A new approach to 'on-demand' treatment of lifelong premature ejaculation by treatment with a combination of a 5-HT 1A receptor antagonist and SSRI in rats.

Lifelong premature ejaculation (PE) in men lacks an adequate on-demand pharmacological treatment. Although selective serotonin reuptake inhibitors (SSRIs) are used for PE they only work after chronic treatment, or if used on-demand, less adequately than chronic SSRI treatment. It has been shown that the addition of a behaviorally silent 5-HT 1A-receptor antagonist to an SSRI can generate acute inhibitory effects on male rat sexual behavior. Atlas987 is a selective 5-HT 1A-receptor antagonist with equal potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT 1A receptors in rat and human brain. To investigate whether Atlas987 together with the SSRI paroxetine, a combination called Enduro, induces acute inhibitory effects on male rat sexual behavior, we tested Enduro in Wistar rats in a dose-dependent manner. We first tested the 5-HT 1A receptor antagonist Atlas987 in 8-OH-DPAT induced serotonergic behavior in rats. Second, we tested Enduro in a dose-dependent manner in male sexual behavior. Third, we tested the effective time window of Enduro's action, and lastly, we measured the plasma levels of Atlas987 and paroxetine over an 8-h period. Results showed that Enduro acutely and dose-dependently reduced the number of ejaculations and increased the ejaculation latencies. The behavioral pattern induced reflected a specific effect on sexual behavior excluding non-specific effects like sedation or sensoric-motoric disturbances. The time-window of activity of Enduro showed that this sexual inhibitory activity was at least found in a 1-4 h' time window after administration. Plasma levels showed that in this time frame both Atlas987 and paroxetine are present. In conclusion, in rats, Enduro is successful in acutely inhibiting sexual behavior. These results may be therapeutically attractive as "on demand" treatment for life-long premature ejaculation in men. </p

Shot Noise in Mesoscopic Conductors

Theoretical and experimental work concerned with dynamic fluctuations has developed into a very active and fascinating subfield of mesoscopic physics. We present a review of this development focusing on shot noise in small electric conductors. Shot noise is a consequence of the quantization of charge. It can be used to obtain information on a system which is not available through conductance measurements. In particular, shot noise experiments can determine the charge and statistics of the quasiparticles relevant for transport, and reveal information on the potential profile and internal energy scales of mesoscopic systems. Shot noise is generally more sensitive to the effects of electron-electron interactions than the average conductance. We present a discussion based on the conceptually transparent scattering approach and on the classical Langevin and Boltzmann-Langevin methods; in addition a discussion of results which cannot be obtained by these methods is provided. We conclude the review by pointing out a number of unsolved problems and an outlook on the likely future development of the field.Comment: 99 two-column pages; 38 .eps figures included. Submitted to Physics Reports. Many minor improvements; typos corrected; references added and update

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

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