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Serotonin and Sexual Behavior
Abstract
Serotonin's (5-HT) classical role in regulation of sexual behavior is to inhibit copulation. However, the neurotransmitter exerts a more complex influence on the behavior dependent on the particular aspect of the behavior examined. In this chapter, the historical basis for consideration of 5-HT as a major player in sexual behavior is discussed. Current information about the role of 5-HT in the sexual dysfunction that is associated with the use of selective serotonin reuptake inhibitors is reviewed. Information on specific 5-HT receptor subtypes, though far from complete, implicates 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3 and 5-HT7 receptors as potential mediators of 5-HT's influence on sexual behavior. Evidence for the involvement of each of these receptor subtypes is reviewed, and their different effects in males and females examined. Finally, the possible biological significance of serotonin's contribution to sexual behavior is examined.
... Although the DRN and MRN have also overlapping projections, these do not overlap in the projected structure but go to different subareas [16]. MRN and DRN have reciprocal connections and both structures express high densities of 5-HT 1A receptors; however, the main, but unanswered, question is whether and how these extremely complex interactions (and not only between serotonergic structures) interact during the performance of sexual behavior [17,18]. Most research into these areas has been performed in males (mostly rodents) whereas in females data are largely lacking. ...
... In how far (serotonergic) systems in the brain involved in sexual processes are (dis) similar in males and females is unknown, but clearly needs experimental studies. s0010 Serotonin and female sexual behavior p0040 Several review articles have nicely and extensively reviewed the role of 5-HT in female sexual behavior [17,18]. Although inconsistencies are present, most evidence supports the hypothesis that increased serotonergic activity is inhibitory whereas reduced 5-HT activity is associated with enhanced female sexual activity. ...
... Under a high endogenous tone (e.g., after SSRIs), the role of 5-HT 1A receptors becomes important. Both 5-HT autoreceptors and postsynaptic 5-HT 1A receptors are involved in various aspects of sexual behavior [10] and postsynaptic 5-HT 1A receptors are present in many areas of the brain and spinal cord, in line with the involvement of different brain areas in different aspects of sexual behavior [10,18,59]. Although acute administration of 5-HT 1A -receptor agonists facilitates male sexual behavior [10,28], chronic administration (e.g., of buspirone [28] and flesinoxan [36]) leads to diminished effects, although some slight prosexual activity remains present. ...
The widespread serotonergic system in the central nervous system and spinal cord is equipped with one neurotransmitter, 14 different serotonin receptors, and a transporter. The serotonergic system is involved in practically all behavioral and physiological functions, including sexual behavior. Serotonin (5-hydroxytryptamine (5-HT)) plays a modulatory role in both male and female sexual behavior and 5-HT1A and 5-HT2 receptors appear most clearly involved in modulating sexual activity. In general, activation of the serotonergic system decreases sexual behavior, while inhibition increases it. Selective 5-HT reuptake inhibitors (SSRIs) have inhibitory sexual side effects in both humans and rodents. SSRIs are first choice antidepressants and provide an interesting translational tool to better understand the role of the 5-HT system in healthy and disease conditions such as in major depression. Although available data do not indicate a large serotonergic role in sexual behavior under basal conditions, under stressed or depressed conditions it might play an important role.
... Pharmacological studies often use submaximal oestrogen (or progesterone) doses in ovariectomized females which produce submaximal lordosis quotients and generate a model that can be pharmacologically manipulated. Early studies showed that reduction of monoamine levels in the brain (e.g. by pCPA or reserpine) activated lordosis in suboptimally oestrogen-primed ovariectomized rats, while activation of 5-HT function inhibits it (for review, see Uphouse 2000;Uphouse and Guptarak 2010). With the emerging availability of selective 5-HT receptor ligands more specific studies could be performed, but still serotonergic psychopharmacology has been mainly restricted to 5-HT 1A and 5-HT 2 receptors. ...
... Activation of 5-HT 2A/2C receptors (e.g. by DOI) facilitates lordosis in suboptimally primed rats (Mendelson and Gorzalka 1990), whereas 5-HT 2A/2C receptor antagonists inhibit it ( Hunter et al. 1985;Mendelson and Gorzalka 1985). These effects seem also to be mediated in the hypothalamus probably in close interaction with those mediated by 5-HT 1A receptors (Uphouse 2000;Uphouse and Guptarak 2010). ...
... Matuszcyk et al. (1998) found that chronic fluoxetine reduced sexual behaviour in female rats. This and other studies ( Maswood et al. 2008;Uphouse and Guptarak 2010) are complicated by the fact that natural cycling females were used and fluoxetine affected the cycle, at least in a large number of the animals. A better strategy would be to chronically treat ovariectomized female rats with an SSRI, prime them with a dose of oestrogen and progesterone to induce lordosis and to test the effects of the SSRI in this model. ...
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.
... The serotonergic system plays an important modulatory role in sexual behavior (Uphouse and Guptarak, 2010;. This is, for example, illustrated by the effects of chronic SSRI treatment in depressed patients that results in enhanced 5-HT levels often causing sexual dysfunctions like in men delayed ejaculation and libido problems (Segraves and Balon, 2014). ...
... Early studies in male rats identified 5-HT 1A receptor (R) agonists like 8-OH-DPAT, the azapirones (e.g., buspirone, ipsapirone, and gepirone) and others (e.g., flesinoxan) as prosexual drugs (Ahlenius et al., 1981;Ahlenius and Larsson, 1985;reviewed in: Snoeren et al., 2014). The prototypal 5-HT 1A receptor agonists (±) and (+) -8-OH-DPAT, potently stimulate male rat sexual behavior; in a certain time frame (e.g., 30 min), the number of ejaculations increases associated with shortened ejaculation latencies and fewer intromissions to reach ejaculation (Hillegaart and Ahlenius, 1998;Uphouse and Guptarak, 2010;Chan et al., 2011). Although (±) 8-OH-DPAT has also 5-HT 7 R agonistic effects (Thomas et al., 1999), this mechanism cannot explain the pro-sexual effects because other 5-HT 1A receptor agonists without 5-HT 7 R agonistic activity, also display pro-sexual effects (Snoeren et al., 2014). ...
Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT 1A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT 1A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT 1A autoreceptors and postsynaptic 5-HT 1A heteroreceptors alter when extracellular 5-HT levels are chronically increased. Serotonin transporter knockout (SERT −/−) rats exhibit enhanced extracellular 5-HT levels and desensitized 5-HT 1A receptors. These rats model neurochemical changes underlying chronic SSRI-induced sexual dysfunction. We want to determine the role of presynaptic versus postsynaptic 5-HT 1A receptors in the pro-sexual effects of 5-HT 1A receptor agonists in SERT +/+ and in SERT −/− rats. Therefore, acute effects of the biased 5-HT 1A receptor agonists F-13714, a preferential 5-HT 1A autoreceptor agonist, or F-15599, a preferential 5-HT 1A heteroreceptor agonist, and S15535 a mixed 5-HT 1A 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-HT 1A auto-and hetero-receptors, exerted pro-sexual activity in both SERT +/+ and Frontiers in Behavioral Neuroscience | www.frontiersin.org 1 March 2020 | Volume 14 | Article 40 Esquivel-Franco et al. 5-HT 1A Receptors in Sexual Behavior SERT −/− rats. Applying these specific pharmacological tools has not solved whether pre-or post-synaptic 5-HT 1A 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-HT 1A receptor ligands used, is sufficient to differentiate pre-and/or post-synaptic 5-HT 1A receptor contributions in male rat sexual behavior.
... MRN and DRN have reciprocal connections, and both structures express high densities of 5-HT 1A receptors. An unanswered question is whether and how these extremely complex interactions (including those with non-serotonergic structures) interact during sexual behavior [39,40]. Most research in these areas is performed in males (mostly rodents). ...
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.
... further pharmacological studies have been performed on the 914 PGi-lesioned male rat. 5-HT synthesis, facilitates ejaculation and increases the num-920 ber of ejaculations[160]. Also localized injection of the neurotoxin921 5,7-DHT, decreasing central 5-HT levels, facilitates sexual behav-922 ior, suggesting that central 5-HT neurotransmission has an inhibi-923 tory action on ejaculatory and other sexual activities 924 [161]. ...
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.Key words
Antidepressants
Sexual behaviorPremature ejaculation
Delayed ejaculation
Rat model
Cohort studies
Endophenotype
Pharmacology
Genetics
Serotonin
... The sexual-drive-dependent release of 5-hydroxytryptamine in women is experimentally harder to demonstrate because the hormone estrogen is suspected to temporally prolong the intermediacy of this neurotransmitter (Uphouse and Guptarak, 2010). However, in human beings, the 5-hydroxytryptaminemediated sexual neurotransmission did not obviously depend on gender, because erectile dysfunctions as well as low vaginal lubrications are common side effects for patients with pharmacologically increased central 5-hydroxytryptamine levels (Goldstein and Goodnick, 1998;Rosen et al., 1999). ...
Doubters of Freud’s theory of drives frequently mentioned that his approach is outdated and therefore cannot be useful for solving current problems in patients with mental disorders. At present, many scientists believe that affects rather than drives are of utmost importance for the emotional life and the theoretical framework of affective neuroscience, developed by Panksepp, strongly underpinned this view. Panksepp evaluated seven so-called command systems and the SEEKING system is therein of central importance. Panksepp used Pankseppian drives as inputs for the SEEKING system but noted the missing explanation of drive-specific generation of SEEKING activities in his description. Drive specificity requires dual action of the drive: the activation of a drive-specific brain area and the release of the neurotransmitter dopamine. Noticeably, as Freud claimed drive specificity too, it was here analyzed whether a Freudian drive can evoke the generation of drive-specific SEEKING activities. Special importance was addressed to the imperative motor factor in Freud’s drive theory because Panksepp’s formulations focused on neural pathways without specifying underlying neurotransmitter/endocrine factors impelling motor activity. As Panksepp claimed sleep as a Pankseppian drive, we firstly had to classified sleep as a Freudian drive by using three evaluated criteria for a Freudian drive. After that it was possible to identify the imperative motor factors of hunger, thirst, sex, and sleep. Most importantly, all of these imperative motor factors can both activate a drive-specific brain area and release dopamine from dopaminergic neurons, i.e., they can achieve the so-called drive specificity. Surprisingly, an impaired Freudian drive can alter via endocrinological pathways the concentration of the imperative motor factor of a second Freudian drive, obviously in some independence to the level of the metabolic deficit, thereby offering the possibility to modulate the generation of SEEKING activities of this second Freudian drive. This novel possibility might help to refine the general understanding of the action of Freudian drives. As only imperative motor factors of Freudian drives can guarantee drive specificity for the generation of SEEKING activities, the impact of Freud’s construct Eros (with its constituents hunger, thirst, sex, and sleep) should be revisited.
... In rodents, serotonin's main effects in the POA are to inhibit different aspects of sex-related behaviors (Uphouse, 2010). For example, measurement of 5-HT levels in microdialysates from the POA of behaving male rats presented with an opportunity to mate with females showed that successful copulations were associated with low 5-HT levels. ...
