Oestradiol Modulation of Serotonin Reuptake Transporter and Serotonin Metabolism in the Brain of Monkeys

Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is an important brain neurotransmitter that is implicated in mental and neurodegenerative diseases and is modulated by ovarian hormones. Nevertheless, the effect of oestrogens on 5-HT neurotransmission in the primate caudate nucleus, putamen and nucleus accumbens, which are major components of the basal ganglia, and the anterior cerebral cortex, mainly the frontal and cingulate gyrus, is not well documented. The present study evaluated 5-HT reuptake transporter (SERT) and 5-HT metabolism in these brain regions in response to 1-month treatment with 17β-oestradiol in short-term (1 month) ovariectomised (OVX) monkeys (Macaca fascicularis). SERT-specific binding was measured by autoradiography using the radioligand [³H]citalopram. Biogenic amine concentrations were quantified by high-performance liquid chromatography. 17β-Oestradiol increased SERT in the superior frontal cortex and in the anterior cingulate cortex, in the nucleus accumbens, and in subregions of the caudate nucleus of OVX monkeys. 17β-Oestradiol left [³H]citalopram-specific binding unchanged in the putamen, as well as the dorsal and medial raphe nucleus. 17β-Oestradiol treatment decreased striatal concentrations of the precursor of 5-HT, 5-hydroxytryptophan, and increased 5-HT, dopamine and 3-methoxytyramine concentrations in the nucleus accumbens, caudate nucleus and putamen, whereas the concentrations of the metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid remained unchanged. No effect of 17β-oestradiol treatment was observed for biogenic amine concentrations in the cortical regions. A significant positive correlation was observed between [³H]citalopram-specific binding and 5-HT concentrations in the caudate nucleus, putamen and nucleus accumbens, suggesting their link. These results have translational value for women with low oestrogen, such as those in surgical menopause or perimenopause.

High fat diet decreases beneficial effects of estrogen on serotonin-related gene expression in marmosets

“…Ovarian hormone replacement to ovariectomized (Ovx) macaques changed the expression of serotonin related genes and proteins in a manner that would cause an increase in serotonin neurotransmission (Bethea, Lu, 2002, Centeno et al, 2007, Sanchez et al, 2005, Smith et al, 2004). In a similar macaque model, E increased serotonin in several compartments of the basal ganglia and in frontal and cingulate cortex, supporting the concept that E increased serotonin neurotransmission (Sanchez et al, 2013). Also, E decreased raphe 5HT1A receptors of hemi-parkinsonian macaques, thereby removing the ‘brakes’ on serotonin neuronal activity (Sanchez, Morissette, 2013).…”

“…In a similar macaque model, E increased serotonin in several compartments of the basal ganglia and in frontal and cingulate cortex, supporting the concept that E increased serotonin neurotransmission (Sanchez et al, 2013). Also, E decreased raphe 5HT1A receptors of hemi-parkinsonian macaques, thereby removing the ‘brakes’ on serotonin neuronal activity (Sanchez, Morissette, 2013). An important component of improved serotonin function was the ability of E to decrease expression of CRF-R1 and increase expression of CRF-R2 in dorsal raphe (Sanchez et al, 2010).…”

Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study

“…Interestingly, both phases potentially offset brain biology in a manner likely to increase risk for depressive symptoms. In response to an elevation in estradiol, SERT protein levels may increase for a protracted period as seen in nonhuman primates, e.g., in frontal cortex projection areas (28,29). Therefore, possibly, the initial GnRHa-induced stimulatory phase elevates SERT levels in cortical projection areas in a protracted period of time in susceptible individuals.…”

“…In rodents and nonhuman primates, estrogen administration potentially increases serotonergic tone by increasing serotonin synthesis (23), decreasing degradation (24), and decreasing inhibitory feedback to serotonergic neurons in the dorsal raphe nucleus (25,26). However, this may be counterbalanced by an estradiol-induced increase in serotonin transporter (SERT) gene expression (27) and protein levels (28) predominantly in cortical projection areas (29). Nevertheless, the contribution from SERT responses across phases of sex-steroid hormone fluctuation and the timing of such serotonergic integration of ovarian steroid hormone information are far from clear and sparsely studied in humans.…”

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

“…T and its metabolite, DHT, plus aromatase inhibition (DHT+ATD), increased mRNA expression of the gene coding for TPH2 to the same extent (Bethea et al , 2014). TPH2 is the rate-limiting enzyme in serotonin synthesis (Jequier et al , 1969), and studies in females indicate that increased TPH2 mRNA is accompanied by increased TPH2 protein (Bethea et al , 2000) and increased serotonin in forebrain areas (Sanchez et al , 2013). T and DHT also increased the mRNA expression for the serotonin reuptake transporter (SERT) (Bethea et al , 2014), which correlates with increased synaptic serotonin in human (Parsey et al , 2006) and macaque studies (Sanchez et al , 2013).…”