Sexual Dysfunction, Depression and Antidepressants: A Translational Approach

Major depression is frequently associated with sexual dysfunctions. Most antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), induce additional sexual side effects and, although effective antidepressants, deteriorate sexual symptoms, which are the main reason that patients stop antidepressant treatment. Many strategies have been used to circumvent the additional sexual side effects, but results are rather disappointing. Recently, new antidepressants have been introduced, vilazodone and vortioxetine, which seem to lack sexual side effects in the early registration trials. Much research with large numbers of depressed patients and adequate methodological tools still has to confirm in daily use the absence of sexual side effects of new antidepressants. Animal models that in an early phase of drug development may predict putative sexual side effects of new antidepressants are extremely useful and could speed up development of new antidepressants. A rat model of sexual behavior is described that has a very high predictive validity for sexual side effects in man. Several characteristics of present antidepressants with regard to sexual dysfunctions are also present in the rat model and establish its validity. The animal model can also be used in the search for new psychotropics without sexual side effects or for drugs with sexual stimulating activity

Olfaction and Depression: Does the Olfactory Bulbectomized Rat Reflect a Translational Model for Depression?

The olfactory bulbectomized (OBX) rat is extensively used as an animal model to detect putative antidepressant drugs. The model has some unusual characteristics, as it detects antidepressant activity of drugs only after medium to long-term administration, thereby reflecting the human situation, as antidepressants do not work acutely but only after long-term administration. The slow onset of action of antidepressants is a major drawback of current antidepressants and the availability of an animal depression model that potentially reveals rapid onset of antidepressant activity might be a great asset. Although an animal model of depression ideally should reflect correlates of human depression, several ‘surrogate’ parameters, like ‘hyperactivity’, reflect astonishingly well the ‘antidepressant’ profile of antidepressants in human depression. Using a new environment (open field) and a home cage to measure activity, imipramine, a classic tricyclic antidepressant, reduced hyperactivity in OBX rats, both in home cage and open field. Telemetrically measured, OBX-induced hyperactivity was already found after a couple of days and indicated that the OBX model is able to detect early (days) effects of (classic) antidepressants. Although imipramine treatment for 3, 7 and 14 days reduced OBX-induced hyperactivity, daily treatment with imipramine for 14 days, but not for 3 or 7 days, reduced hyperactivity (both in home cage and open field) of OBX rats up to 6 weeks after cessation of treatment, indicating neuroplastic changes in the brain. The attractiveness of the OBX model for detection of antidepressants lies in the resemblance to the human situation (onset of action). Moreover, the model suggests that long-term antidepressant treatment (in rats at least 14 days) leads to long-term behavioral changes that far outlast the presence of the antidepressant in the body. Whether this aspect contributes to efficient antidepressant effects needs further investigation

Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression

Funding Information: JDAO was supported by the European Union?s Horizon 2020 research and innovation program under the Marie Sk?odowska Curie Individual Fellowship under Grant 660152-DEPREG; and a NARSAD young investigator grant under Grant 25206. ASR was supported by a scholarship awarded by the Fulbright Center The Netherlands. TLB was supported by the National Institutes of Mental Health under Grant numbers P50-MH099910, MH 104184, MH 091258, MH 087597, MH 073030, and MH 108286. EJ was supported by the National Institutes of Health National Research Service Award F32 under Grant MH 109298. We thank Judith Swart, Wanda Douwenga and Christa Reitzema-Klein for their assistance with the early life stress procedure, drug administration and sample collection. Publisher Copyright: © 2020, © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Peer reviewedPublisher PD

Perinatal fluoxetine exposure disrupts the circadian response to a phase-shifting challenge in female rats

Funding Information: This research was funded by the Dobberke foundation, grant number UPS/BP/4151 2016-27.Peer reviewedPublisher PD

Perinatal fluoxetine treatment and dams’ early life stress history have opposite effects on aggressive behavior while having little impact on sexual behavior of male rat offspring

Funding Information: This work was supported by the NARSAD young investigator grant from the Brain and Behavior Research Foundation (Grant No. 25206) and by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie (Grant Agreement No. 660152).Peer reviewedPublisher PD

Female rat sexual behavior is unaffected by perinatal fluoxetine exposure

Serotonin plays an important role in adult female sexual behavior, however little is known about the influence of serotonin during early development on sexual functioning in adulthood. During early development, serotonin acts as neurotrophic factor, while it functions as a modulatory neurotransmitter in adulthood. The occurrence of serotonin release, could thus have different effects on behavioral outcomes, depending on the developmental period in which serotonin is released. Because serotonin is involved in the development of the HPG axis which is required for puberty establishment, serotonin could also alter expression patterns of for instance the estrogen receptor ɑ (ERɑ). The aim of our study was to investigate the effects of increased serotonin levels during early development on adult female rat sexual behavior during the full behavioral estrus in a seminatural environment. To do so, rats were perinatally exposed with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg FLX) and sexual performance was tested during adulthood. All facets of female sexual behavior between the first and last lordosis (behavioral estrus), and within each copulation bout of the behavioral estrus were analyzed. Besides the length and onset of the behavioral estrus and the sexual behaviors patterns, other social and conflict behavior were also investigated. In addition, we studied the effects of perinatal FLX exposure on ERɑ expression patterns in the medial preoptic nucleus, ventromedial nucleus of the hypothalamus, medial amygdala, bed nucleus of the stria terminalis, and the dorsal raphé nucleus. The results showed that perinatal fluoxetine exposure has no effect on adult female sexual behavior. The behavioral estrus of FLX-females had the same length and pattern as CTR-females. In addition, FLX- and CTR-females showed the same amount of paracopulatory behavior and lordosis, both during the full behavioral estrus and the "most active bout". Furthermore, no differences were found in the display of social and conflict behaviors, nor in ERɑ expression patterns in the brain. We conclude that increases in serotonin levels during early development do not have long-term consequences for female sexual behavior in adulthood.</p

Aggression and Sexual Behavior: Overlapping or Distinct Roles of 5-HT_1A and 5-HT_1B Receptors

Distinct brain mechanisms for male aggressive and sexual behavior are present in mammalian species, including man. However, recent evidence suggests a strong connection and even overlap in the central nervous system (CNS) circuitry involved in aggressive and sexual behavior. The serotonergic system in the CNS is strongly involved in male aggressive and sexual behavior. In particular, 5-HT1A and 5-HT1B receptors seem to play a critical role in the modulation of these behaviors. The present chapter focuses on the effects of 5-HT1A- and 5-HT1B-receptor ligands in male rodent aggression and sexual behavior. Results indicate that 5-HT1B-heteroreceptors play a critical role in the modulation of male offensive behavior, although a definite role of 5-HT1A-auto- or heteroreceptors cannot be ruled out. 5-HT1A receptors are clearly involved in male sexual behavior, although it has to be yet unraveled whether 5-HT1A-auto- or heteroreceptors are important. Although several key nodes in the complex circuitry of aggression and sexual behavior are known, in particular in the medial hypothalamus, a clear link or connection to these critical structures and the serotonergic key receptors is yet to be determined. This information is urgently needed to detect and develop new selective anti-aggressive (serenic) and pro-sexual drugs for human applications

Tramadol: effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects

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.\ud \ud 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.\u