Serotonin (5-HT) inhibits aggression and modulates aspects of sexual behaviour in many species, but the mechanisms responsible are not well understood. Here, we exploited the social dominance hierarchy of Astatotilapia burtoni to understand the role of the serotonergic system in long-term maintenance of social status. We identified three populations of 5-HT cells in dorsal and ventral periventricular pretectal nuclei (PPd, PPv), the nucleus of the paraventricular organ (PVO) and raphe. Dominant males had more 5-HT cells than subordinates in the raphe, but the size of these cells did not differ between social groups. Subordinates had higher serotonergic turnover in the raphe and preoptic area (POA), a nucleus essential for hypothalamic-pituitary-gonadal (HPG) axis function. The relative abundance of mRNAs for 5-HT receptor (5-HTR) subtypes 1A and 2A (htr1a, htr2a) was higher in subordinates, a difference restricted to the telencephalon. Because social status is tightly linked to reproductive capacity we asked whether serotonin turnover and the expression of its receptors correlated with testes size and circulating levels of 11-ketotestosterone (11-KT). We found negative correlations between both raphe and POA serotonin turnover and testes size, as well as between htr1a mRNA levels and circulating 11-KT. Thus increased serotonin turnover in non-aggressive males is restricted to specific brain nuclei and is associated with increased expression of 5-HTR subtypes 1A and 2A exclusively in the telencephalon.
... Fluoxetine, like all SSRIs, acts within the central nervous system by inhibiting the reuptake of serotonin from the synaptic cleft and increasing extracellular serotonin levels ( Malagie et al., 1995;Ranganathan et al., 2001;Fuller et al., 2006). Serotonin is one of the most abundant neuromodulators in vertebrates and regulates physiological functions (Mössner and Lesch, 1998;Hood et al., 2006), a wide range of behaviors ( Charney et al., 1990;Jimerson et al., 1990;Meltzer, 1990;Leibowitz and Alexander, 1998;Uphouse and Guptarak, 2010) and cognitive functions (e.g. Ögren et al., 1985;review in Barnes and Sharp, 1999). ...
... This study aimed to identify the serotonergic neuronal groups in the brain of the rock cavy by 5-HT immunohistochemistry. It is well known that the serotonergic system is associated with several functions, including regulation of the sleep-wake cycle (Portas et al., 2000), dream control and hallucinogenic states (Fischman, 1983), arousal and attention (Robbins, 1997), memory and learning (McEntee and Crook, 1991), mood control (Cools et al., 2007), reward processing (Kranz et al., 2010), feeding behavior (Takase and Nogueira, 2008;Magalhães et al., 2010), sexual behavior (Uphouse and Guptarak, 2010), thermoregulation (Lin et al., 1998;Hodges et al., 2008), nociceptive sensory processing (Bardin et al., 2000;Zeitz et al., 2002), circadian regulation (Pontes et al., 2010;Cavalcante et al., 2011), among others. Moreover, 5-HT dysfunction has been associated with several neuropathological processes, such as sleep disturbances (Neylan et al., 2001), anxiety, aggression (Van Praag, 1996Ramboz et al., 1998;Lowry et al., 2008b), depression (Jacobs, 2002;Michelsen et al., 2007;Lowry et al., 2008b), anorexia and bulimia (Kaye et al., 2005), as well as neurodegenerative disorders such as Alzheimer's (Meltzer et al., 1998), Parkinson's (Nicholson and Brotchie, 2002) and Huntington's (Waeber and Palacios, 1989) diseases (see also Vergé and Calas, 2000). ...
Serotonin, or 5-hydroxytryptamine (5-HT), is a substance found in many tissues of the body, including as a neurotransmitter in the nervous system, where it can exert different post-synaptic actions. Inside the neuro-axis, 5-HT neurons are almost entirely restricted to the raphe nuclei of the brainstem. As such, 5-HT-immunoreactivity has been considered a marker of the raphe nuclei, which are located in the brainstem, at or near the midline. The present study investigated distribution of serotonergic neurons in the brain of the rock cavy (Kerodon rupestris), a rodent species inhabiting the Brazilian Northeast. The cytoarchitectonic location of serotonergic neurons was established through a series of 5-HT immunostained sections, compared with diagrams obtained from adjacent coronal and sagittal sections stained by the Nissl method. The following nuclei were defined: the rostral group, consisting of rostral linear raphe, caudal linear raphe, median and paramedian raphe, dorsal raphe, and pontine raphe nuclei, and the caudal group composed of raphe magnus, raphe pallidus and raphe obscurus nuclei. Other serotonergic neuronal clusters, such as the supralemniscal group and the rostral and caudal ventrolateral medulla oblongata clusters, were found outside the midline. Rare 5-HT-producing neurons were identified in the lateral parabrachial nucleus and in the pontine reticular formation, mostly along fibers of the lateral lemniscus. Despite exhibiting some specializations, the picture outlined for serotonergic groups in the rock cavy brain is comparable to that described for other mammalian species.
Severe psychiatric condition, including major unipolar depression (MDD) and post-traumatic stress disorders (PTSD), are characterized by a strong comorbidity with suicide ideations and attempts. Predictors of suicide risk in humans include impulsivity and aggressiveness, which can be reproduced in rodents by aggressive behavior using the resident-intruder test and other behavioral tests that measure the impulsivity, irritability, and hopelessness of rodents. Animal models of behavioral traits of suicide in humans provide means to better understand the neurobiology of suicidal behavior, as well as they help to understand neural mechanisms and circuits underlying suicide. The search for biomarker-tailored therapies against suicide is urgently needed. Neurosteroid biosynthesis modulates emotional state and stress response and evidence shows that its downregulation during pathophysiological conditions underlays rapid changes in mood and may result in affective disorders. Similarly, several lines of preclinical and clinical evidence suggest that these neuromodulators may underlay suicidal risk and thereby may offer valuable biomarkers. Hereinafter, we analyze animal model approaches that reproduce suicidal-like behaviors in rodents and we highlight findings on the role of neurosteroid biosynthesis in suicidal behavior observed in stress-models of PTSD/suicide in humans.
