GABAA1a receptors -: Involvement in sleep regulation and potential of selective agonists in the treatment of insomnia

gamma-Aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the mammalian brain, and it may play an important role in sleep regulation. The effects of GABA are mediated by activation of two classes of receptors, i.e. GABA(A) and GABA(B) receptors. GABA(A) receptors are assumed to have a pentameric glycoprotein structure, composed of different polypeptide subunits and, as a result, are highly heterogeneous. The GABA(A1a) receptor subclass (previously termed the benzodiazepine BDZ(1) receptor) represents approximately half of all GABA(A) receptors. BDZ hypnotics exert their sleep-inducing action by increasing the GABA(A) receptor-mediated chloride ion (Cl-) current. Possibly due to their nonspecific effect at the different subtypes of GABA(A) receptors, these drugs can also induce daytime sedation, anterograde amnesia and rebound insomnia. Additionally, they affect the sleep EEG in a specific manner (the so-called 'spectral GABA-BDZ signature'), and may lead to tolerance and dependence. Given the drawbacks of BDZs, newer compounds with a preferential selectivity for GABA(A1a) receptors were developed. It was hoped that they would have fewer adverse effects than nonspecific BDZs. The available data, however, do not support the notion that the pharmacodynamics of these newer agents result in markedly different clinical effects compared with the BDZ hypnotics. As with the BDZs, the pharmacokinetics are clinically more important than the pharmacodynamics. it is concluded that there are no major differences in hypnotic efficacy and safety between the newer, selective GABA(A1a) receptor agonists and the classical. nonselective BDZs.