Antidepressants, Sexual Behavior, and Translational Models for Male Sexual Dysfunction: Development of Animal Models, Pharmacology, and Genetics

The discovery and development of the first generations of antidepressants in the last century, the tricyclic antidepressants and serotonin reuptake blockers, were a breakthrough in the pharmacological treatment of major depression. Along with the antidepressant activity came the sexual side effects, which contributed considerably to the high level of stopping treatment. In the subsequent search for new and better antidepressants, early detection of potential sexual side effects is of paramount importance, hence the need for predictive animal models. Sexual behavior of the male rat has been frequently used to detect inhibiting effects of psychotropic drugs. We developed a male rat model of sexual behavior that mirrored the human profile of antidepressants: sexual inhibitory effects only after chronic but not after acute administration. We extensively describe the methodology and the model and show the profile of various antidepressants and other psychotropics in male rat sexual behavior. To generate male rats for our experiments, we employ large cohorts of male Wistar rats that are trained once weekly in 30-min tests with estrous females for at least 4–7 times. During this training each individual rat develops its own stable sexual phenotype, being between 0 and 5 ejaculations per 30-min test. Such a (endo)phenotype appears very stable over time and animals can be used repeatedly for pharmacological experiments for over a year, providing an ideal intra-male experimental model. For testing the effects of drugs (e.g., antidepressants) on sexual behavior, we standardly use rats with stable ejaculation numbers of 2–3 per test, providing a model that is sensitive to both sexual-stimulating (prosexual) and sexual-inhibiting effects, and are able to dissect acute and chronic effects of drugs. The effects of various drugs tested in this model over the last decades are given. By using the large cohort approach and sexual training, we discovered that the number of rats with 0, 1, 2, 3, 4, or 5 ejaculations (E) per test shows a bell-shaped distribution. Relatively few rats have either 0 or 1 E or 4 or 5 E/test, whereas those with 2 or 3 E/test are much more abundant. Based on the similarity of rat ejaculation number distribution with that of ejaculation latency distribution in human males, we postulate that fast ejaculating rats (4 or 5 E/test) are a translational model for premature ejaculation, whereas slow or not ejaculating rats (0 or 1 E/test) could model an-ejaculation or delayed ejaculation in men. Several pharmacological experiments are described supporting the use of these translational endophenotypic models of normal, slow, and fast ejaculating rats. The importance of the serotonergic system and in particular the role of 5-HT1A receptors in male sexual behavior is highlighted. The serotonin transporter knockout rat illustrates the influence of genetic modifications in male rat sexual behavior. This model displays a comparable sexual phenotype as chronically SSRI-treated rats. Such a genetic model may be useful in detecting underlying mechanisms of sexual dysfunctions (like delayed ejaculation) but may also contribute to the study of critically involved neurochemical systems. Finally, testing drugs with multimodal mechanisms of action in such genetic models might unravel new mechanisms involved, finally contributing to better treatments.