Introduction:
Depression is a psychiatric disorder with higher incidence in women. Among the most common and less investigated adverse effects of antidepressants are the female sexual dysfunctions. Up to one third of the patients fail to respond to antidepressants; therefore, more treatment alternatives are necessary. The combination of mirtazapine plus venlafaxine, known as "California Rocket Fuel" has shown to be an option for treatment-resistant depression. However, there are no reports of the effects of this combination in animal models and its action on female sexual behavior is unknown.
Aim:
To analyze the effect of mirtazapine and venlafaxine alone or combined -given at doses with actions on the forced swim test- on female rat sexual behavior.
Methods:
Mirtazapine (10, 20 or 40 mg/kg) and venlafaxine (15, 30 or 60 mg/kg) or their combinations (20/30, 10/15, 5/7.5 and 2.5/3.75 mg/kg mirtazapine and venlafaxine, respectively) were injected to sexually receptive female rats. We evaluated their effect on the forced swim test (FST). The doses that reduced immobility were tested on proceptivity and receptivity.
Results:
Mirtazapine (40 mg/kg) and venlafaxine (60 mg/kg), administered alone, or combined (mirtazapine, 5, 10 and 20 mg/kg plus venlafaxine, 7.5, 15 and 30 mg/kg) reduced immobility, but affected motor activity. However, the reduced locomotion after the lowest combination (5/7.5 mg/kg) was smaller. Mirtazapine at 40 mg/kg reduced proceptivity and receptivity, while 60 mg/kg venlafaxine only decreased proceptivity. The combination of 5/7.5 mg/kg mirtazapine and venlafaxine did not affect female sexual behavior.
Conclusions:
Mirtazapine and venlafaxine exerted an effect in the FST, which was also evident when sub-effective doses of both antidepressants were combined. This combination also lacked adverse effects on female sexual behavior. The results suggest that "California Rocket Fuel" could be an effective antidepressant therapy with no adverse sexual effects in women.
This review focusses on the role of serotonin and especially 5-HT1A receptors in female rat sexual behavior. In addition, the differences and/or similarities with male rats are discussed. Overall, in both males and females 5-HT1A receptors do not appear to be involved in sexual behavior under normal circumstances, but become very important under conditions of elevated serotonin levels. 5-HT1A receptor agonists facilitate sexual behavior in male rats, but inhibit female sexual activity. At first sight, this seems quite conflicting, but could be due to our definitions of different elements of sexual behavior. Three different phases can be distinguished in rats' sexual cycle, the introductory (precopulatory), the copulatory and the executive (ejaculatory) phase. Different mechanisms and brain regions are involved in these phases. If the appropriate phases of males and females are properly compared, the role of 5-HT1A receptors in rats might be more similar than assumed thus far.
In this review, first a historical perspective of serotonin's (5-HT) involvement in female sexual behavior is presented. Then an overview of studies implicating 5-HT is presented. The effect of drugs that increase or decrease CNS levels of 5-HT is reviewed. Evidence is presented that drugs which increase 5-HT have negative effects on female sexual behavior while a decrease in 5-HT is associated with facilitation of sexual behavior. Studies with compounds that act on 5-HT1, 5-HT2 or 5-HT3 receptors are discussed. Most evidence indicates that 5-HT1A receptor agonists inhibit sexual behavior while 5-HT2 or 5-HT3 receptors may exert a positive influence. There is substantial evidence to support a role for 5-HT in the modulation of female consummatory sexual behavior, but studies on the role of 5-HT in other elements of female sexual behavior (e.g. desire, motivation, sexual appetite) are few. Future studies should be directed at determining if these additional components of female sexual behavior are also modulated by 5-HT.
These experiments were designed to determine if prior sexual experience reduced the negative effect of mild stress on female sexual behavior. In the first experiment, ovariectomized rats were hormonally primed with estradiol benzoate and progesterone for 3 consecutive weeks during which they received 6 mating experiences in a male's home cage or received no sexual experience. The next week, females were primed with 10μg estradiol benzoate two days before a 5min restraint. Both groups were resistant to the negative effects of the stressor. In the second experiment, females received 0, 1, 2, or 3 weeks of 10μg estradiol benzoate and were restrained on the fourth week after priming with 10μg estradiol benzoate. Rats without prior hormonal priming showed a decline in lordosis behavior after restraint but prior priming with estradiol benzoate reduced this effect. In the third experiment, rats received 3 weeks of hormonal priming with estradiol benzoate and progesterone with or without sexual experience. An additional group received no sexual experience or hormonal priming. Females were then given a 3-week hormone vacation before testing in the restraint paradigm. All groups showed a decline in lordosis behavior after restraint. The fourth experiment was identical to the third except that sexual experience in the male's cage and in a pacing apparatus were compared. There was no effect of either type of sexual experience on the response to restraint. Possible mechanisms responsible for effects of prior hormonal priming are presented and the absence of an effect of sexual experience is discussed in comparison to findings in male rats.
Fluoxetine, like other selective serotonin reuptake inhibitors, inhibits women's sexual desire and female rats' sexual behavior. Bupropion produces pro-sexual effects in women with and without depression, and yohimbine increases men's and male rats' sexual motivation, but their effects on female rats' proceptivity are unknown.
To investigate the effects of fluoxetine, bupropion, and yohimbine on proceptivity and receptivity in the naturally cycling female rat.
