Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT1 A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT1 A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT1 A autoreceptors and postsynaptic 5-HT1 A heteroreceptors alter when extracellular 5-HT levels are chronically increased. Serotonin transporter knockout (SERT-/-) rats exhibit enhanced extracellular 5-HT levels and desensitized 5-HT1 A receptors. These rats model neurochemical changes underlying chronic SSRI-induced sexual dysfunction. We want to determine the role of presynaptic versus postsynaptic 5-HT1 A receptors in the pro-sexual effects of 5-HT1 A receptor agonists in SERT+/+ and in SERT-/- rats. Therefore, acute effects of the biased 5-HT1 A receptor agonists F-13714, a preferential 5-HT1 A autoreceptor agonist, or F-15599, a preferential 5-HT1 A heteroreceptor agonist, and S15535 a mixed 5-HT1 A autoreceptor agonist/heteroreceptor antagonist, on male sexual behavior were assessed. A clear and stable genotype effect was found after training where SERT+/+ performed sexual behavior at a higher level than SERT-/- rats. Both F-15599 and F-13714 induced pro-sexual activity in SERT+/+ and SERT-/- animals. Compared to SERT+/+, the F13714-dose-response curve in SERT-/- rats was shifted to the right. SERT+/+ and SERT-/- rats responded similar to F15599. Within both SERT+/+ and SERT-/- rats the potency of F-13714 was much stronger compared to F-15599. S15535 had no effect on sexual behavior in either genotype. In SERT+/+ and SERT-/- rats that were selected on comparable low sexual activity (SERT+/+ 3 or less ejaculations and SERT-/- 5 or less ejaculations in 10 weeks) S15535 also did not influence sexual behavior. The two biased compounds with differential effects on 5-HT1 A auto- and hetero-receptors, exerted pro-sexual activity in both SERT+/+ and SERT-/- rats. Applying these specific pharmacological tools has not solved whether pre- or post-synaptic 5-HT1 A receptors are involved in pro-sexual activity. Moreover, the inactivity of S15535 in male sexual behavior in either genotype was unexpected. The question is whether the in vivo pharmacological profile of the different 5-HT1 A receptor ligands used, is sufficient to differentiate pre- and/or post-synaptic 5-HT1 A receptor contributions in male rat sexual behavior.

As lifelong premature ejaculation (PE) and subjective PE are two different PE subtypes, the measurement of their characteristic features requires different objective measures. In this article, we address the differences between lifelong PE and subjective PE, in terms of the extent of variation of sexual performance and propose a new objective measure for research of subjective PE. By considering lifelong PE as a mainly "male" sex disorder and subjective PE as a mainly "man" sex disorder, we show that stopwatch-mediated intravaginal ejaculation latency time (IELT) measurement is most adequate for research of lifelong PE, but inadequate for research of subjective PE. Subjective PE needs another objective measure to capture its key characteristics. Arguments are provided to show that the characteristics of subjective PE are different from the key features of lifelong PE. The core issue in lifelong PE is the very short IELT with a very small variation in sexual performance. Subjective PE is characterized by a higher variation of sexual performance. Stopwatch-mediated IELT measurement is essential in case of small variation of sexual performance. In contrast, measurement of various parameters of penile intravaginal thrusting is suggested to be more appropriate in case of high variation of sexual performance observed in subjective PE. In conclusion, research of lifelong PE should be performed by stopwatch measurement of the IELT whereas research of subjective PE should be performed by movement tracker devices, designed to be bound to the males body and/or inserted into the women's vagina with robust software to measure intravaginal thrusting variation performance. Future studies are warranted to provide scientific data to support this hypothesis.

Recently, the ICD-11 for Mortality and Morbidity Statistics (ICD-11-MMS, 2018 Version) has been published with a new definition of premature ejaculation (PE), including a third PE subtype. This definition differs from Diagnostic and Statistical Manual of Mental Disorders (DSM-5) definition of PE. We hereby address the similarities and differences between ICD-11-MMS and DSM-5 definition of PE and call attention to the illogical policy of some European (EU) National Regulatory Agencies to remain with a 1-min cut-off point of ejaculation time for Lifelong, Acquired and Subjective PE. The advantage of ICD-11-MMS is the inclusion of a third PE subtype, which is congruent with Subjective PE. A serious disadvantage of DSM-5 is that a 1-min criterion is used for both Lifelong and Acquired PE, and that a third PE subtype is not mentioned. Despite the incomplete DSM-5 definition of PE, some EU regulatory agencies adhere to a definition of PE which relies only on the 1-min ejaculation time cut-off point of DSM-5, and do not recognize the more recent PE definitions of ICD-11-MMS and International Society for Sexual Medicine. There is no scientific evidence for this illogical position. The continued use of a 1-min cut-off point for all subgroups of PE ignores the existence of Acquired PE (Intravaginal Ejaculation Latency Time (IELT) <3 min) and Subjective PE (IELT <approx. 6 min), both of which have been shown to be clinically and psychologically important. In conclusion, some EU regulatory agencies are not recognizing ongoing developments in the definition of three different subgroups of PE. We propose combining the DSM-5 and ICD-11 MMS definitions to optimize the whole PE spectrum for future registered drug treatment studies, so that it properly reflects patient needs.

