Enhancement of the activation of GABA A receptors is a common feature of many sedative and hypnotic drugs, and it is probable that the GABA A receptor complex is a molecular target for these drugs in the mammalian central nervous system. We set out to elucidate the role of the two predominant (␣ 1 and ␤ 2 ) subunits of GABA A receptor in sedative drug action by studying mice lacking these two subunits. Both ␣ 1 (Ϫ/Ϫ) and ␤ 2 (Ϫ/Ϫ) null mutant mice showed markedly decreased sleep time induced by nonselective benzodiazepine, flurazepam, and GABA A agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol. The sleep time induced by the ␤-selective drug etomidate was decreased only in ␤ 2 (Ϫ/Ϫ) knockout mice. In contrast, ␣ 1 (Ϫ/Ϫ) mice were more resistant to the ␣ 1 -selective drug zolpidem than ␤ 2 (Ϫ/Ϫ) or wild-type animals. Knockout mice of both strains were similar to wild-type mice in their responses to pentobarbital. The duration of loss of the righting reflex produced by ethanol was decreased in male mice for both null alleles compared with wild-type mice, but there were no differences in ethanol-induced sleep time in mutant females. Deletion of either the ␣ 1 or ␤ 2 subunits reduced the muscimolstimulated 36 Cl Ϫ influx in cortical microsacs suggesting that these mutant mice have reduced number of functional brain GABA A receptors. Our results show that removal of either ␣ 1 or ␤ 2 subunits of GABA A receptors produce strong and selective decreases in hypnotic effects of different drugs. Overall, these data confirm the crucial role of the GABA A receptor in mechanisms mediating sedative/hypnotic effects.

Glycine receptors (GlyRs) are pentameric ligand-gated ion channels that inhibit neurotransmission in the adult brainstem and spinal cord. GlyR function is potentiated by ethanol in vitro, and a mutant GlyR subunit ␣ 1 (S267Q) is insensitive to the potentiating effects of ethanol. To test the importance of GlyR for the actions of ethanol in vivo, we constructed transgenic mice with this mutation. Under the control of synapsin I regulatory sequences, transgenic expression of S267Q mutant GlyR ␣ 1 subunits in the nervous system was demonstrated using [ 3 H]strychnine binding and immunoblotting. These mice showed decreased sensitivity to ethanol in three behavioral tests: ethanol inhibition of strychnine seizures, motor incoordination (rotarod), and loss of righting reflex. There was no change in ethanol sensitivity in tests of acute functional tolerance or body temperature, and there was no change in ethanol metabolism. Transgene effects were pharmacologically specific for ethanol, compared with pentobarbital, flurazepam, and ketamine. These results support the idea that glycine receptors contribute to some behavioral actions of ethanol and that ethanol sensitivity can be changed in vivo by transgenic expression of a single receptor subunit.

Benzodiazepines are one of the most prescribed medications as first-line treatment of anxiety, insomnia, and epilepsy around the world. Over the past two decades, advances in the neuropharmacological understanding of gamma aminobutyric acid (GABA)A receptors revealed distinct contributions from each subtype and produced effects. Recent findings have highlighted the importance of α1 containing GABAA receptors in the mechanisms of addiction and tolerance in benzodiazepine treatments. This has shown promise in the development of tranquilizers with minimal side effects such as cognitive impairment, dependence, and tolerance. A valium-like drug without its side effects, as repeatedly demonstrated in animals, is achievable.

Activation of the dopamine D(1)receptor in a stressful environment may be stronger in GIRK2 deficient mice, and this modified function of D(1) receptors may cause the transient hyperactive behavioral phenotype of these mice.