We studied the effect of chronic (minimum 14 days) fluoxetine (1.25 mg/kg, subcutaneous) and bupropion (5 mg/kg, intraperitoneal) and acute yohimbine (1 mg/kg, intraperitoneal) on sexual behavior of female rats selected in natural proestrus during an ejaculatory series. We also analyzed the effects of these treatments on locomotor activity.
The main outcome measures were frequencies of hops/darts and ear wiggling, lordosis quotient and intensity, and locomotor activity.
Fluoxetine inhibited ear wiggling and hopping/darting, while bupropion stimulated hopping/darting. These treatments did not modify the lordosis quotient and its intensity. Yohimbine did not change any aspect of female sexual behavior. At the doses and treatments used, fluoxetine and bupropion did not alter locomotor activity or disturb the length of the estrous cycle; however, yohimbine inhibited locomotor activity.
The motivational components of female sexual behavior are more sensitive than the receptive components to the inhibitory actions of fluoxetine. Bupropion selectively stimulated hopping/darting, while yohimbine lacked an action on female sexual behavior. Ventura-Aquino E and Fernández-Guasti A. The antidepressants fluoxetine and bupropion differentially affect proceptive behavior in the naturally cycling female rat. J Sex Med **;**:**-**.
The ability of dopamine (DA) receptor antagonists to disrupt anticipatory and consummatory measures of sexual behavior displayed by male rats in bilevel chambers was investigated. In Experiment 1, systemic administration of haloperidol, pimozide, and the D1 antagonist SCH 23390 reduced the number of anticipatory level changes (LC) displayed during a 5-min period before the introduction of a sexually receptive female, increased the mount and intromission latencies (ML and IL), and decreased the number of intromissions before ejaculation (NI) and the total number of ejaculations (NE). The dosages of these drugs required to reduce the LC were lower than those required to increase the ML or IL. Clozapine and the D2 antagonist sulpiride reduced the LC and increased the IL at comparable dosages, although neither drug affected the NI or NE. High dosages of haloperidol, pimozide, and clozapine delayed or abolished level changing and the initiation of copulation. In Experiment 2, bilateral infusions of haloperidol into the nucleus accumbens reduced the LC but did not affect consummatory measures of copulation, whereas bilateral infusions into the dorsal striatum increased the NE. Midline infusions of haloperidol to the medial preoptic area (MPOA) produced nearly all the effects of systemic administration, including a reduced LC, increased ML and IL, a decreased NI, and a decreased NE. These results indicate that both anticipatory and consummatory measures of sexual behavior were disrupted by DA receptor antagonists; however, the measure of anticipatory sexual behavior was more sensitive to disruption than consummatory measures of copulation. DA in the nucleus accumbens and MPOA may be involved in the control of anticipatory sexual behavior, whereas in the MPOA it may also be involved in the initiation of copulation and copulatory rate.
Serotonin (5-HT) receptors are part of the G protein-coupled and ligand-gated ion channel families. 5-HT exerts its diverse actions by binding to cell surface receptors which can be classified into seven distinct families (5-HT, to 5-HT gamma) according to their structural diversity and mode of action. Some of the 5-HT families are comprised of multiple receptors which share similar structural and mechanistic properties but display very different operational profiles. Evidence continues to mount in support of the important roles of the 5-HT receptors in various neuropsychiatric disorders such as anxiety, depression, schizophrenia, migraine and drug addiction. The 5-HT receptors may also play an important role in obesity, aggression, sexual behaviour and cardiovascular disorders. A number of selective/non-selective 5-HT agonist and antagonist ligands (drugs) have been developed to challenge many of these disease states.
THE role of 5-HT (serotonin) in regulating lordosis was investigated by combining peripheral administration of the 5-HT agonists 8-OH-DPAT (8-hydroxy-2-[di-N-propylamino]tetralin) or TFMPP (1-[m-trifluoromethylphenyl] piperazine), with intrahypothalamic application of the 5-HT neurotoxin 5,7-DHT (5,7-dihydroxytryptamine). The 5-HT1A agonist, 8-OH-DPAT, significantly inhibited lordosis in 5,7-DHT-treated and non-treated rats. TFMPP, an agonist at 5-HT1B and 5-HT1C receptors, significantly facilitated lordosis in 5,7-DHT-treated and non-treated rats. Our results show that both inhibitory and facilitatory influences of hypothalamic 5-HT on lordosis, are modulated via postsynaptic receptors.
We examined the effects in male rats of bilateral transection of two nerves previously implicated in erectile function, the viscerocutaneous branch of the pelvic nerve (Vc) and the hypogastric nerve (HgN). In Experiment 1 (conducted in Storrs), males underwent simultaneous or successive section of Vc and HgN and were tested for copulation, reflexive erection, and noncontact erection (NCE), i.e. in response to remote cues from estrous females. NCE is considered to be analogous to `psychogenic' erection in humans, for which the HgN has been ascribed a significant role. In all three types of test, males had a moderate to severe deficit in erectile function after Vc transection. Section of HgN alone had no apparent pro- or anti-erectile effect in any context, nor did it affect the decrement resulting from Vc surgery. Regardless of treatment, all groups retained some erectile potential in each type of test. The loss of bladder function after Vc surgery and of seminal plug deposition after HgN section gave evidence that the targeted nerves were in fact severed. In Experiment 2 (conducted in Xalapa), males were tested only for NCE, but (a) they were tested every 3 days beginning 3 days after each surgery, (b) the interval between the two surgeries was more than 2 weeks, rather than 1 week as in Experiment 1, to allow more time for recovery from general effects of surgery and for hypothetical plasticity of neural function. In the first test after the first surgery, all groups had a modest reduction in the proportion of males displaying NCE, relative to sham-operated males. However, this deficit did not extend to measures of NCE latency or number, and was absent after the second test. After the second surgery, when all males except those with sham operations had both nerves cut, none of the groups exhibited a significant deficit in NCE, and all groups had at least one test in which at least half the males responded. Thus, (a) HgN section did not significantly impair NCE, reflexive erection, or copulation; (b) Vc section impaired, but did not eliminate, erection in all three contexts, but even those effects may be transient; and (c) transection of both nerves, simultaneously or successively, did not cause a greater impairment in erection than did cutting just the Vc. We infer that the HgN may have no pro-erectile role in erection in rats, even in a model analogous to psychogenic erection. The Vc is probably the most important nerve mediating pro-erectile function in NCE, as in reflexive erection and copulation, but this nerve may not be essential for erection in rats in any context, at least in some males.
