Borrow, Amanda P.

Handa, Robert J.

Holschbach, Mary

English

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Nova Southeastern University NSUWorks Faculty Articles College of Psychology 1-1-2017 Honing in on Hormone-Sensitive Neural Targets for Therapeutic Intervention: Mission Impossible? Mary Holschbach Amanda P. Borrow Robert J. Handa Follow this and additional works at: https://nsuworks.nova.edu/cps_facarticles  Part of the Psychology Commons FSOFuture Sci. OAEditorial332017First draft submitted: 15 May 2017; Accepted for publication: 19 May 2017; Published online: 27 July 2017Keywords:  anxiety • depression • estradiol • estrogen • estrogen receptor • hormone therapy • hypothalamic paraventricular nucleus • oxytocin • raphe • serotoninStress-related neuropsychiatric disorders, such as depression and anxiety, are debili-tating diseases that impose a great cost for patients, their families and society. Current first-line treatments for major depressive dis-order and anxiety disorders target serotoner-gic neurotransmission, but the female-biased prevalence of these disorders has long sug-gested 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 child-birth 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 symp-toms 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 post-partum 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 par-ticularly useful targets for endocrine therapy.Principle among antidepressant drug ther-apies are selective serotonin reuptake inhibi-tors (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 aug-ments 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 estrogen:androgen ratio in adrenocortical cell cultures, p ossibly by Honing in on hormone-sensitive neural targets for therapeutic intervention: mission impossible?Mary A Holschbach1, Amanda P Borrow1 & Robert J Handa*,11Dept. Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA *Author for correspondence:  Tel.: +1 970 491 5338 bhanda@colostate.edu10.4155/fsoa-2017-0060 © 2017 Robert J Handa Future Sci. OA (2017) 3(4), FSO222 eISSN 2056-5623 Editorialpart ofFor reprint orders, please contact reprints@future-science.comfuture science groupEditorial    Holschbach, Borrow & Handai ncreasing aromatase activity [9]. This further strength-ens the need for understanding the relationship between the serotonin system and endocrine systems. Efficacious treatments are needed for distinct popu-lations (e.g., women who hope to become mothers and perimenopausal women), and perhaps targeting identified hormone-sensitive neural circuits directly rather than providing systemic treatments could be an  alternative strategy.Serotonergic brain regions, such as the dorsal raphe, are exquisitely sensitive to hormones. Treating non-human primates with estradiol increases a number of genes and/or proteins that enhance serotonin neuro-transmission, including TPH2, serotonin-1A receptors and serotonin-1B receptors [10,11]. ERs are expressed by serotonergic and nonserotonergic neurons of the dorsal raphe. However, estrogens are certainly not the only hormones that affect serotonergic neurotransmission. The neurons of the dorsal raphe also express high levels of glucocorticoid receptors, progesterone receptors and OTRs. Of these, the OTR is of particular interest. In fact, administering OT to healthy men has dramatic effects on serotonin signaling in the brain. By visual-izing binding of a serotonin-1a receptor antagonist, Mottolese et al. showed that OT reduces extracel-lular serotonin in the dorsal raphe and several of its targets, including the amygdala. Administering OT to men increased between-region correlation in antago-nist binding in the dorsal raphe and the amygdala, which suggests enhanced cross-talk between the two regions [12]. These findings are of particular importance because while both serotonin and OT were known to act in the amygdala to mediate behavioral responses to threatening stimuli, it was previously unknown whether the two systems operated i ndependently or could interact.In addition to being a potent regulator of serotonin signaling, the neural OT system could be a therapeu-tic target itself. While OT is classically known for its roles in reproduction [13] and social behavior [14], it also modulates mood and affect. Preclinical research has reported both anxiolytic [15] and antidepressive [16] effects of OT. Moreover, electroconvulsive therapy (ECT) increases neurophysin I, which is stimulated by estrogen and released stoichiometrically with OT, and the treatment-induced increase is greater in patients for whom ECT reduced depressive symptoms than those who were not relieved by ECT [17]. In contrast, a more recent report indicated that while depressed patients had lower levels of circulating OT than nonpatients, neither antidepressant drugs nor ECT had any effect on serum OT levels [18]. Patients with mood disorders may show abnormalities in OT function, as brain tissue from depressed human subjects indicates an e levation of OT mRNA in the paraventricular nucleus of the hypothalamus, a major site of OT synthesis [19] for oxytocin neurotransmission to forebrain sites that regulate behaviors [20]. This finding has also been observed in