Honing in On Hormone-Sensitive Neural Targets for Therapeutic Intervention: Mission Impossible?

Abstract

Keywords: anxiety • depression • estradiol • estrogen • estrogen receptor • hormone therapy • hypothalamic paraventricular nucleus • oxytocin • raphe • serotoninStress-related neuropsychiatric disorders, such as depression and anxiety, are debilitating diseases that impose a great cost for patients, their families and society. Current first-line treatments for major depressive disorder and anxiety disorders target serotonergic neurotransmission, but the female-biased prevalence of these disorders has long suggested a role for hormones in the etiology and treatment of these diseases. Perhaps the most common hypothesis in this regard is that ovarian hormones promote resilience whereas declining hormone levels (e.g., after childbirth or menopause) increase susceptibility to depressive disorders. In fact, administering the potent estrogen, estradiol, as hormone therapy to perimenopausal women improves mood [1]. Moreover, polymorphisms in the genes for estrogen receptor (ER) α and the enzyme that metabolizes serotonin are both independently linked to depressive symptoms in menopausal women [2]. In addition to serotonin, times of endocrine flux may also contribute to vulnerability by causing dysregulation in oxytocin (OT) signaling. Methylation of the OT receptor (OTR) gene is associated with diagnoses of anxiety and/ or depression in older women [3] and postpartum women [4]. The relationship between OT and affect may be enhanced during these periods because estradiol regulates both OT and OTR through activation of ER-β and -α, respectively [5]. Together these data implicate gonadal steroid hormones, such as estradiol, and its cognate receptors as integral modulators of genes that regulate mood and anxiety. This further raises the possibility of harnessing hormone-sensitive brain networks as a therapeutic intervention for patients with diseases involving mood and affect. In this article, we will discuss two potential neural networks, the serotonergic system and the OTergic system, that could prove to be particularly useful targets for endocrine therapy.Principle among antidepressant drug therapies are selective serotonin reuptake inhibitors (SSRIs), which prolong serotonergic signaling by increasing the time serotonin spends in synapses. Estrogenic hormones have been shown to mediate the efficacy of serotonin-related treatments. The anxiolytic effects of SSRI treatment are prevented by ovariectomy and are restored by estrogen replacement [6], and estrogen treatment augments the antidepressant effects of SSRIs in ovariectomized rats [7]. These results may be attributed to a serotonergic coordination of the anxiolytic and antidepressant effects of estrogen, as estradiol increases the expression of the serotonin transporter and serotonin-1B autoreceptor and blocking the serotonin-1B autoreceptor prevents the anxiolytic effects of estrogen [6,8]. Moreover, SSRI treatment itself can alter the endocrine state of patients. SSRIs are known to be endocrine disruptors and can reduce fertility, reduce androgens and increase the ...