Alteration in the Sensitivity of GABAA Receptors to Allosteric Modulatory Drugs in Rat Hippocampus After Chronic Intermittent Ethanol Treatment

Chronic intermittentethanol (CIE)-treated rats exhibited a kindlinglike persistent increase in withdrawal hyperexcitability. The alteration of GABA_A receptor (QABA_AR) function in the hippocampus was suggested as a possible mechanism underlying the hyperexcitability observed in CIE rats, because (1) GABA_AR agonist (muscimol)-evoked ³⁸Cl- efflux was decreased; (2) paired-pulse inhibition in the CA1 area, predominantly due to GABA_AR-mediated recurrent inhibition, was persistently decreased; and (3) GABA_AR subunit expression was altered in the hippocampus from CIE rats. To further characterize the functional alteration of GABA_AR after CIE treatment, their sensitivity to acute ethanol, a steroid anesthetic (alphaxalone), and a benzodiazepine inverse agonist (DMCM; methyl-6, 7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) were studied using either synaptically evoked GABA_AR responses or exogenously applied muscimol-evoked responses in hippocampal slices. Bath application of ethanol (60 mM) enhanced the area of GABA_AR-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 μM) on GABAAR-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 μM) on muscimol-evoked responses was significantly larger in CIE rats (p = 0.002). These results suggest that the sensitization of GABA_AR 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.