Estradiol increases Pet-1 and serotonin transporter mRNA in the midbrain raphe nuclei of ovariectomized rats

Abstract

Previous research has shown that estradiol increases the anorexia associated with serotonin (5-HT) neurotransmission. To examine further the putative relationship between estradiol and 5-HT, we investigated whether estradiol increases the expression of Pet-1 and the 5-HT transporter (5-HTT), two genes implicated in the development and regulation of the 5-HT system. Ovariectomized (OVX) rats (n = 5-6/group) were treated with 0, 2, or 10 μg estradiol benzoate (EB) in sesame oil on 2 consecutive days. Food intake and body weight were recorded 2 days later when EB-treated rats typically display signs of behavioral estrus (e.g., reduced feeding). Following the collection of behavioral data, rats were perfused, brains were removed, and coronal sections were cut through the midbrain raphe nuclei. Pet-1 and 5-HTT mRNA levels were quantified throughout the dorsal and median raphe nuclei (DRN and MRN) by conducting in situ hybridization on free-floating tissue sections using 35S-labeled cDNA probes. As expected, EB treatment decreased food intake and body weight on the day that modeled estrus. At this same time, EB treatment increased Pet-1 and 5-HTT mRNA levels within the DRN and MRN. We conclude that a physiologically relevant regimen of estradiol treatment in OVX rats increases Pet-1 and 5-HTT mRNA levels in the midbrain raphe nuclei at a time when the anorexigenic effect of estradiol is apparent. Further studies are required to determine whether the increased expression of Pet-1 and 5-HTT mRNA play a causal role in the anorexigenic effect of estradiol.

Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

“…Although the mechanism(s) underlying the sex-specific differences in body composition are unknown, sex-specific differences in the long-term effects of prenatal exposure to SSRIs and childhood overweight have also been reported in human studies (Grzeskowiak et al, 2013). It is likely that these differences are related to estrogen as there is considerable evidence 1) that estrogen plays an important role in the regulation of body weight homeostasis and 2) that there is considerable cross-talk between estrogen and serotonergic signaling pathways as estrogen has been shown to up regulate serotonin transporter (SERT) expression, enhancing serotonergic signaling pathways (Brown and Clegg, 2010;Rivera et al, 2009).…”

GPR30 is necessary for estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the rat hypothalamus

“…Pet-1, which is necessary for development of the serotonin system (Hendricks et al, 1999; Hendricks et al, 2003; Iyo et al, 2005; Maurer et al, 2004), directly binds to Pet-1 elements in the human 5-HT 1A receptor promoter region, and is critical for 5-HT 1A receptor expression in the midbrain (Jacobsen et al, 2011). In macaques, long-term OVX reduced expression of Pet-1 in the DRN (Bethea et al, 2011), while in rats, two-day administration of estradiol after OVX increased Pet-1 mRNA levels in the DRN (Rivera et al, 2009), indicating a clear role for regulation of midbrain 5-HT 1A receptor expression by estradiol. A reduction in inhibitory DRN 5-HT 1A autoreceptors, induced by estradiol via Pet-1, may play a role in desensitizing post-synaptic 5-HT 1A receptors in the PVN by increasing serotonergic tone, similar to chronic SSRI treatment.…”

Altered ventilatory and thermoregulatory control in male and female adult Pet-1 null mice

“…Differences in 5-HT innervation and/or function among male and female rats have been reported or hypothesized (Behan et al 2003; Barker et al 2009), in addition to functional differences as evidenced by higher brain [5-HT] and TPH protein levels (Carlsson et al 1988), and higher ratios of 5-HT/5-HIAA (an index of serotonergic activity) in the dorsal raphé nucleus in females compared to males (Dominguez et al 2003). Receptors for female sex steroids are also differentially expressed within 5-HT neurons (Alves et al 1998; Bethea et al 2006; Bethea et al 2008; Donner et al 2009), and manipulating estradiol levels alter expression levels of Pet-1 and SERT mRNA (Rivera et al 2009). Thus, there is the potential for female sex steroids directly enhancing 5-HT neuronal function in a gender-specific manner.…”