A case is described of a 40-year-old woman with persistent spontaneous orgasms after use of cannabis and five hours of intense pounding sexual activity. She presented with severe anxiety, in particular suffering from restless genital syndrome (ReGS). However, she did not fulfill any of the five criteria of ReGS. It was concluded that her spontaneous orgasms were the result of the use of cannabis combined with the long duration of previous sexual activity. This finding is not only important for physicians, but also for highly exposed subjects such as those active in the sex industry.

In dit hoofdstuk staat het verband tussen veelvoorkomende psychiatrische stoornissen, seksueel functioneren en seksualiteitsbeleving centraal. Uit de klinische praktijk blijkt dat het gesprek over seksualiteit in de ambulante en residentiële psychiatrische zorg nog steeds niet evident is. Daarom worden de voorwaarden voor een positieve benadering van seksualiteit in de hulpverlening kort geschetst. De bijwerkingen van psychofarmaca op seksualiteit en de mogelijke behandelingsstrategieën daarvoor worden beschreven. Het hoofdstuk eindigt met twee handzame overzichten over enerzijds geneesmiddelen die het seksueel functioneren bevorderen en anderzijds de farmacologische mechanismen die daaraan ten grondslag liggen. Ten slotte wordt een aantal blijvende uitdagingen voor de psychiatrie en de seksuologie opgesomd.

Tramadol may offer a useful intervention for treating PE. As all primary studies had suffered from selection, allocation, performance, or assessment bias, additional rigorous well-designed controlled trials are warranted to further investigate the potential long-term risks of tramadol and to determine the safe and the effective minimum daily dose. Clinical research on drug abuse and sexual dysfunction is an emerging field. To date, small numbers of studies have been performed and further studies are warranted.

Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the μ-opioid and the 5-HT system. First the μ-opioid receptor agonist properties of tramadol were tested with naloxone, a μ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT1A receptor antagonist, were tested on the behavioral effects of tramadol. Finally the effects of paroxetine, a selective serotonin reuptake inhibitor, combined with naloxone or WAY100,635 treatment, were compared to the effects of tramadol combined with these drugs. Results showed that naloxone, at a sexually inactive dose, could only partially antagonize the inhibitory effect of tramadol. Moreover, low and behaviorally inactive doses of WAY100,635, strongly decreased sexual behavior when combined with a behaviorally inactive dose of tramadol. Finally we showed that the effects of paroxetine on sexual behavior resembled the effects of tramadol, indicating that tramadol's inhibitory effects on sexual behavior are primarily and mainly caused by its SSRI properties and that its μ-opioid receptor agonistic activity only contributes marginally. These findings support the hypothesis that tramadol exerts inhibition of premature ejaculations in men by its 5-HT reuptake inhibiting properties.

The influence of testosterone on libido has been widely accepted in spite of clear indications that libido is also influenced by psychosocial factors, which are related for example by cultural and religious factors. Recent research has provided evidence that a decreased libido may be caused by 1. a highly sensitive brain for sexual cues and strong psychological inhibition, and 2. by a low sensitive brain for sexual cues. This distinction shows two different fundamental mechanisms to increase sexual desire. Firstly, activation of 5-HT1A receptors in the frontal lobe diminishes psychological inhibition. Secondly, increasing genital NO contents increases libido on the condition that the brain has been primed 4 hours before with a low dosage of testosterone. Understanding of both mechanisms is essential for a better understanding of patients with libido difficulties.

Oxytocin (OT) is a nonapeptide with an impressive variety of physiological functions. Among them, the ‘prosocial’ effects have been discussed in several recent reviews, but the direct effects on male and female sexual behavior did receive much less attention so far. As our contribution to honor the lifelong interest of Berend Olivier in the control mechanisms of sexual behavior, we decided to explore the role of OT in the present review. In the successive sections, some physiological mechanisms and the ‘pair-bonding’ effects of OT will be discussed, followed by sections about desire, female appetitive and copulatory behavior, including lordosis and orgasm. At the male side, the effects on erection and ejaculation are reviewed, followed by a section about ‘premature ejaculation’ and a possible role of OT in its treatment. In addition to OT, serotonin receives some attention as one of the main mechanisms controlling the effects of OT. In the succeeding sections, the importance of OT for ‘the fruits of labor’ is discussed, as it plays an important role in both maternal and paternal behavior. Finally, we pay attention to an intriguing brain area, the ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl), apparently functioning in both sexual and aggressive behavior, which are at first view completely opposite behavioral systems.

