MODULATORY MECHANISMS OF CYCLIC AMP-STIMULATED STEROID CONTENT IN RAT-BRAIN CORTEX

The modulation of cyclic AMP dependent neurosteroidogenesis was studie d in minces prepared from the cerebral cortex of adult rat. Forskolin or dibutyryl-cyclic AMP enhanced pregnenolone and progesterone product ion in a time and dose-dependent manner. The forskolin effect was mimi cked by the cyclic AMP phosphodiesterase inhibitor isobutyl-methyl-xan thine, but not by the adenylate cyclase inactive forskolin analogue 1, 9,dideoxy-forskolin. 4'-chloro-diazepam, a high affinity ligand for th e mitochondrial diazepam binding inhibitor (DBI) receptor, also elicit ed a time dependent increase in steroidogenesis. The forskolin and the 4'-chloro-diazepam stimulated pregnenolone increase was prevented by preexposing the rat brain cortical minces to phenyl)-N-methyl-N-(1-met hyl-propyl)-3-isoqinoline carboxamide (PK 11195), a high affinity liga nd for the mitochondrial DBI receptor endowed with antagonistic proper ties. The protein synthesis inhibitor cycloheximide prevented the fors kolin and 4'-chloro-diazepam stimulation of pregnenolone formation. In brain cortical minces of adrenalectomised/ orchiectomised rats dibuty ryl-cyclic AMP increased both pregnenolone and progesterone formation, while forskolin only increased progesterone. These data show that cyc lic AMP enhances brain steroidogenesis by acting on a labile protein s ubstrate which interacts with the mitochondrial DBI receptor.