GABAA receptors are part of a superfamily of ligand-gated ion channels, including nicotinic acetylcholine receptors and glycine receptors, which exist as pentamers arranged around a central ion channel. When activated, they hyperpolarize the postsynaptic neuron by facilitating an inward chloride current (without a G protein messenger), decreasing the likelihood of the neuron firing an action potential. γ-aminobutyric acid type A (GABAA) receptors have separate binding sites for GABA, barbiturates, benzodiazepines, loreclezole, and picrotoxin (Chap. 14).31 Barbiturates and benzodiazepines bind to separate receptor sites and enhance the affinity for GABAA at its receptor site.
The GABA receptor is a pentamer comprised of two α subunits, two β subunits, and one additional subunit, most commonly γ, which is a key element in the benzodiazepine binding site. Each receptor has two GABA binding sites that are located in a homologous position to the benzodiazepine site between the α and β subunits. Although the mechanism is unclear, benzodiazepines have no direct functional effect without the presence of GABA. Conversely, certain barbiturates (perhaps all, in a dose-dependent manner) and propofol can directly increase the duration of channel opening, thereby producing a net increase in current flow without GABA binding. This process has therapeutic implications and accounts for why high-dose barbiturates are nearly universally successful in stopping status epilepticus and treating severe withdrawal.
This prototypical pentameric GABAA receptor assembly is derived from permutations and combinations of two, three, four, or even five different subunits. The subtypes of GABA receptors can even vary on the same cell. In fact, GABA receptors are heterogeneous receptors with different subunits and distinct regional distribution. Although the preponderance of subtypes α1β2γ2, α2β3γ2, and α3β3γ2 accounts for 75% of GABA receptors, there are at least 16 others of import.44 The recognition of additional subunits of GABAA receptors has permitted the development of targeted pharmaceuticals, such as zolpidem.5
Previously, ethanol was thought to have GABA receptor activity, although a clearly identified binding site was not evident. Traditional explanations for this effect included (1) enhanced membrane fluidity and allosteric potentiation (so-called cross-coupling) of the five proteins that construct the GABAA receptor, (2) interaction with a portion of the receptor, and/or (3) enhanced GABA release. Research with chimeric reconstruction of GABAA and N-methyl-d-aspartate (NMDA) channels demonstrates highly specific binding sites for high doses of ethanol that enhance GABAA and inhibit NMDA receptor-mediated glutamate neurotransmission. However, research has not clarified whether ethanol at low doses is a direct agonist of GABAA receptors or a potentiator of GABAA receptor binding.32
Ethanol exhibits six mechanisms of adaptation to chronic exposure and is the prototypical xenobiotic for studying neuroadaptation and withdrawal.11,23,27 These six mechanisms appear to apply to benzodiazepines as well.1,32 The mechanisms are (1) altered GABAA receptor gene expression via alterations in mRNA and peptide concentrations of GABAA receptor subunits in numerous regions of the brain (genomic mechanisms), (2) posttranslational modification through phosphorylation of receptor subunits with protein kinase C (second-messenger effects), (3) subcellular localization by an increased internalization of GABAA receptor α1-subunit receptors (receptor endocytosis), (4) modification of receptor subtypes with differing affinities for agonists to the synaptic or nonsynaptic sites (synaptic localization), (5) regulation via intracellular signaling by the NMDA, acetylcholine, serotonin, and β-adrenergic receptors, and (6) neurosteroidal modulation of GABA receptor sensitivity and expression.9,17,25 Furthermore, changes in GABAA subunit composition and function are evident within one hour of administration of a single dose of ethanol.26
Intracellular signaling via the NMDA subtype of the glutamate receptor appears to explain the “kindling” hypothesis, in which successive withdrawal events become progressively more severe.7,27 The activity of excitatory neurotransmission increases the more it fires, a phenomenon known as long-term potentiation, and is the result of increased activity of mRNA and receptor protein expression, a genomic effect of intracellular signaling.41 As NMDA receptors increase in number and function (upregulation) and GABAA receptor activity diminishes, withdrawal becomes more severe.16,27,40 The dizocilpine (MK-801) binding site of the NMDA receptor appears to be the major contributor, and this effect is recognized in neurons that express both NMDA and GABAA receptors.2 When alcohol or any xenobiotic with GABA agonist activity is withdrawn, inhibitory control of excitatory neurotransmission, such as that mediated by the now upregulated NMDA receptors, is lost.28 This loss results in the clinical syndrome of withdrawal: CNS excitation (tremor, hallucinations, seizures), and autonomic stimulation (tachycardia, hypertension, hyperthermia, diaphoresis) (Chap. 81).37
Volatile solvents, such as gasoline, diethyl ether, and toluene, are widely abused xenobiotics whose effects also appear to be mediated by the GABA receptor (Chap. 84).35,39 These solvents can produce CNS inhibition and anesthesia at escalating doses via the GABAA receptor in a fashion similar to that of ethanol.6,18,46