Modulatory mechanisms of cyclic AMP-stimulated steroid content in rat brain cortex.
The modulation of cyclic AMP dependent neurosteroidogenesis was studied in minces prepared from the cerebral cortex of adult rat. Forskolin or dibutyryl-cyclic AMP enhanced pregnenolone and progesterone production in a time and dose-dependent manner. The forskolin effect was mimicked by the cyclic AMP phosphodiesterase inhibitor isobutyl-methyl-xanthine, but not by the adenylate cyclase inactive forskolin analogue 1,9,dideoxy-forskolin. 4'-Chloro-diazepam, a high affinity ligand for the mitochondrial diazepam binding inhibitor (DBI) receptor, also elicited 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 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinoline carboxamide (PK 11195), a high affinity ligand for the mitochondrial DBI receptor endowed with antagonistic properties. The protein synthesis inhibitor cycloheximide prevented the forskolin and 4'-chloro-diazepam stimulation of pregnenolone formation. In brain cortical minces of adrenalectomised/orchiectomised rats dibutyryl-cyclic AMP increased both pregnenolone and progesterone formation, while forskolin only increased progesterone. These data show that cyclic AMP enhances brain steroidogenesis by acting on a labile protein substrate which interacts with the mitochondrial DBI receptor.
Roscetti
G
G
Dip. to Medicina Sperimentale, Università di Roma, Tor Vergata, Italy.
Ambrosio
C
C
Trabucchi
M
M
Massotti
M
M
Barbaccia
M L
ML
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000315:Adrenalectomy; D000818:Animals; D001570:Benzodiazepinones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005576:Colforsin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009919:Orchiectomy; D011284:Pregnenolone / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism
D001570:Benzodiazepinones; D007546:Isoquinolines; D018160:Receptors, Cytoplasmic and Nuclear; C078199:diazepam-binding inhibitor receptor; D005576:Colforsin; C028513:4'-chlorodiazepam; D011374:Progesterone; D003994:Bucladesine; D011284:Pregnenolone; D003513:Cycloheximide; D000242:Cyclic AMP; C047983:1,9-dideoxyforskolin; D015056:1-Methyl-3-isobutylxanthine; C037850:PK 11195