Eelke M.S. Snoeren

The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects

Current antidepressants have a delayed onset of action and disturbing side effects, including inhibition of sexual behavior. It is hypothesized that novel drugs, hitting multiple disease-relevant targets, may yield a new generation of superior antidepressants. One such approach is simultaneous inhibition of serotonin, norepinephrine and dopamine transporters. We tested the triple uptake inhibitor (TUI), DOV 216,303 (5, 10 and 20 mg/kg) after 1, 7 and 14 days administration in the olfactory bulbectomized (OBX) rat depression model, and in a model of rat sexual behavior to detect putative sexual side effects. Chronic, but not acute treatment of DOV 216,303 (20 mg/kg) normalized OBX-induced hyperactivity in the open field, similar to the effect of imipramine (20 mg/kg). None of the doses of DOV 216,303 had any effect on sexual behavior at any time point. The results indicate that DOV 216,303 displays antidepressant efficacy and is devoid of sexual side effects.

The Serotonin Transporter Plays an Important Role in Male Sexual Behavior: A Study in Serotonin Transporter Knockout Rats

INTRODUCTION Serotonin (5-HT) is an important neurotransmitter for sexual behaviors. Heterozygous (+/-) serotonin transporter (SERT) rats and SERT knockout rats (-/-) have serotonergic disturbances with significant elevations of basal extracellular 5-HT levels. AIM To investigate the putative role of the SERT in male sexual behavior. METHODS After extensive sexual training, the effects of the 5-HT(1A/7) receptor agonist ± 8-OH-DPAT, the 5-HT(1A) receptor antagonist WAY100 635 and a combination of both on sexual behaviors of SERT(-/-) and SERT(+/-) knockout and wildtype (SERT(+/+) ) male Wistar rats were examined. MAIN OUTCOME MEASURES Male rat sexual behaviors of mounts, intromissions, and ejaculations. RESULTS SERT(-/-) had lower basal ejaculation frequencies than SERT(+/-) and SERT(+/+) animals. ± 8-OH-DPAT enhanced sexual performance in all three genotypes to the same extent. WAY100635 dose-dependently inhibited sexual behavior in all three genotypes with significant dose to genotype interactions. WAY100635 exerted the strongest effects in SERT(-/-) animals. The combination of a dose range of ± 8-OH-DPAT and a selected dose of WAY100635 revealed only partial antagonism by ± 8-OH-DPAT of the sexual inhibitory effects of WAY100635. CONCLUSIONS Absence of the serotonin transporter reduces basal ejaculatory performance in male rats. Pharmacological experiments suggest that separate pools of 5-HT(1A) receptors regulate different aspects of sexual performance in male rats. 5-HT(7) receptors may play a minor role in the partial recovery of sexual behavior after combination of ± 8-OH-DPAT and WAY100635. The SERT(-/-) rat may be a model for chronic SSRI treatment, delayed ejaculation, anorgasmia, and/or low libido.

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.

Differences in Sexual Behaviour in Male and Female Rodents: Role of Serotonin

Serotonin plays an important role in both male and female sexual behaviour. In general, reduction of 5-HT function facilitates, whereas enhancement inhibits sexual behaviour. Most fundamental research on the involvement of 5-HT in sex has been performed in rats. Selective serotonin reuptake inhibitors (SSRIs) have comparable effects on male and female sexual behaviour in rats; they inhibit it but only after chronic administration. Activation of the 5-HT(1A) receptor facilitates sexual behaviour in male rats but inhibits sexual behaviour in female rats, suggesting a differential role for 5-HT(1A) receptors in male and female rats. Research on sexual behaviour in rats with null mutations in the serotonin transporter (SERT) indicated also a differential role for 5-HT(1A) receptors in male and female sexual behaviour. Evidence exists that different pools of 5-HT(1A) receptors have differential roles in various parts of the cascade of sexual events occurring during sexual interactions. Roles for other 5-HT receptors are less well defined although 5-HT(1B), 5-HT(2A/B) and 5-HT(7) receptors seem to be involved. Identification of putative differential or comparable roles in female and male sexual activities requires more research.

Female ultrasonic vocalizations have no incentive value for male rats.

