In search of animal models for male sexual dysfunction

Around half of all men have sexual problems. The main complaints and prevalence are orgasmic disorders (10%), premature ejaculation (PE) (27%), and erectile difficulties (10%). These statistics do not include the sexual side effects of medications such as antidepressants. Research experiments in humans can be very time consuming or unethical. The present thesis deals with the development of an animal (rat) model that has face, predictive, and construct validity towards human sexual behavior and its disorders, and can be used to study the effects but also the side effects of psychoactive drugs on sexual behavior. Sexually trained male rats have stable low, normal or fast ejaculating behaviors. Low ejaculating rats can be used to examine orgasmic problems, while fast ejaculating rats for premature ejaculations. Normal ejaculating rats can be used to investigate side effects of medication (either stimulatory or inhibitory). The animal model provides face and predictive validity to the human situation where the inhibitory effects of SSRIs appear after chronic administration, and not after acute administration. In line with clinical experience, marked blockade of serotonin transporters (SERT) interfered with male sexual behavior, in contrast to the dopamine (DA) and noradrenaline (NA) reuptake inhibitor, bupropion. Further, other drugs that primarily increase levels of DA and NA versus serotonin (5-HT) (the 5-HT1A agonist, buspirone; the triple reuptake inhibitor, DOV216,303 and the 5-HT2C antagonist, S32006) exerted no detrimental influence or a mild stimulatory effect on sexual performance, and they are predicted to have little or no sexual side-effects in men. It is suggested that blockade of DA transporters (DAT) or NA transporters, as well as 5-HT2C receptor blockade, would be a useful avenue for the treatment of antidepressant-induced sexual inhibition. SERT knockout (SERTKO) rats have a permanent disturbance in the serotonergic system and were used to examine the effects of permanently elevated levels of 5-HT in the brain on sexual behaviors. Experiments with SERTKO rats revealed the existence of separate pools of 5-HT1A receptors with varying degree of sensitivity or desensitivity, revealing a possible mechanism underlying sexual dysfunctions. The SERTKO rat would be an interesting animal model to study modulating effects of various drugs on a perturbed serotonergic central nervous system. In addition, a novel use of the antibiotic clavulanic acid was discovered. This drug showed sexual stimulatory activity. A possible underlying mechanism is unknown, but further research on this seems very interesting. The thesis has provided important insights into male sexual function. Our research may lead to help to find new antidepressants without sexual side effects and drugs for the treatment of male sexual dysfunction