Differential Regulation of GABA_A Receptor Gene Expression by Ethanol in the Rat Hippocampus Versus Cerebral Cortex

Abstract

Abstract:Previous research has shown that chronic ethanol consumption dramatically alters GABAA receptor a, and a 4 subunit gene expression in the cerebral cortex and GABAA receptor a, and a6 subunit gene expression in the cerebellum. However, it is not yet known if chronic ethanol consumption produces similar alterations in GA-BAA receptor gene expression in other brain regions. One brain region of interest is the hippocampus because it has recently been shown that a subset of GABAA receptors in the hippocampus is responsive to pharmacologically relevant concentrations of ethanol. Therefore, we directly compared the effects of chronic ethanol consumption on GABAA receptor subunit gene expression in the hippocampus and cerebral cortex. Furthermore, we investigated whether the duration of ethanol consumption (14 or 40 days) would influence regulation of GABAA receptor gene expression in these two brain regions. Chronic ethanol consumption produced a significant increase in the level of GABAA receptor a4 subunit peptide in the hippocampus following 40 days but not 14 days. The relative expression of hippocampal GABAA receptor a1, a2, a3, /32/3, or Y2 was not altered by either period of chronic ethanol exposure. In marked contrast, chronic ethanol consumption for 40 days significantly increased the relative expression of cerebral cortical GABAA receptor a4 subunits and significantly decreased the relative expression of cerebral cortical GABAA receptor a, subunits. This finding is consistent with previous results following 14 days of chronic ethanol consumption. Hence, chronic ethanol consumption alters GABAA receptor gene expression in the hippocampus but in a different manner from that in either the cerebral cortex or the cerebellum. Furthermore, these alterations are dependent on the duration of ethanol exposure.

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

“…Thus, the hippocampus may be one of several brain regions in the limbic neuroanatomical circuit underlying PTZ-induced convulsions whereby line differences in GABA A receptors exist. Certainly, chronic ethanol exposure and withdrawal significantly alters the expression and peptide levels of several GABA A receptor subunits in the hippocampus of male rats (↓ α1, ↑ α4, ↑ γ2, ↓ δ; Cagetti et al, 2003;Grobin et al, 2000;Matthews et al, 1998), but the relevance of these changes in expression to GABA A receptor subunit assembly or trafficking, composition of synaptic versus extra-synaptic receptors, or phosphorylation state of GABA A receptors (see Kumar et al, 2004;Liang et al, 2004) to the present findings is not known. Additional factors influencing GABA A receptor function are the rapid diffusion of hippocampal receptors from extra-synaptic to synaptic domains (Thomas et al, 2005) and GABA A receptor associated proteins (Chen and Olsen, 2007).…”

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

“…Increases in a4 subunit protein were implicated in withdrawal from ethanol (Matthews et al, 1998;Sanna et al, 2003) and BZs (Follesa et al, 2001), while neurosteroid treatment was associated with withdrawal-anxiety, upregulation of GABAR a4 subunits and a reduction in mIPSC decay (Smith, 2002). Although a4 subunit protein was upregulated immediately after 1-week FZP treatment (Chen et al, 2000), mIPSC decay was unaltered on days 1 and 2 of withdrawal (Table 2; Zeng and Tietz, 1999).…”

The role of GABAA receptors in the development of alcoholism

“…In contrast, a consistent finding in rodents is that chronic ethanol consumption decreases cortical mRNA and peptide levels of α 1 subunits but increases α 4 levels (Devaud et al, 1996(Devaud et al, , 1997Grobin et al, 1998;Matthews et al, 1998). Cortical peptide levels for β 2/3 and γ 1 and mRNA for γ 2S increase in ethanol-dependent rats (Devaud et al, 1997).…”