Mechanisms of Sleep Induction by GABA<sub>A</sub> Receptor Agonists
J Clin Psychiatry 2007;68(suppl 5):6-12
© Copyright 2016 Physicians Postgraduate Press, Inc.
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Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian
central nervous system. GABAA receptors are pentameric complexes that function as ligand-gated
chloride ion channels. Two types of inhibitory neurotransmission are mediated via GABAA 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 GABAA 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 GABAA receptors, and recent research demonstrating subunit-dependent modulation of receptors by novel pharmacologic agents will be discussed.