In the last two decades much progress has been made in the neurobiological, pharmacological and neuro-imaging research of sexual dysfunctions. to present an overview of current treatment options to provide better understanding of underlying (neuro)biological mechanisms use of evidence-based research articles Erectile dysfunction and lifelong premature ejaculation, previously regarded as pure psychological disorders, are currently regarded as (neuro)biologically and even genetically influenced dysfunctions. On the other hand, vaginismus and a substantial part of dyspareunia remain to have mainly psychological causes. Antidepressant and antipsychotic induced sexual side effects remain difficult to be treated. Switching to another drug with less sexual side effect remains the first option of treatment, but may negatively interfere with the underlying psychiatric disorder. Although antidepressant-induced sexual side effects are reversible, SSRI-induced sexual side effect may persist for a very long time after SSRI discontinuation. This so called, post SSRI sexual dysfunction (PSSD) is probably the most serious side effect of SSRI treatment. A new libido-increasing drug is currently investigated in multi-centered trials. Its mechanism of action is totally new in neuropharmacology. In addition, a new antidepressant with a complex neuropharmacological underlying mechanism of action, may be the first manifestation of the advent of newly produced antidepressants without sexual side effects. evidence-based drug treatment of a number of sexual dysfunctions has replaced non-evidence based psychotherapies. Still, psycho-education and counseling remain essential for an effective treatment of sexual disorders.

Post-orgasmic unwell being denoted as postorgasmic illness syndrome (POIS) was for the first time reported by Waldinger and Schweitzer in 2002 [1]. Recently, Waldinger et al. investigated 45 Caucasian males with complaints of POIS and categorized their symptoms in 5 preliminary criteria [2,3]. POIS is characterized by local mucosal manifestations (nasal congestion, itching eyes), and systemic features (flu-like syndrome with feverishness, muscle tension, exhaustion, foggy head, concentration difficulties, and mood irritability), occurring within 30–60 minutes after ejaculation. The symptoms always starts off after ejaculation, often reaching its peak severity at the second day and gradually diminishes within 1–7 days [3]. Affected males usually try to avoid ejaculating by planning intercourse or by abstaining from sexual activity. Waldinger et al. showed that 88% of the males had a positive intracutaneous (IC) skin-prick test for autologous semen and postulated that POIS is an expression of an auto-immune process. Support for this hypothesis comes from positive effects of hyposensitization treatment with diluted autologous semen in two men with POIS.

In 2010 the International Society of Sexual Medicine published its practice guideline for the diagnosis and treatment of premature ejaculation. This guideline was translated and adapted on a number of points by a committee consisting of members of two Dutch sexological societies, the 'WVSD' and the 'NVVS'. The most important subjects in this guideline are: (a) the case history is the most important diagnostic tool; (b) a physical examination is usually not necessary; (c) determination of the subtype of premature ejaculation can guide treatment; (d) pharmacotherapy alone is only applicable for primary premature ejaculation; (e) combination therapy is preferable for the secondary form of premature ejaculation, and pharmacotherapy is contraindicated for the other 2 subtypes.

In the last two decades an increasing number of sexual behavioral studies in laboratory animals has contributed to a better understanding of the neural basis of ejaculatory functioning. In addition, these studies, which mainly involved male and female Wistar rats, elucidated basic mechanisms that underly the psychopharmacology of SSRI-induced ejaculation delay. Notably, a new animal model for premature and retarded ejaculation has been developed. This model has been shown to be of eminent importance for the investigation of ejaculatory disorders. Moreover, it has been proven useful into the investigation of female rat sexual motivation. Translational research translates findings of animal research into human application. Indeed, objective and systematic psychopharmacological research in men with lifelong premature ejaculation yields a remarkable similarity with data that have been found in animals. Sofar, animal research of premature ejaculation remarkably predicts data in men with lifelong PE, on the condition that clinical human research was performed according to evidence based research principles.

