VITAMIN INTERVENTION FOR STROKE PREVENTION (VISP) CLINICAL TRIAL

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The long-term goal of this research is to define the mechanism(s) by which progesterone (P) increases prolactin secretion in estrogen (E)-primed nonhuman primates. Prolactin secretion is a useful indicator of serotonin function and deficits in prolactin release are reported for patients with major clinical depression. We hypothesize that the serotonin (5HT) neural system transduces the action of ovarian steriods on prolactin secretion and mood. We showed that E and P alter the expression of 3 genes that are pivotal in serotonin neurotransmission, tryptophan hydroxylase, serotonin reuptake transporter and the serotonin 1A autoreceptor. We are now determining the functional consequences of these changes in gene expression. First, TPH protein levels were measured with Western blot and densitometric analysis in monkeys treated with E, P, E+P, modified steroids and the estrogen antagonist tamoxifen. TPH protein levels increased with E and addition of P had no further ef fect . Conjugated equine estrogens significantly increase TPH protein and addition of medroxyprogesterone acetate (MPA) blocks this effect. Hence, there is a marked difference in the action of natural progesterone and MPA on TPH protein levels. Tamoxifen significantly decreased TPH protein levels. These observations have significant implications for hormone replacement therapy and the regulation of mood in postmenopausal women and for the increased incidence of depression in breast cancer patients treated with tamoxifen. Little, if any, change was observed in the expression of 3 postsynaptic receptors for serotonin, 5HT1A, 2A or 2C, in the hypothalamus with E and P. Future studies will examine the functional consequences of the reported changes in expression of SERT and 5HT1A autoreceptor genes, as well as the effect of E+P on mechanisms regulating serotonin degradation. FUNDING NIH HD17269, HD18185 PUBLICATIONS Pecins-Thompson M, Brown NA, Bethea CL. Regulation of serotonin reuptake transporter mRNA expression by ovarian steroids in rhesus macaques. Mol Brain Res 53:120-129, 1998. Pecins-Thompson M, Bethea CL. Ovarian steroid regulation of serotonin-1A autoreceptor messenger RNA expression in the dorsal raphe of rhesus macaques. Neuroscience 89:267-277, 1998.