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Modulation of Neurosteroid Synthesis/Accumulation by l ‐Ascorbic Acid in Rat Brain Tissue: Inhibition by Selected Serotonin Antagonists
Author(s) -
Roscetti Gianna,
Del Carmine Renata,
Trabucchi Marco,
Massotti Marino,
Purdy Robert H.,
Barbaccia Maria Luisa
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71031108.x
Subject(s) - ascorbic acid , endocrinology , medicine , pregnenolone , neuroactive steroid , chemistry , serotonin , pharmacology , receptor , biology , gabaa receptor , hormone , steroid , food science
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 m M ) 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 µ M ), 1‐(3‐chlorophenyl)piperazine (1.0 µ M ), and 5‐methoxytryptamine (0.4 µ M ) 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.