalone allosterically increased [3H]flunitrazepam binding in the CA1 area only in CIE rats (by 20 to 25%, p < 0.01), but not in controls. On the other hand, the negative modulatory effect of DMCM (1 microM) on muscimol-evoked responses was significantly larger in CIE rats (p = 0.002). These results suggest that the sensitization of GABA(A)R to acute ethanol and benzodiazepine inverse agonists, and possibly neurosteroids, may underlie ethanol dependence after multiple ethanol withdrawal episodes. These altered pharmacological properties are most consistent with changes in the subunit composition in the CA1 area of this rat model of alcohol dependence.