In anxiety research, the search for models with sufficient clinical predictive validity to support the translation of animal studies on anxiolytic drugs to clinical research is often challenging. This review describes the stress-induced hyperthermia (SIH) paradigm, a model that studies the activation of the autonomic nervous system in response to stress by measuring body temperature. The reproducible and robust SIH response, combined with ease of testing, make the SIH paradigm very suitable for drug screening. We will review the current knowledge on the neurobiology of the SIH response, discuss the role of GABAA and serotonin (5-HT) pharmacology, as well as how the SIH response relates to infectious fever. Furthermore, we will present novel data on the SIH response variance across different mice and their sensitivity to anxiolytic drugs. The SIH response is an autonomic stress response that can be successfully studied at the level of its physiology, pharmacology, neurobiology and genetics and possesses excellent animal-to-human translational properties.
In the mammalian brain 5-HT1B receptors are present as autoreceptors regulating the release of serotonin (5-HT) by inhibitory feedback. The antagonistic properties of NAS-181 ((R)-(+)-2-[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methane sulfonate), a new selective antagonist for the rodent 5-HT1B receptor, were determined by using an agonist-induced decrease of extracellular 5-HT. The 5-HT1B receptor agonist CP93129 (0.030.3 wM) applied by reversed microdialysis, dose-dependently reduced 5-HT levels in rat frontal cortex. The suppressant effect of CP93129 (0.1 wM) was smaller in the presence of fluvoxamine (3-10 wM), a 5-HT reuptake inhibitor. The effects of NAS-181 on CP93129 were compared with GR127935, a mixed 5-HT 1B/1D receptor antagonist, and SB224289, a 5-HT1B receptor antagonist. Both in the presence and absence of fluvoxamine, the suppressant effect of CP93129 on extracellular 5-HT was attenuated by NAS-181 (1 wM) and GR127935 (10 wM), but not by SB224289 (1 wM). In the absence of fluvoxamine, GR127935, SB224289 and NAS-181 all reduced 5-HT levels, suggesting partial agonistic properties of these compounds. In conclusion, the results show that NAS-181 is a potent 5-HT1B receptor antagonist.
The role of 5-HT (serotonin) in regulating lordosis was investigated by combining peripheral administration of the 5-HT agonists 8-OH-DPAT (8-hydroxy-2-[di-N-propylamino]tetralin) or TFMPP (1-[m-trifluoromethylphenyl]piperazine), with intrahypothalamic application of the 5-HT neurotoxin 5,7-DHT (5,7-dihydroxytryptamine). The 5-HT1A agonist, 8-OH-DPAT, significantly inhibited lordosis in 5,7-DHT-treated and non-treated rats. TFMPP, an agonist at 5-HT1B and 5-HT1C receptors, significantly facilitated lordosis in 5,7-DHT-treated and non-treated rats. Our results show that both inhibitory and facilitatory influences of hypothalamic 5-HT on lordosis, are modulated via postsynaptic receptors.
The 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone or TVXQ 7821 (ipsapirone) but not the 5-HT1B agonist RU 24969, attenuated the hyperphagic response to 8-OH-DPAT administered on the next day. Attenuation was still apparent on the fifth day after either 8-OH-DPAT or buspirone but not on the tenth day after 8-OH-DPAT administration. The ability of 8-OH-DPAT to reduce raphe 5-HIAA levels was also impaired by previous 8-OH-DPAT treatment. However, the 8-OH-DPAT or 5-methoxy-N,N-dimethyltryptamine-induced 5-HT syndromes were unaltered. The results indicate that a single pretreatment with 5-HT1A agonists rapidly desensitises 5-HT1A presynaptic receptor-mediated responses. This effect may mediate the antidepressant-like action of the drugs in an animal model of depression.
Experiments initiated by W.C. Young and collaborators in the early 1930s (reviewed by Young 1961, 1969) have dominated the work on control of feminine mating behavior by ovarian hormones. The conceptual developments of this group still guide research in the field as well as in related fields, e.g., the hormonal control of body weight regulation (Wade 1976). In initial attempts to identify the endocrine factors controlling the induction of sexual receptivity in the guinea pig, it was found that growth of the Graafian follicle was accelerated in the hours preceding the onset of sexual behavior (Myers et al. 1936). Knowing that exogenous administration of luteinizing hormone (LH) induces rapid growth of the preovulatory follicle (Foster and Hisaw 1935), Dempsey et al. (1936) found that administration of LH to cyclic guinea pigs induced sexual receptivity if given at a stage of the estrous cycle when the ovaries contained ripe follicles; but not if given early in the cycle or if given to ovariectomized animals pretreated with estrogen. It was shown that the LH acted on the well-developed ovarian follicles, stimulating the production of a factor which in turn induced the behavior. The follicular factor was identified as progesterone. Thus, the hormonal factors controlling the display of sexual behavior during the guinea pig estrous cycle were shown to be estrogen and progesterone, and it was shown that progesterone acted on a background of estrogen priming, i.e., after a period of estrogen conditioning.
