Steroid regulation of tryptophan hydroxylase protein in the dorsal raphe of macaques

Background: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme for th e synthesis of serotonin, and serotonin is a pivotal neurotransmitter in th e regulation of mood affective behavior, pituitary hormone secretion, and n umerous autonomic functions. We previously demonstrated that estradiol (E) and progesterone (P) increase TPN mRNA levels in the dorsal raphe of macaqu es. Methods: This study employed western blotting and densitometric quantitatio n to determine whether the changes observed at the level of gene expression were manifested by changes in TPH protein expression and whether modified estrogens or progestins had actions similar to the native ligands, In addit ion, the effect of the antiestrogen tamoxifen was examined. Ovariectomized (ovx) rhesus and cynomolgus macaques were untreated or treated with E, P, E +P, equine estrogens (EE) medroxyprogesterone (MPA), EE+MPA, or tamoxifen. The dorsal raphe region was subjected to Western analysis. Results: E treatment for 28 days increased TPH protein mass four to six fol d over ovariectomized controls. Addition of P to the E regimen or treatment with P for 28 days after E priming did not after TPH from E treatment alon e. Treatment of ovx macaques with a low dose of P caused a two-fold increas e in. TPH protein. Treatment of ovariectomized macaques for 30 months with EE alone or MPA alone significantly increased TPH protein; however, unlike P, the addition of MPA to the EE regimen blocked the stimulatory effect of EE. Tamoxifen treatment significantly reduced TPH protein compared to EE an d ovariectomized control animals. Conclusion: The stimulatory effect of E and P an TPH protein in the dorsal raphe of macaques correlates with the previously observed effect at the lev el of mRNA expression. P had no effect on the stimulatory action off, where as MPA blocked the stimulatory effect of EE. Tamoxifen acted as a potent an tiestrogen on TPH protein expression. If TPH protein, mass influences serot onin synthesis, then these steroids will impact many autonomic systems that are regulated by serotonin. (C) 2000 Society of Biological Psychiatry.