Altered Pharmacology of Synaptic and Extrasynaptic GABA_AReceptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence

Abstract

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 ␥-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 ␣4 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 ␣1 subunit decreases at synaptic and extrasynaptic GABA A Rs, whereas ␣4 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.

Short-term steroid treatment increases δ GABAA receptor subunit expression in rat CA1 hippocampus: Pharmacological and behavioral effects

“…3A,B). These are values approximately two-fold greater than observed under control conditions (P<0.001), similar to previous reports (Liang et al, 2004). A lower concentration of THIP (5 μM) produced a 70-80 pA current following steroid treatment, while the THIP-generated current recorded under control conditions was barely detectable.…”

“…This tonic current is also a major target of GABA-modulatory drugs such as BDZs, anesthetics, barbiturates, steroids and ethanol (Bai et al, 2000;Belelli and Herd, 2003;Liang et al, 2004;Stell et al, 2003;Wei et al, 2004). Our data as well suggest that the tonic component produces a greater response to BDZs recorded under control conditions.…”

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).…”

Altered Expression of the δ Subunit of the GABAAReceptor in a Mouse Model of Temporal Lobe Epilepsy

“…Other studies have reported increases in either the ␥2 or ␣4 subunit (Brooks-Kayal et al, 1998;Fritschy et al, 1999). Similar, potentially interrelated changes in the ␦, ␣4, and ␥2 subunits have also been observed in a chronic, intermittent, ethanol model of alcohol withdrawal (Cagetti et al, 2003) that exhibits decreased inhibition and a decreased threshold for pentylenetetrazol seizures (Kokka et al, 1993;Kang et al, 1998;Liang et al, 2004). Thus, the profile of decreased ␦ and increased ␣4 and ␥2 subunit expression may predominate in several animal models with increased seizure susceptibility.…”