Neurosteroid regulation of GABAィイD2AィエD2 receptor function and its application to development of new psychotropic drugs.

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This study aimed to clarify a role of the neurosteroid system in the regulation of GABAィイD2AィエD2 receptor in normal and psychologically stressed animals, and to obtain basic information on whether the neurosteroid system can be a target for developing new psychotropic drugs. Mice were exposed to social isolation stress (SIS) or psychological stress with communication box paradigm (SCBP). Group-housed mice (GR) were used as normal control.SIS decreased the brain content of the positive allosteric GABAィイD2AィエD2 receptor modulator allopregnanolone (ALLO), and shortened pentobarbital (PB) sleep. Fluoxetine reversed SIS-induced changes in the ALLO content and PB sleep without affecting these parameters in GR. Blockade of ALLO biosynthesis shortened PB- and muscimol-induced sleep, and suppressed GABAィイD2AィエD2-gated current in the pyramidal neurons. DBI, an endogenous peptide capable of interacting with central and mitochondrial benzodiazepine receptors (MBR), shortened PB sleep in GR without … More affecting socially isolated mice. SIS suppressed DBI gene expression in the hypothalamus. The MBR agonist FGIN-l-27 normalized PB sleeping time in socially isolated mice and the effect was antagonized by the a negative allosteric GABAィイD2AィエD2 receptor modulator pregnenolone sulfate (PS). SCBP increased lipid peroxidation products in the brain via activating neuronal nitric oxide synthase. Majonoside-R2 suppressed this increase in a PS reversible manner.These results demonstrate that ALLO has a permissive role in the GABAergic neurotransmission in the normal animals and that the decrease in the ALLO content impairs the GABAィイD2AィエD2 receptor function, resulting in a psycho-pathophysiological state. Moreover, it is likely that SIS causes a decrease in PB sleep partly by increasing DBI activity and that DBI gene expression in the hypothalamus is regulated by a negative feedback mechanism. Moreover, the involvement of neurosteroids in the effect of fluoxetine and majonoside-R2 suggests that the neurosteroid system could be a new target for psychotropic drug development. Less