Mechanisms of Sleep Induction by GABAA Receptor Agonists

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system. GABA_A receptors are pentameric complexes that function as ligand-gated chloride ion channels. Two types of inhibitory neurotransmission are mediated via GABA_A receptors. Phasic inhibition results from the activation of receptors at the synapse by intermittent release of high concentrations of GABA from presynaptic terminals. Tonic inhibition, in contrast, is mediated by the continuous activation of receptors located outside the synaptic cleft by low concentrations of ambient GABA. These “extrasynaptic” receptors have a higher affinity for GABA and slower rates of desensitization and deactivation than do the classical “synaptic” receptors. A variety of subunit families make up GABA_A receptors; a total of 19 distinct subunits have been cloned. This diversity in subunit composition results in substantial anatomical, functional, and pharmacologic heterogeneity. Receptors containing the α1, α2, or α3 subunits with γ2 are usually found at synapses and are sensitive to benzodiazepines and zolpidem, whereas α4 and α6 subunits are often found with δ and play a role in extrasynaptic receptors (in thalamus and dentate), as does the α5 subunit (in CA1). The α4βδ receptors are insensitive to benzodiazepines and zolpidem, but show high sensitivity to other sedative-hypnotic drugs, including ethanol and the novel hypnotic drug gaboxadol (THIP). This review will examine the role of heterogeneity of GABA_A receptors, and recent research demonstrating subunit-dependent modulation of receptors by novel pharmacologic agents will be discussed.