Effects of Ovarian Steroids and Raloxifene on Proteins that Synthesize, Transport, and Degrade Serotonin in the Raphe Region of Macaques

Abstract

In the monkey dorsal raphe, we reported that 1-month (mo) of estrogen replacement, with or without progesterone supplementation for 14 days, significantly increased tryptophan hydroxylase-1 (TPH-1) mRNA; decreased serotonin reuptake transporter (SERT) mRNA and decreased monoamine oxidase (MAO)-A mRNA, but had no effect on MAO-B mRNA. Here, we questioned what effect would 1 or 5 mo of ovarian hormones or the selective estrogen receptor modulator (SERM), raloxifene, have on TPH protein and phosphorylation, and on protein expression of SERT, MAO-A or MAO-B? Raloxifene antagonizes estrogen in breast or uterus, but estrogen-like activities in the brain have been reported. Cytoplasmic and membrane extracts of the dorsal raphe region were processed for Western blotting. TPH, phosphoserine, SERT, MAO-A, and MAO-B were detected with specific antibodies. The optical densities of the signals were measured with NIH image and analyzed by ANOVA. Both 1 and 5 mo of estrogen, with or without progesterone, and 5 mo of raloxifene significantly increased TPH protein. Administration for 5 mo of estrogen plus progesterone and raloxifene also increased TPH phosphorylation. Estrogen, with or without progesterone, for 1 mo had no effect on SERT protein. However, 5 mo of estrogen and 5 mo of raloxifene increased SERT protein. Estrogen alone or combined with progesterone for 1 mo caused a significant reduction in MAO-A. Yet, after 5 mo of the same treatments, MAO-A was not different from spayed controls. Estrogen alone had no effect on MAO-B. However, the addition of progesterone significantly increased MAO-B. Raloxifene for 5 mo had no effect on MAO-A or MAO-B. Thus, to various extents, estrogen, progesterone, and raloxifene may increase serotonin production and transport. The expression of the degradative enzymes suggests a complex combination of gene transcription, post-transcriptional processing, and substrate feedback mechanisms.

Monoamine Oxidase A Activity and Norepinephrine Level in Hippocampus Determine Hyperwheel Running in SPORTS Rats

“…Thus, the elevated level of extracellular NE in the hippocampus of SPORTS rats seems to be the result of impaired MAOA protein synthesis that unknown factors contribute to. In this regard, several hormones such as ovarian steroids have been reported to regulate both transcriptional and translational expression of MAOA (Smith et al, 2004). However, little information is available for the precise mechanisms for translation of the MAOA gene, including the transcriptional starting site, the complete sequences of 3 0 and 5 0 untranslated regions, and the specific binding proteins for MAOA mRNA.…”

Serotonin in microdialysate from the mediobasal hypothalamus increases after progesterone administration to estrogen primed macaques

“…Of note, estrogen and progesterone increase tryptophan hydroxylase −2 (TPH-2) expression and translation (Sanchez et al, 2005;Smith et al, 2004), while decreasing 5-HT1A autoreceptor expression, translation and coupling to the G protein Pecins-Thompson and Bethea, 1998). However, the effect of estrogen and progesterone treatment on extracellular serotonin in macaques needs confirmation.…”

Sexual attractiveness: a comparative approach of morphological, behavioral neurophysiological signaling in women and nonhuman primate females

“…The latteu impaius the uelocation of seuotonin metabolites fuom the postsynaptic membuane into puesynaptic uegions. All of these components do effect the metabolism of centual seuotonin expuession uates (Smith et al, 2004). The mentioned elements aue key stuuctuues to influence e.g., female depuession and of couuse behavioual expuession uates duuing the female cycle.…”