In search for animal models of female sexual dysfunction

Abstract

Female Sexual Dysfunction (FSD) is a disorder that affects around 40% of the population. Low sexual arousal and low sexual desire are the most common problems. The mechanisms underlying the disorder are still unclear. The aims of this thesis were 1) the search for animal models of FSD, 2) the development of new treatments and 3) to investigate the effects of common used antidepressants on female sexual behavior. In the first part, two rat models are described which were validated with pharmacological studies. First, there is the so-called “avoiders” model, based on different endophenotypes in natural cycling female rats. Male-avoiders show significantly less sexual behavior than male-approachers. This suggests that these rats can be used as model for women suffering from female sexual dysfunction. Further investigation with apomorphine (dopamine type 1 receptor agonist) showed a different responsiveness between normal and dysfunctional rats, which suggests that the dopamine system could be involved in the different sexual behavior of the avoiders. Other pharmacological studies showed that the serotonin 1a receptor and serotonin transporter systems are the same as the controls. The second model is the “sub-primed” model in which female rats are ovariectomized and primed with low levels of estrogens. These rats show significant lower levels of sexual behavior. In this model, we tested a new treatment for FSD: the combination treatment of testosterone and vardenafil (phosphodiesterase-5 inhibitor). In a clinical trial this treatment was shown to be effective in women. It also turned out to have beneficial effects in sexual dysfunctional rats without affecting healthy rats. Our findings make mechanistic studies into this field possible. The second part of the thesis focuses on the side-effects of chronic selective serotonin reuptake inhibitors (SSRIs). Depressed women complain about sexual dysfunctions. It is unclear whether this is due to the disease itself or their pharmacological treatment. First, a serotonin transporter (SERT) knockout rat was tested for their basal sexual activity. This study showed that SERT knockout rats have normal sexual activity compared to controls. Second, female rats were chronically treated with paroxetine (SSRI) for 56 days and tested for their sexual behavior. Again, no differences in sexual activity were found compared the controls. In addition, administration of serotonin 1a receptor agonist (()8-OH-DPAT) and antagonist (WAY-100635) was used to study the effects of chronic blockade of the SERT on the serotonin 1a receptor. In both studies, serotonin 1a receptor desensitization was found. This may protect against FSD