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Pharmacology and Neuroscience

Trophic hormones and other stimuli acutely regulate steroid biosynthesis in classical steroid producing tissues. Expression of the steroidogenic acute regulatory (StAR) protein is vital for this regulation. The brain releases trophic hormones and is a target tissue for steroid hormones. Brain tissue also metabolizes certain steroids, resulting in pharmacologically active compounds called neurosteroids. Interestingly, the brain also appears capable of producing steroids that are converted to neurosteroids. Whether steroid production is regulated in the brain, and how it might be regulated, is completely unknown. We have found for the first time that StAR protein is in rat and mouse brain cells. Furthermore, StAR mRNA and protein is significantly increased by cyclic AMP in rat astrocytes and the protein is cycloheximide-sensitive, two key properties of StAR in adrenal and reproductive glands. The object of this grant is to determine if steroid production is regulated in brain cells, to determine what role StAR plays in the regulation, and to determine how psychotropic drugs affect StAR expression and neurosteroid production. We will study brain cells from different brain areas including cells from mice lacking the StAR protein. Regional differences in the ability and degree of steroid synthesis will be correlated with StAR expression. Novel mechanisms of neurosteroidogenesis and StAR expression such as neurotransmitter, drug, and peptide receptor subtype activation, as well as the role of calcium will be studied. Molecular mechanisms controlling StAR expression will be examined also. Together, these studies will increase our understanding of the capabilities of different mammalian brain cells for StAR expression and regulated steroid production. They will also determine molecular mechanisms involved in StAR expression and neurosteroid regulation. Ultimately, these studies will help our understanding of the role of steroids and StAR in brain function.