GABA Receptor Plasticity in Alcohol Withdrawal

Chronic intermittent ethanol (CIE) treatment and withdrawal in rats produces behavioral changes modeling human alcohol dependence including increased seizure susceptibility, which are associated with long-lasting changes in inhibitory neurotransmission involving the γ-aminobutyric acid (GABA) type A receptors (GABAR). The propensity for dependence on alcohol involves both brain reward mechanisms and the withdrawal syndrome, leading to increased consumption. The withdrawal syndrome includes hyperactivity and hyperexcitability, increased anxiety, sleep disorders, including tolerance to sedative actions of ethanol and other sleep aids, and increased seizure susceptibility. Using a rat model of alcohol dependence involving CIE administration with multiple episodes of intoxication and withdrawal, we deduced that multiple withdrawals produce a kindling-like phenomenon. We also demonstrated that behavioral changes are induced by one dose of ethanol (5 g/kg, gavage) in rats and result from changes in subunit composition, subcellular location, pharmacology and function of GABARs. Ethanol (EtOH)-sensitive extrasynaptic α4/δ-containing GABAR-mediated tonic inhibitory currents are rapidly down-regulated, followed by a slower down-regulation of benzodiazepine (BZ)-sensitive α1/γ2-mediated inhibitory synaptic currents and increased compensatory α4/γ2 synaptic GABAR currents in parallel with increased sensitivity to low millimolar (mM) concentrations of EtOH. While these changes are transient and normalize in a few days, CIE treatment (>30 doses) makes this remodeling of GABAR persistent. We conclude that GABAR plasticity is essential to development of EtOH dependence including seizure susceptibility, and may provide a possible model of epileptogenesis in mammalian brain.