Penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) responds to low-power laser irradiation: a case study and hypothesis about the role of transient receptor potential (TRP) ion channels.

Treatment of paroxetine-induced penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) by Low-power Laser Irradiation (LPLI) is unknown in medical literature. The aim of the current article is to report partial efficacy of LPLI for paroxetine-induced persistent penile anesthesia. We report on a male patient who presented with a history of reversible loss of smell, taste and skin sensitivity occurring within a week after start of 20mg/day paroxetine-hemihydrate for a depressive period. Concurrently, patient suffered from penile anesthesia, scrotum hypesthesia, anejaculation and erectile difficulties with normal sexual desire. During 2.5 years of paroxetine treatment and throughout 2 years after paroxetine discontinuation, genital and sexual complaints persisted. Penile anesthesia was treated by LPLI with single and multi diode pulsed laser probes. After 20 LPLI-treatment sessions of 15min each, patient reported partial return of penile touch and temperature sensation. Clinical improvement of glans penis sensitivity was reported to 20% and 40%, compared to pre-paroxetine treatment penile sensitivity during erect and flaccid states, respectively. However, anejaculation and erectile difficulties remained unchanged. Briefly, in the current patient with early onset of PSSD, LPLI treatment reduced paroxetine-induced penile anesthesia. It is hypothesized that SSRI treatment induces disturbances of transient receptor potential (TRP) ion channels of mechano-, thermo- and chemosensitive nerve endings and receptors resulting in the penile anesthesia in PSSD. It is further hypothesized that there are two types of PSSD, one of which occurs soon after the start of SSRI treatment.

Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?

Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization. This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling.

Combination of testosterone and vardenafil increases female sexual functioning in sub-primed rats.

INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is a common problem in women and may have a negative impact on quality of life. A recent clinical study shows an increase in sexual drive of HSDD women after cotreatment of testosterone and vardenafil (phosphodiesterase type 5 inhibitor). AIM: In this study, we investigated the effect of testosterone and vardenafil on sexual activity in female rats. MAIN OUTCOME MEASURES: Proceptive (darts and hops), receptive (lordosis), and paced-mating (percentages after exits and contact-return latencies) behaviors were quantified. METHODS: Ovariectomized female rats, sub-primed with only estradiol and fully primed with estradiol and progesterone, were tested in a paced-mating sex test and sexual behaviors were quantified. The sub-primed rats are thought to model HSDD. The effect of testosterone (100 and 300 µg, subcutaneous [SC]) and vardenafil (10 mg/kg, per os [PO]) alone and testosterone (300 µg, SC) in combination with vardenafil (3 and 10 mg/kg, PO) were tested. We also studied the effects of testosterone (300 µg, SC) + intracerebroventricular (ICV) injections of vardenafil (25 and 50 µg) on sexual activity. RESULTS: No effect of testosterone and vardenafil alone was found, but cotreatment of testosterone and vardenafil (PO) caused a significant increase in proceptive and receptive behavior in the sub-primed female rats. Testosterone and vardenafil did not affect fully primed females. ICV administration of vardenafil combined with systemic testosterone, on the other hand, had no effect on sexual activity in both sub-primed and fully primed female rats. CONCLUSIONS: We conclude that cotreatment of subcutaneous testosterone and oral vardenafil increase sexual activity in sub-primed female rats. Our data supports the human finding that combination treatment of testosterone and vardenafil could be used as a new treatment for women with HSDD.

Chronic paroxetine treatment does not affect sexual behavior in hormonally sub-primed female rats despite 5-HT1(A) receptor desensitization.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) cause sexual dysfunctions in humans. However, because SSRIs are used to treat depression, it is unclear whether the problems are caused by the drug, by the depression itself, or an interaction between both. AIM: The present study investigated the effects of chronic paroxetine treatment on sexual behavior in female rats. Furthermore, we tested whether 5-hydroxytryptamine (5-HT)1(A) receptors were desensitized in these females. METHODS: Ovariectomized female rats, either sub-primed with estradiol or fully primed with estradiol and progesterone, were tested in a paced mating test. Proceptive (darting and hopping), receptive (lordosis), and paced mating-related (percentages of exits and contact-return latencies) behaviors were quantified during the course of 56 days of chronic paroxetine treatment (10 mg/kg and 20 mg/kg per day). The 5-HT1(A) /5-HT7 receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide ((±)8-OH-DPAT) alone and in combination with the selective 5-HT1(A) receptor antagonist WAY-100635 was administered to study putative 5-HT1(A) desensitization in the same females. MAIN OUTCOME MEASURES: Proceptive, receptive, and paced mating behaviors were quantified. RESULTS: Acute and chronic paroxetine treatment did not change proceptive and receptive behaviors in both sub-primed and fully primed female rats. In all groups, (±)8-OH-DPAT showed a clear dose-dependent inhibition of sexual behaviors in vehicle-treated females and a right-shifted dose-response effect in the paroxetine-treated rats. WAY-100635 attenuated the inhibiting effect of the 5-HT1(A) receptor agonist in all females. These data suggest 5-HT1(A) receptor desensitization after chronic paroxetine treatment. CONCLUSIONS: Chronic paroxetine treatment does not cause sexual side effects in sub- or fully hormonally primed female rats. Furthermore, chronic treatment causes adaptive changes in the serotonin system such as desensitization of 5-HT1(A) receptors, which may counteract the inhibiting effects of increased extracellular serotonin levels in the chronic paroxetine-treated rats.

