Modulation of neurosteroid synthesis/accumulation by L-ascorbic acid in rat brain tissue: inhibition by selected serotonin antagonists.
We have investigated the possibility that the synthesis/accumulation of neurosteroids, i.e., brain-produced steroids putatively endowed with modulatory actions in the CNS, is regulated by monoaminergic receptor-mediated mechanisms. In minces of rat brain cortex, L-ascorbic acid concentration-dependently (0.07-1.0 mM) increases the levels of pregnenolone, allotetrahydrodeoxycorticosterone, and dehydroepiandrosterone. This effect of L-ascorbic acid is region-dependent: in hippocampus, progesterone and allopregnanolone are also increased, whereas dehydroepiandrosterone is unchanged, and in corpus striatum only progesterone is increased significantly. 5-Hydroxytryptamine (10 microM), 1-(3-chlorophenyl)piperazine (1.0 microM), and 5-methoxytryptamine (0.4 microM) mimic the effect of L-ascorbic acid, whereas a pretreatment with p-chlorophenylalanine (400 mg/kg i.p., 2 days) reduces the amplitude of the L-ascorbic acid effect on brain cortical neurosteroids. The effect of L-ascorbic acid is blocked by the nonselective serotonin antagonists methiothepin, clozapine, methysergide, and pizotifen, but not mesulergine, spiperone, MDL 72222, and DL-propranolol, nor by the catecholaminergic receptor antagonists prazosin and S(-)-sulpiride. L-Ascorbic acid is not additive with dibutyryl-cyclic AMP and, furthermore, the inhibition of adenylate cyclase by MDL 12330A, but not of phospholipase C by U-73122, markedly attenuates the L-ascorbic acid-induced increase of pregnenolone in rat brain cortical minces. Together these data suggest that L-ascorbic acid plays a role in the modulation of neurosteroidogenesis, presumably by favoring the activation of the purported serotonin type 6 receptor by endogenous serotonin.
Department of Neuroscience, University of Rome Tor Vergata, Roma, Italy.
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Roscetti
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Del Carmine
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Trabucchi
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Massotti
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Purdy
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Barbaccia
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D010134:Fenclonine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D006728:Hormones / Q000378:metabolism*; D008297:Male; D011284:Pregnenolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D006727:Hormone Antagonists; D006728:Hormones; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D012701:Serotonin; D011284:Pregnenolone; D001205:Ascorbic Acid; D010134:Fenclonine