The ultimate aim in the study of the nervous system is the explanation of behavior: the demonstration of how behavioral responses are produced as a function of nerve cell activity. Even for small bits of neural tissue and restricted aspects of behavior, the number of nerve cells involved is so large and their connections are so complex that large numbers of hypotheses can be imagined. As a result, in the history of beavioral studies, a great deal of “neurologizing” has occurred. Broad speculation about the overall “organization of the brain” and the manner in which it controls behavior has been entertained because, in most cases, the number of facts available to rule out hypotheses has been small. Thus, no comprehensive hypothesis really could be proved. It has seemed necessary to pick a situation where it would be fruitful to gather a great number of behavioral, neuroanatomical, and neurophysiological facts and thus to narrow down the allowable hypotheses to a small number. If enough relevant facts can be brought to bear, and hypotheses can be conclusively ruled out, then a strong inference (Platt, 1964) of the correct hypothesis will finally be possible. In turn, principles can be stated clearly and can be tested.
Neurons in the central nervous system concentrate estrogen, progesterone, testosterone or dihydrotestosterone, and corticosterone. The location of these neurons in the brain has been determined by using autoradiographic (Pfaff 1968; Pfaff and Keiner 1973; Stumpf et al. 1975; Morrell and Pfaff 1981) and steroid receptorbinding techniques (McEwen et al. 1979). Steroid sex hormone-binding cells are found in the medial preoptic area, medial hypothalamus, and limbic forebrain areas in the vertebrate brain; in general, these neurons are found in brain regions that participate in behavioral and pituitary reproductive functions (McEwen et al. 1979). In contrast corticosterone-concentrating neurons are found primarily in the hippocampus.
Objective:
To review and assess the update studies regarding selective serotonin reuptake inhibitors (SSRIs) in the treatment of premature ejaculation (PE) and then provide practical recommendations and possible mechanisms concerning state of the art knowledge for the use of SSRIs in alleviating PE.
Data sources:
Using the Medline, 48 articles published from January 1st, 1996 to August 1st, 2006 concerning the use of SSRIs and their possible mechanisms in alleviating PE were found and reviewed.
Study selection:
PE, rapid ejaculation, early ejaculation and SSRIs were employed as the keywords, and relevant articles about the use of SSRIs and their possible mechanisms in the treatment of PE were selected.
Results:
Many kinds of SSRIs, such as fluoxetine, sertraline, paroxetine and citalopram, have widely been employed to treat PE. However, their effects are moderate and there is no a universal agreement about the kind, dose, protocol and duration. Dapoxetine, as the first prescription treatment of PE, may change this bottle-neck situation. SSRIs are suggested to be used in young men with lifelong PE, and acquired PE when etiological factors are removed but PE still exists. Phosphodiesterase 5 inhibitors (PDE(5)-Is) are suggested to be employed alone or combined with SSRIs when SSRIs fail to treat PE or sexual dysfunction associated with SSRIs occurs. The protocol of taking drugs on demand based on taking them daily for a suitable period is proposed to be chosen firstly. The possible mechanisms include increasing serotonergic neurotransmission and activating 5-hydroxytryptamine 2C (5-HT(2C)) receptors, then switching the ejaculatory threshold to a higher level, decreasing the penile sensitivity and their own effect of antidepression.
Conclusion:
The efficacies of the current SSRIs are moderate in the treatment of PE and they have not been approved by the FDA, therefore new SSRI like dapoxetine needs to be further evaluated.
Depression is a common cause of sexual dysfunction, but also antidepressant medication is often associated with sexual side effects. This article includes two related studies.The first double-blind, placebo-controlled study was conducted in men with lifelong rapid ejaculation and aimed to assess putative differences between the major selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine, and sertraline) with regard to their ejaculation-delaying effect. Sixty men with an intravaginal ejaculation latency time (IELT) of 1 minute or less were randomly assigned to receive fluoxetine 20 mg/day, fluvoxamine 100 mg/day, paroxetine 20 mg/day, sertraline 50 mg/day, or placebo for 6 weeks.During the 1-month baseline and 6-week treatment periods, the men measured their IELT at home using a stopwatch. The trial was completed by 51 men.During the 6-week treatment period, the geometric mean IELT in the placebo group was constant at approximately 20 seconds. Analysis of variance revealed a between-groups difference in the evolution of IELT delay (p = 0.0004); in the paroxetine, fluoxetine, and sertraline groups there was a gradual increase to about 110 seconds, whereas in the fluvoxamine group, IELT was increased to only approximately 40 seconds. The paroxetine, fluoxetine, and sertraline groups differed significantly (p < 0.001, p < 0.001, p = 0.017, respectively) from placebo but the fluvoxamine group did not (p = 0.38). Compared with baseline, paroxetine exerted the strongest delay in ejaculation, followed by fluoxetine and sertraline. There was no clinically relevant delay in ejaculation with fluvoxamine. In men with lifelong rapid ejaculation, paroxetine delayed ejaculation most strongly, whereas fluvoxamine delayed ejaculation the least. The second double-blind, placebo-controlled study was carried out in men with lifelong rapid ejaculation (IELT <or=to 1 minute) and in men with lifelong less-rapid ejaculation (IELT > 1 minute) to investigate whether data about SSRI-induced