New insights into the mechanism of action of hypnotics

Between 1987 and 1989, the different protein subunits that make up the rece ptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) wer e identified. These make up the alpha, beta, gamma and sigma families, for each of which exist several subtypes. This receptor is the molecular target of modern hypnotic drugs (i.e. benzodiazepines, zopiclone, zolpidem and za leplon). In the 10 years that have followed this milestone, significant pro gress has been made in exploring the molecular mechanisms of hypnotic drug action. Receptor subtype specificity of hypnotics has been explained in ter ms of differential affinity for receptors containing different a subunits, which are expressed in different brain regions. Zolpidem and zaleplon bind preferentially to alpha(1)-containing receptors, whereas benzodiazepines an d zopiclone are aspecific. Different sets of subunits are encoded in contig uous 'cassettes' on the genome, and the transcription of each set appears t o be regulated coherently. The predominant GABA(A) receptor composition fou nd in the brain is alpha(1)beta(2)gamma(2) which are all encoded on human c hromosome 5. Targeted gene disruption has provided clues to the physiologic al functions served by GABA(A) receptors containing different subunits. Rec eptors containing gamma(2) appear to have a vital role in maintaining appro priate central inhibition, Ps-containing receptors may also be important de terminants of excitability in certain brain regions, whereas a clear role f or alpha(5)- alpha(6)- and gamma(3)-containing receptors has not yet been e stablished by these techniques. Site-directed mutagenesis has indicated tha t benzodiazepines bind to a cleft on the GABA(A) receptor surface at the in terface between the alpha and gamma subunits. Other drugs (flumazenil, zopi clone, zolpidem) also bind to the a subunit, but interact with amino acids in different binding domains to the benzodiazepines. The molecular mechanis m of hypnotic dependence has been explored, and seems to involve downregula tion of transcription of the normally prevalent alpha(1), beta(2) and gamma (2) subunits, and the reciprocal upregulation of the expression of rarer su bunits. Chronic treatment with hypnotic drugs that may have less dependence potential, such as zopiclone and zolpidem, appears to produce more limited change in GABA(A) receptor subunit expression. These ideas will be importa nt both for designing new hypnotic drugs with a better safety/efficacy prof ile, and for evaluating more appropriate ways of using the drugs available today.