Ultrasonic vocalizations (USVs) are emitted in response to a sexual partner before, during, and after copulation. These vocalizations are the so-called 50-kHz USVs and can be subdivided into flat and frequency-modulated (FM) 50-kHz trill calls. In the present series of experiments, the potential unconditioned and conditioned incentive properties of female 50-kHz USVs for male rats were examined. USVs were recorded from sexually receptive females during the precopulatory phase. A complete 10-min song, or single flat or FM trill calls were selected as auditory stimuli for Experiments 1 and 2. As FM trill calls, a multistep call was used in Experiments 1 and 2a, and an upward ramp call was used in Experiment 2b. The auditory stimuli were played back with a loudspeaker to naïve and sexually experienced male rats in a sexual incentive motivation test. The odor of a sexually receptive female rat was also used as an incentive stimulus for comparison. In a third experiment, a devocalized female, a sham female and a male rat were used as incentive stimuli. It was found that the auditory stimuli did not induce approach behavior in naïve and sexually experienced male rats, but the olfactory stimulus did. In addition, the males spent equal amounts of time in the vicinity of devocalized and vocalizing females. These data show that 50-kHz USVs neither are unconditioned nor conditioned incentives for male rats.

Translational research into sexual disorders : Pharmacology and genomics

The existence of sexual dysfunctions in men, including premature and retarded ejaculation poses challenges to develop translational models in rats that may help in improving treatment and delineate the neural mechanisms of action. Most of our current understanding of the neurobiology, neuroanatomy and psychopharmacology of sexual behavior and ejaculatory function has been derived from preclinical studies in the rat. When large populations of male rats are tested on sexual activity during four successive tests, over time individual rats display a very stable sexual behavior that is either slow, normal or fast as characterized by the number of ejaculations performed. These sexual endophenotypes are postulated as rat counterparts of premature (fast rats) or retarded ejaculation (slow rats). Psychopharmacology in these endophenotypes may help to delineate the underlying mechanisms and pathology. This is illustrated by the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior of rats. Further unravelling of sexual endophenotypes may benefit from the use of chromosomal substitution strains in mice that enable the localization of relevant chromosomal areas and genes involved in ejaculation processes. These preclinical studies and models contribute to a better understanding of the neurobiology of ejaculation and boost the development of novel drug targets to treat ejaculatory disorders such as premature and retarded ejaculation.

Chronic Paroxetine Treatment Does Not Affect Sexual Behavior in Hormonally Sub‐primed Female Rats Despite 5‐HT1A 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.

The role of odors and ultrasonic vocalizations in female rat (Rattus norvegicus) partner choice.

Intrasexual competition for access to a female mate is believed to be unusual in wild male rats, which suggests that female choosiness could be more important. It has been shown that females spend more time with one male than with others when tested in a multiple partner paradigm. The male of first entry is visited most. The role of ultrasonic vocalizations (USVs) and male odors in the female rats initial choice to approach one male instead of another are studied in these experiments. In Experiment 1, female rats were allowed to choose between 3 different intact males, whereas in Experiment 2, females could choose between a devocalized male and 2 intact males. Both experiments started with a 15-min period with inaccessible males followed by a 15-min period with accessible males in which the female could copulate with the males of her choice. The results showed that female rats spent more time with the male of first entry over the males visited subsequently. No differences were found in USV subtype patterns emitted by the different males or the time spent sniffing the different males in the period preceding the choice. In addition, the results of Experiment 2 showed that females visited the silent males as much as the vocalizing males. Thus, the present experiments did not offer any evidence suggesting that USVs or individual differences in male odors play any role in female mate choice. Other factors that were not investigated in this study might be involved in female rat mate selection, but it should also be considered that mate selection could be random.

Silent or Vocalizing Rats Copulate in a Similar Manner

Both male and female rats produce 50 kHz ultrasonic vocalizations (USVs) in the presence of a sexual partner and during copulation. Previous studies showed that USVs have no incentive value for rats. In this study, we evaluated the role of USVs in behavior during copulation. Three groups of rats were used: sham males paired with sham females, devocalized females paired with sham males, and sham females paired with devocalized males. During the copulation test, the USVs emitted by the sham rat were recorded and the sexual behavior of both the male and the female were observed. The results revealed that devocalized and sham females showed similar patterns of sexual behavior and no difference was found in the copulatory behavior of devocalized and sham males. Also the behavior of the partner of a sham rat was comparable to the partner of a devocalized rat. In addition, almost no changes in USVs emission were found in the 5 seconds before and/or after a copulatory behavior. It can be concluded that USVs play no important role in rat copulatory behavior at least in sexually naïve rats.

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.