a preclinical model of depression known as the chronic stress model, as exposure to the chronic stress paradigm has induced an upregulation of OT mRNA within the paraventricular nucleus of the male rat [21]. Thus, it appears that affective disorders may be associated with dysregulated OT signaling.The effects of OT on mood are believed to stem from this hormone’s mediation of two distinct path-ways: the serotonergic system and the hypothalamo–pituitary–adrenal (HPA) axis. Approximately, a fourth of serotonergic neurons in the dorsal raphe express OTR and, conversely, a third of OTR expressing neurons in the raphe are serotonergic. These neuro-anatomical results are consistent with the observa-tion that although OT acts in the raphe to reduce anxiety [22], this may not be due to OT action directly on serotonergic neurons because knocking out OTR from serotonergic cells had no effect on anxiety-like behavior [23]. These data suggest that OT’s anxio-lytic effects in the raphe may instead be coordinated by nonserotonergic neurons. The HPA axis, a major regulator of neuroendocrine stress responsivity, fre-quently shows dysregulation in patients with mood disorders [24], where depressed patients are unable to respond to glucocorticoids with negative feedback inhibition in a dexamethasone:corticotropin releasing hormone suppression test. While central OT largely has a suppressive effect on the HPA axis [25], the nature of OT’s influence on this axis appears to be site-depen-dent since OT reportedly acts on the anterior pituitary gland to augment HPA axis activity through enhanc-ing the secretogoue activity of corticotropin releasing hormone receptor CRFR1 [26]. Given this divergence in OT’s effects on HPA axis activity, any treatment tar-geting the OT system to alleviate affective symptoms must consider its sites of action.Despite the anti-anxiety and antidepressive qualities of OT, its clinical utility has been limited by its inabil-ity to penetrate the blood–brain barrier. Intranasal OT administration has shown potential in reducing symp-toms of anxiety and, to a lesser extent, depression when delivered in high enough concentrations [27]. However, further investigation is still required to determine the efficacy of this treatment. Research using OTR agonists is currently limited, and while intracerebro-ventricular administration of the agonist carbetocin decreases anxiety-like behavior in the mouse, this compound has no effects on behavior when admin-istered peripherally [28], providing further support for the hypothesis that the blood–brain barrier prevents 10.4155/fsoa-2017-0060 Future Sci. OA (2017) 3(4), FSO222Honing in on hormone-sensitive neural targets for therapeutic intervention    Editorialfuture science groupperipheral OT manipulations from being effective. Thus, there is currently no known OTR agonist with therapeutic potential for the treatment of affective disorders. One promising means for indirectly activat-ing the OT system is through treatment with estro-gens. Estradiol upregulates expression of both OT and OTR [5]. If the OT system could be targeted by a circuit-specific endocrine therapy such as a selective ER modulator, it may be possible to induce a central OT response to peripherally administered treatments. Unfortunately, one caveat is that current compounds would not be feasible as they would likely cause off target effects in other brain regions.Serotonin and OT are two of several neuromodula-tors with strong links to affect and mood disorders in humans and with robust literatures indicating involve-ment in nonhuman animal models of depression- and anxiety-related behaviors. Both of these neurotrans-mitter systems are sensitive to regulation by gonadal hormones, particularly estradiol. The development of approaches that can target ER activity with restricted effects to estrogen sensitive neural circuits in specific brain nuclei could open a new therapeutic avenue. Although recent advances have been able to deliver estradiol specifically to the brain [29], thereby bypassing potential peripheral side effects, brain region or circuit level specificity of such a targeted approach is beyond the reach of today’s technology. The race to develop brain region or circuit-specific therapeutics could one day yield many beneficial treatment avenues for phar-maceutical exploration.Author contributionsMA Holschbach and AP Borrow wrote the article with support and assistance from RJ Handa.Financial & competing interests disclosureFunding  from NIH  via  R01  NS039951  and MH082900  sup-ported this work. The authors have no other relevant affilia-tions or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter  or materials  discussed  in  the manuscript  apart  from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creative-commons.org/licenses/by/4.0/ReferencesPapers of special note have been highlighted as:  • of interest; •• of considerable interest1 Schmidt PJ, Rubinow DR. 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Honing in on Hormone-Sensitive Neural Targets for Therapeutic Intervention: Mission Impossible?

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

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