Many structurally different classes of compounds with central nervous system (CNS) depressant effects, such as the barbiturates, general anesthetics, neurosteroids, alcohol, and the benzodiazepines, modulate synaptic inhibition mediated by the GABAA receptor (GABAA-R) in the mammalian CNS. In many cases, this is likely to be the primary mechanism by which these drugs induce acute intoxication, provide clinically useful therapy, exert side effects, and/or mediate abuse liability. The molecular nature of the interaction of these agents with the GABAA-R is not well understood and, with the exception of the benzodiazepines, the sites of binding have not been characterized. The goals of the proposed research are to study the pharmacology and electrophysiology of chimeric receptors containing portions of human GABAA-R subunits together with complementary pieces of the related glycine receptors or the GABA rho subunits (the 'GABAc receptor'). In particular, the proposed research will focus on the barbiturates. These chimeras were chosen to combine homologous ligand- gated receptor subunits that are modulated by barbiturates (e.g., GABA-Rs) with those that are insensitive to barbiturate modulation (e.g., the rho1 subunit) to gain information about the molecular nature of the sites of interaction.
