Early induction of rat brain tryptophan hydroxylase (TPH) mRNA following parachlorophenylalanine (PCPA) treatment.
Tryptophan hydroxylase (TPH) is the first and presumably rate-limiting enzyme in serotonin (5-HT) biosynthesis. End-product inhibition of rate-limiting enzymes is common and 5-HT is known to inhibit TPH activity in vivo. However, it is not known whether levels of 5-HT could also be involved in the regulation of the TPH gene. In order to determine whether TPH gene regulation is dependent on the 5-HT concentration, 5-HT levels were reduced by the administration of parachlorophenylalanine (PCPA). PCPA is a potent, specific and irreversible inhibitor of TPH activity which drastically reduces 5-HT concentration in the 5-HT neurons and terminals. When PCPA was administered, TPH activity in both cell bodies and nerve terminal areas, was reduced to 10% of control values and recovered to the control levels by day 7 in raphe nucleus, and within 14 days in the hypothalamus. In serotonergic terminal areas, 5-HT could not be detected immunohistochemically at day 1, but slowly recovered within 2 weeks. At all time points examined, aromatic L-amino acid decarboxylase (AADC) levels were not changed either in the cell body or terminal areas. The steady state levels of TPH mRNA estimated by in situ hybridization increased at day 1 and returned to control levels by day 4. AADC message levels were not altered throughout the periods. These data suggest that a decrease in 5-HT concentration may lead to an up-regulation of TPH gene transcription, by an, as yet, unknown mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Laboratory of Molecular Neurobiology, Cornell University Medical College, W.M. Burke Medical Research Institute, White Plains, NY 10605.
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D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D010134:Fenclonine / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014365:Tryptophan Hydroxylase / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D014365:Tryptophan Hydroxylase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D010134:Fenclonine