In the last two decades enormous progress has been made in the characterization of premature ejaculation (PE). Although lifelong (primary) PE and acquired (secondary) PE has been known since the 1980s, a new classification of PE has been proposed in 2006 by Waldinger et al., who distinguished two other PE subtypes, e.g., premature-like ejaculatory disfunction and natural variable PE. In 1943, Bernhard Schapiro noted that family members of men with PE often have PE as well. In 1998, Waldinger et al postulated that lifelong PE, and particularly the short intravaginal ejaculation latency time (IELT), may be genetically determined. They postulated that the IELT is distributed according to a continuum, from men who always ejaculate very rapidly to men who always ejaculate after a very long intravaginal ejaculation time. Research in male rats showed this continuum. In two stopwatch studies, such a continuum was also shown in a random sample of men. In 2009, Janssen et al. publish ed a DNA study performed in men with lifelong PE. This study showed that 5-HTT polymorphism was involved in the ejaculation latency time. It appeared that in men with lifelong PE, males with LL genotype had a 100% faster ejaculation time than men with an SS genotype. It is postulated that the IELT is genetically determined by a cluster of genetic polymorphisms of the 5-HTT, 5-HT receptors, 5-HT enzymes and/or polymorphisms of other neurotransmitter systems.

INTRODUCTION:Serotonin plays a key role in sexual behavior. In serotonin transporter (SERT) knockout rats (-/-), basal extracellular 5-HT levels are considerably increased, indicating a serotonergic disturbance. Heterozygous SERT(+/-) rats express 50% of SERT in comparison to wild-type rats and may therefore model the s/s phenotype of the human SERT promoter (5-HTTLPR) polymorphism.AIM:In the present study, we used both homozygote and heterozygote SERT knockout and wild-type rats (+/+) to study the putative role of the SERT in female sexual behavior.METHODS:Female rats were brought into estrous by hormonal injections before a paced mating sex test. The effects of the 5-HT(1A)/5-HT(7) receptor agonist (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (+/-8-OH-DPAT) (0.03-1 mg/kg s.c.) and the 5-HT(1A) receptor antagonist WAY-100635 (0.1-1-mg/kg i.p.) on sexual behaviors of the females were tested separately and in a selected combination of both in all three genotypes.MAIN OUTCOME MEASURES:Proceptive (darting and hopping) and receptive (lordosis) behaviors were quantified.RESULTS:Basal proceptive and receptive sexual activities were not different between SERT+/+, +/- and -/- female rats. The dose-effect curve after +/-8-OH-DPAT for these activities was clearly shifted to the right in SERT-/- animals compared to other genotypes. WAY-100635 alone had no effect on sexual behavior in any genotype, but was able to antagonize the +/-8-OH-DPAT-induced decrease in sexual activities indicating the involvement of the 5-HT(1A) receptor.CONCLUSIONS:The absence (-/-) or reduced (+/-) expression of SERT does not affect basal sexual activity in female rats in a paced mating situation. The data indicate a desensitized 5-HT1A receptor in the SERT-/-, but not in the SERT+/- females. Under normal basal conditions, desensitized 5-HT1A receptors apparently do not play a role in female sexual behavior of the SERT-/-. However, upon activation of the 5-HT1A receptor in "normal" females (SERT+/+ and SERT+/-), a hyposexual behavior is induced.

Bacteriophage JC1 is a Podoviridae phage with a C1 morphotype, isolated on host strain Burkholderia cenocepacia Van1. Phage JC1 is capable of infecting an expansive range of Burkholderia cepacia complex (Bcc) species. The JC1 genome exhibits significant similarity and synteny to Bcep22-like phages and to many Ralstonia phages. The genome of JC1 was determined to be 61,182 bp in length with a 65.4% G + C content and is predicted to encode 76 proteins and 1 tRNA gene. Unlike the other Lessieviruses, JC1 encodes a putative helicase gene in its replication module, and it is in a unique organization not found in previously analyzed phages. The JC1 genome also harbours 3 interesting moron genes, that encode a carbon storage regulator (CsrA), an N-acetyltransferase, and a phosphoadenosine phosphosulfate (PAPS) reductase. JC1 can stably lysogenize its host Van1 and integrates into the 5′ end of the gene rimO. This is the first account of stable integration identified for Bcep22-like phages. JC1 has a higher global virulence index at 37 °C than at 30 °C (0.8 and 0.21, respectively); however, infection efficiency and lysogen stability are not affected by a change in temperature, and no observable temperature-sensitive switch between lytic and lysogenic lifestyle appears to exist. Although JC1 can stably lysogenize its host, it possesses some desirable characteristics for use in phage therapy. Phage JC1 has a broad host range and requires the inner core of the bacterial LPS for infection. Bacteria that mutate to evade infection by JC1 may develop a fitness disadvantage as seen in previously characterized LPS mutants lacking inner core.