A new female rat animal model for hypoactive sexual desire disorder; behavioral and pharmacological evidence.

INTRODUCTION: Female sexual dysfunction (FSD) affects 33-48% of women. Female rats with low sexual activity might model FSD. AIM: In this study, we have investigated whether in a population of normal female rats, subpopulations of rats exist with different levels of sexual behavior. METHODS: Sexually experienced, intact, estradiol-primed female rats were placed in an empty compartment adjacent to a compartment with a male. The females were allowed, during 30 minutes, to switch between the compartments via a hole through which only the females could pass (paced mating). Next, we investigated the acute effects on female sexual behavior of apomorphine, a D(1) - and D(2) -type dopamine receptor agonist, (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (± 8-OH-DPAT), a 5-HT1A receptor agonist, and paroxetine, a selective serotonin reuptake inhibitor. MAIN OUTCOME MEASURES: Time spent in compartments, proceptive behaviors, contact-return latencies, and percentages of exits were quantified. RESULTS: Based on their behavior in the paced mating sex test, estradiol-primed, intact female rats can be divided into three groups: those that mostly avoid the male, a large middle group, and those that mostly approach the male. The avoiders also showed significantly less proceptive behavior than the male approachers. The sexual behavior of the females was relatively stable over time, suggesting the existence of different endophenotypes in female rats. Apomorphine and ± 8-OH-DPAT had an inhibiting effect on sexual behavior, but only females dosed with apomorphine showed a different response in avoiders and approachers, more inhibiting effect in avoiders than approachers. Paroxetine had no effect on proceptive behavior. DISCUSSION: The stable, male-avoiding behavior of some females might correspond to the characteristics of women with FSD. Therefore, these avoiders are a promising new model for FSD, specifically for sexual desire and/or arousal disorders. Furthermore, the apomorphine data suggest that differences in the dopamine system may (partly) underlie the differences in sexual behaviors between avoiders and approachers.

Persistent genital arousal disorder in 18 Dutch women: Part I. MRI, EEG, and transvaginal ultrasonography investigations.

INTRODUCTION: Systematic blood analysis and electroencephalographic (EEG) and magnetic resonance imaging (MRI) study in women with persistent genital arousal disorder (PGAD) are needed to get more insight into the syndrome's etiology and pathogenesis. AIM: To investigate possible causes of PGAD. METHODS: Eighteen women fulfilling all five criteria of PGAD were included in the study. In-depth interviews and routine blood and hormonal investigations, together with EEG and MRI scans of the brain and pelvis, were performed in all women. Transvaginal ultrasonography (TVUS) and MRI scans with contrast were performed in subjects who had indications of abnormalities on MRI scans. MAIN OUTCOME MEASURES: Detailed descriptions of blood, neurophysiological, and (neuro)anatomical findings. RESULTS: The majority of women experienced PGAD symptoms during early menopause without existing laboratory abnormalities, besides those belonging to menopause. The EEG studies showed no severe diffuse or focal abnormalities. The MRI scans of the brain did not show any specific abnormalities, apart from an already known pericallosal aneurysm in one patient and postoperative findings of meningioma surgery in another patient. MRI scans of the pelvis showed clear to moderate-clear indications of pelvic varices in 55% of the women. TVUS confirmed the existence of pelvic varices in nine women; these had a mild, moderate, and severe extent in two, three, and four women. In three of the latter four patients, an additional MRI with gadolinium contrast disclosed mild to moderate dilation of ovarian veins; 39% of the women were known with varices of one or both legs. CONCLUSIONS: The current study did not show overt pathology that could causally explain PGAD sensations. As pelvic varices are a common finding in adult women, the current findings do not allow the conclusion that PGAD is causally related to pelvic varices. However, the high prevalence of pelvic and lower limb varices in the current group of women warrants further research of their role in PGAD.

