Type A gamma-aminobutyric acid (GABA(A)) receptor subunits and benzodiazepine binding: significance to clinical syndromes and their treatment

Gamma (gamma)-aminobutyric acid (GABA) acting via GABA, receptors is the br ain's major inhibitory neurotransmitter system and exerts: a crucial role i n regulating brain excitability. A number of drugs interact with binding si tes on GABA, receptors, and these include benzodiazepines, anticonvulsants, anaesthetics and neurosteroids (e.g. the progesterone metabolite pregnalon e). GABA, receptors comprise five subunits (19 are known currently), and ar e classified into three major groups (alpha, beta and gamma) and several mi nor ones. The subunit make-up of a receptor, particularly its alpha -subuni t content, determines its pharmacological characteristics. Thus, receptors that include an alpha (1) subunit have a benzodiazepine (BZ) type T (BZ[I]) pharmacology and bind zolpidem and CL218,872 with high affinity, whilst re ceptors with alpha (2), alpha (3) or alpha (5) subunits have a BZ type II(B Z[II]) pharmacology and bind these drugs with low affinity. In contrast to receptors that contain a, and a, subunits, which are diazepam-insensitive, both BZ(I) and -(II) bind diazepam and other benzodiazepines. The ligand se lectivity of receptor subunits assists in their characterisation. Using imm unochemical and ligand-binding techniques, the subunit composition of GABA( A) receptors has been shown to exhibit a degree of brain regional specifici ty. GABA, receptors are of great clinical significance in several disorders , including epilepsy, anxiety and alcoholism. In addition to treating epile psy with drugs that target GABA, and BZ binding sites, epileptic lesions ca n be localised presurgically using radiolabelled BZ ligands. BZs are used c ommonly to treat anxiety, and studies suggest that BZ antagonists and inver se agonists (which induce the opposite effect to agonists at receptors) may he useful in alcohol rehabilitation.