Estradiol accelerates the effects of fluoxetine on serotonin 1A receptor signaling

Abstract

A major problem with current anti-depressant therapy is that it takes on average 6–7 weeks for remission. Since desensitization of serotonin (5-HT)1A receptor signaling contributes to the anti-depressive response, acceleration of the desensitization may reduce this delay in response to antidepressants. The purpose of the present study was to test the hypothesis that estradiol accelerates fluoxetine-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus (PVN) of rats, via alterations in components of the 5-HT1A receptor signaling pathway. Ovariectomized rats were injected with estradiol and/or fluoxetine, then adrenocorticotropic hormone (ACTH) and oxytocin responses to a 5-HT1A receptor agonist (+)8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) were examined to assess the function of 5-HT1A receptors in the PVN. Treatment with estradiol for either 2 or 7 days or fluoxetine for 2 days produced at most a partial desensitization of 5-HT1A receptor signaling, whereas 7 days of fluoxetine produced full desensitization. Combined treatment with estradiol and fluoxetine for 2 days produced nearly a full desensitization, demonstrating an accelerated response compared to either treatment alone. With two days of combined treatments, estradiol prevented the fluoxetine-induced increase in 5-HT1A receptor protein, which could contribute to the more rapid to the desensitization. Furthermore, EB treatment for 2 days decreased the abundance of the 35 kD Gαz protein which could contribute to the desensitization response. We found two isoforms of Gαz proteins with molecular mass of 35 and 33 kD, which differentially distributed in the detergent resistant microdomain (DRM) and in Triton X-100 soluble membrane region, respectively. The 35 kD Gαz proteins in the DRM can be sumoylated by SUMO1. Stimulation of 5-HT1A receptors with 8-OH-DPAT increases the sumoylation of Gαz proteins and reduces the 33 kD Gαz proteins, suggesting that these responses may be related to the desensitization of 5-HT1A receptors. Treatment with estradiol for 2 days also reduced the levels of the G-protein coupled estrogen receptor GPR30, possibly limiting to the ability of estradiol to produce only a partial desensitization response. These data provide evidence that estradiol may be effective as a short-term adjuvant to SSRIs to accelerate the onset of therapeutic effects.

Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys by direct and indirect activation of 5-HT2C receptors

“…Molecular/genetic and pharmacological studies have implicated several 5-HT receptor subtypes in the behavioral effects of fluoxetine, citalopram and other 5-HT transport inhibitors. For example, the anti-depressive action produced by chronic fluoxetine administration has been attributed to changes in the level of mRNA or receptor protein, as well as to alterations in downstream signaling, associated with the 5-HT1A, 5-HT2A and 5-HT2C receptor subtypes (Brink et al 2004; Barbon et al 2011; Li et al 2012). 5-HT2B receptors also appear to be involved in the anti-depressant actions of 5-HT transport inhibitors, as the effects of fluoxetine and paroxetine were abolished in 5-HT2B receptor knockout mice compared to wild type mice in a novelty-suppressed feeding (Diaz et al 2012).…”

GPER1 Stimulation Alters Posttranslational Modification of RGSz1 and Induces Desensitization of 5-HT_1A Receptor Signaling in the Rat Hypothalamus

“…Interestingly, while the 90kD and 50kD bands did not completely co-localize with any marker tested in the present study, they did localize with each other and showed some overlap with the plasma membrane marker (Figure 2B). The 80kD and 35kD bands were located in the early endosome, as marked by EEA1 (Figure 2C); however, as the fractions containing the early endosome also contain cytosolic markers [18], these isoforms could be located in the cytosol as well. Finally, the 45kD and 40kD bands were predominantly located in the ER, as determined by colocalization with calreticulin (Figure 2D).…”

“…Subcellular fractionation and isolation of the DRM from cortical tissue was performed as described previously [18]. Protein (10µg/lane) was resolved on a 12% SDS-PAGE gel followed by transfer to polyvinylidene fluoride (PVDF) membrane.…”

“…We found that two-day estradiol treatment accelerates SSRI-induced 5-HT 1A R desensitization [18]; however, the mechanism underlying this effect is still unclear. Minimal estrogen receptor (ER) α is expressed in the PVN, though it is abundant in the peri-PVN region [19].…”

Depression and Serotonergic Changes during the Climacteric and Postmenopausal Stages: Hormonal Influences

“…Coadministration of estradiol with luoxetine has been shown to contribute to 5-HT1A receptor desensitization [38], which is associated with antidepressant efect in humans and in rats evaluated in behavioral despair models [38]. In addition, this combination of estradiol with luoxetine inhibits 5-HTT and increases de novo brain serotonin synthesis by activating tryptophan hydroxylase enzyme [39].…”