Effects of acute and chronic apomorphine on sex behavior and copulation-induced neural activation in the male rat.

Apomorphine is a non-selective dopaminergic receptor agonist. Because of its pro-erectile effects, apomorphine is clinically used for treatment of erectile dysfunction. We investigated the effects of subcutaneous apomorphine administration (0.4 mg/kg rat) on sexual behavior and mating-induced Fos-expression following acute (day 1) or chronic apomorphine treatment (days 8 and 15) in sexually experienced male rats. Consistent facilitatory effects of apomorphine were observed in the reduced numbers of mounts and intromissions over time and an increased ejaculation frequency on day 1. The first post-ejaculatory interval, however, was lengthened, while other behavioral parameters were unaffected. Fos-immunoreactivity induced by acute apomorphine administration (barrel cortex, paraventricular hypothalamic nucleus, central amygdala and locus coeruleus) was strongly reduced after chronic administration. After mating, induction of Fos-immunoreactivity was observed in well-known areas like medial preoptic nucleus and the posterodorsal medial amygdaloid area. Apomorphine, however, reduced mating-induced Fos-immunoreactivity in the nucleus accumbens shell and prevented its occurrence in its core area. This remarkable apomorphine effect was not observed in any other brain area. We conclude that the behavioral (pro-erectile) effects of apomorphine are consistent over time, and that the diminished accumbens-Fos-immunoreactivity and the elongated post-ejaculatory interval may reflect a decreased response to remote cues from the estrus female.

Individual differences in male rat ejaculatory behaviour: searching for models to study ejaculation disorders.

In addition to investigating sexual function in rats that display normal ejaculatory behaviour, studying rats that are either 'hyposexual' or 'hypersexual' may provide important insights into the aetiology of ejaculatory dysfunctions in men, such as premature and retarded ejaculation. To this end, rats were matched into groups of 'sluggish', 'normal' and 'rapid' ejaculators based on their ejaculation frequencies displayed in a series of weekly sexual behaviour tests. Selecting rats on this parameter revealed large and stable differences in other parameters of sexual behaviour as well, including ejaculation latency and mount frequency but not intromission frequency and mount latency, putative indices of sexual motivation. Neuroanatomically, Fos immunoreactivity as a measure of neuronal activation was increased in rapid ejaculators compared with sluggish ejaculators in ejaculation-related brain areas, presumably associated with the differences in ejaculatory behaviour. Although the total number of oxytocin neurones within subregions of the hypothalamus did not differ between groups, in the supraoptic nucleus of the hypothalamus more oxytocin neurones were activated in rapid ejaculators compared with the other groups. Apart from the differences observed in ejaculatory behaviour, groups did not differ with respect to their locomotor activity and approach-avoidance behaviour as measured in the elevated plus-maze. Finally, apomorphine-induced stereotypy was similar in sluggish and rapid ejaculators, suggesting no large differences in dopamine susceptibility. Altogether, the present results suggest stable differences in male rat ejaculatory behaviour. Further exploring the neurobiological mechanisms underlying these differences may be a promising approach to gain insights into the aetiology of sexual dysfunctions such as premature, retarded or an-ejaculation.

Citalopram combined with WAY 100635 inhibits ejaculation and ejaculation-related Fos immunoreactivity.

The role of 5-HT (5-hydroxytryptamine, 5-HT)(1A) receptor activation in the sexual side-effects, in particular delayed ejaculation, of selective serotonin reuptake inhibitors (SSRIs) was studied. Male Wistar rats were treated for 15 days with vehicle, the SSRI citalopram (10 mg/kg/day p.o.), the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCL (WAY 100635, 0.1 mg/kg/ day s.c.), or both drugs combined. Sexual behavior was assessed weekly. One h after the last sexual behavior test, rat brains were processed for Fos-immunohistochemistry. Acute and chronic citalopram mildly inhibited ejaculation, which was strongly augmented by co-administration of WAY 100635. WAY 100635 alone did not alter sexual behavior. Brain sites associated with ejaculation showed reduced Fos-immunoreactivity in rats treated with both citalopram and WAY 100635. Citalopram reduced Fos-immunoreactivity in the arcuate hypothalamic nucleus, an area that might link serotonergic neurotransmission to ejaculation.