Abstract
17β-estradiol treatment has shown benefit against schizophrenia symptoms, however long-term use may be associated with negative side-effects. Selective estrogen receptor modulators, such as raloxifene and tamoxifen, have been proposed as suitable alternatives to 17β-estradiol. An isomer of 17β-estradiol, 17α-estradiol, is considered less carcinogenic, and non-feminising in males, however little is known about its potential as a treatment for schizophrenia. Moreover, the mechanism underlying the therapeutic action of estrogens remains unclear. We aimed to investigate the ability of these estrogenic compounds to attenuate psychosis-like behaviour in rats. We used two acute pharmacologically-induced assays of psychosis-like behaviour: psychotomimetic drug-induced hyperlocomotion and disruption of prepulse inhibition (PPI). Female Long Evans rats were either intact, ovariectomised (OVX), or OVX and chronically treated with 17β-estradiol, 17α-estradiol, raloxifene or tamoxifen. Only 17β-estradiol treatment attenuated locomotor hyperactivity induced by the indirect dopamine receptor agonist, methamphetamine. 17β-estradiol- and tamoxifen-treated rats showed attenuated methamphetamine- and apomorphine (dopamine D1/D2 receptor agonist)-induced disruption of PPI. Raloxifene-treated rats showed attenuated apomorphine-induced PPI disruption only. Baseline PPI was significantly reduced following OVX, and this deficit was reversed by all estrogenic compounds. Further, PPI in OVX rats was increased following administration of apomorphine. This study confirms a protective effect of 17β-estradiol in two established animal models of psychosis, while tamoxifen showed beneficial effects against PPI disruption. In contrast, 17α-estradiol and raloxifene showed little effect on dopamine receptor-mediated psychosis-like behaviours. This study highlights the utility of some estrogenic compounds to attenuate psychosis-like behaviour in rats, supporting the notion that estrogens have therapeutic potential for psychotic disorders.
Highlights
A large body of literature demonstrates the utility of the ‘female’ sex steroid, estrogen, 17β-estradiol (17β), as novel treatment for schizophrenia [1,2,3]
We extended this work by examining the effect of various estrogenic compounds on prepulse inhibition (PPI) disruption and locomotor hyperactivity induced by the monoamine releaser and indirect dopamine receptor agonist, methamphetamine
Consistent with our previous studies [13,34], we found a reduction in uterus weight following OVX (-60% compared to SHAM rats); in contrast, we did not find an increase in body weight as typically demonstrated in OVX Sprague-Dawley (SD) rats [13,34]
Summary
A large body of literature demonstrates the utility of the ‘female’ sex steroid, estrogen, 17β-estradiol (17β), as novel treatment for schizophrenia [1,2,3]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