delayed ejaculation in men with rapid ejaculation may be extrapolated to men with less-rapid ejaculation. After measurement of IELT at home (using a stopwatch) during a 1-month baseline assessment, 32 men with an IELT of 1 minute or less (group 1) or more than 1 minute (group 2) were randomly assigned to receive paroxetine 20 mg/day or placebo for 6 weeks in a double-blind manner. Patients continued to measure their IELTs at home during the 6 weeks of the study. At baseline, 24 patients consistently had IELTs of one minute or less (group 1), and eight patients had IELTs of more than 1 minute (group 2).The geometric mean IELT was 14 seconds in group 1 and 83 seconds in group 2. Twelve patients in group 1 and five in group 2 were randomized to the paroxetine 20 mg/day. The percentage increase in the geometric mean IELT compared with baseline in patients treated with paroxetine was 420% (95% confidence interval [CI], 216-758%) in group 1 and 480% (95% CI, 177-1,118%) in group 2 (p = 0.81). After 6 weeks of treatment with paroxetine, the geometric mean IELT was 92 seconds in group 1 and 602 seconds in group 2 (p < 0.001). Therefore, the paroxetine-induced percentage increase in IELT seems to be independent of the baseline IELT. This suggests that ejaculation-delaying side effects of some SSRIs investigated in men with lifelong rapid ejaculation may be generalized to men with less-rapid ejaculation. (J Clin Psychopharmacol 1998;18:274-281)
Serotonin 5-HT(1A) receptors play an important role in serotonin neurotransmission and mental health. We previously demonstrated that estradiol (E) and progesterone (P) decrease 5-HT(1A) autoreceptor mRNA levels in macaques. In this study, we questioned whether E and P regulate 5-HT(1A) binding and function and G(alpha) subunit protein expression. Quantitative autoradiography for 5-HT(1A) receptors and G proteins using [3H]8-OH-DPAT and [35S]GTP-gamma-S, respectively, was performed on brain sections of rhesus macaques from four treatment groups: ovariectomized controls (OVX), E (28 d), P (28 d), and E (28 d) plus P (the last 14 d) treated. Western blot analysis for G(alpha) subunits was performed on raphe extracts from cynomolgus macaques that were OVX or OVX treated with equine estrogens (EE, 30 months). In the hypothalamus, E or E + P but not P alone decreased postsynaptic 5-HT(1A) binding sites. In the dorsal raphe nucleus (DRN), E, P, and E + P treatments decreased 5-HT(1A) autoreceptor binding. The Kd values for 8-OH-DPAT were the same for each treatment group. Both the basal and the R-(+)-8-OH-DPAT stimulated [35S]GTP-gamma-S binding were decreased during hormone replacement whereas the coupling efficiency between the receptor and G proteins was maintained. Finally, EE treatment reduced the level of G(alphai3), but not G(alphai1), G(alphao), and G(alphaz) in the DRN. In conclusion, these observations suggest that ovarian hormones may increase serotonin neurotransmission, in part, by decreasing 5-HT(1A) autoreceptors, 5-HT(1A) postsynaptic receptors, and the inhibitory G proteins for intracellular signal transduction.
In the 20 yr since it was established that impairment of dihydrotestosterone formation is the cause of a rare form of human intersex, a wealth of information has accumulated about the genetics, endocrinology, and variable phenotypic manifestations, culminating in the cloning of cDNAs encoding two 5 alpha-reductase genes and documentation that mutations in the steroid 5 alpha-reductase 2 gene are the cause of 5 alpha-reductase deficiency. Perplexing and difficult problems remain unresolved, e.g. whether the variability in manifestations is due to variable expressions of steroid 5 alpha-reductase 1 or to effects of testosterone itself. It is also imperative to establish whether defects in steroid 5 alpha-reductase 2, perhaps in the heterozygous state, are responsible for a portion of cases of sporadic hypospadias, to determine whether 5 alpha-reductase plays a role in progesterone action in women, and to elucidate the relation between androgen action and gender role behavior.
INDIRECT serotonergic agonists, whether promoters of 5-HT release such as fenfluramine (5 mg kg(-1)) or inhibitors of 5-HT uptake such as fluoxetine (10 mg kg(-1)), elicited in rats penile erections at a modest but significant level. Their effects were markedly potentiated by the beta-blocker tertatolol, (0.6-5 mg kg(-1)) which 5-HT1A receptor blocking activity, but not by the beta-blocker labetalol (6.25 and 25 mg kg(-1)), which lacks such activity. In addition, tertatolol, but not labetalol, potentiated penile erections induced by meta-chloro-phenylpiperazine (1 mg kg(-1)). Thus, it appears that increasing serotonergic transmission increases only moderately penile erections because of the functional opposition exerted by 5-HT1A (inhibition) and 5-HT1C (activation) serotonin receptors on this response.
: 5α-pregnan-3α-ol-20-one (3α,5α-THP) in the ventral tegmental area (VTA) mediates lordosis of rodents. If fluoxetine's effects on lordosis are mediated in part by midbrain 3α,5α-THP, then fluoxetine regimens that decrease and increase lordosis would be expected to respectively lower and elevate midbrain 3α,5-THP levels. Experiment 1: Ovariectomized (ovx) rats received estradiol benzoate (EB; 5 μg, SC) at 0 and 24 h and fluoxetine (20 mg/kg, IP) or vehicle 30 min before sex testing and tissue collection. Other rats received fluoxetine (10 mg/kg, IP) or vehicle for 15 days followed by EB-priming and testing. Systemic acute or chronic fluoxetine significantly decreased lordosis and midbrain 3α,5α-THP levels compared to vehicle. Experiment 2: Ovx rats with unilateral cannula to the VTA were primed with EB (5 μg; 0, 24 h) and/or progesterone (0 or 100 μg; 44 h, SC). At 47.5 h, fluoxetine (3.6 mM) or vehicle was infused to the VTA. At 48 h, rats were tested. Administering fluoxetine to the VTA significantly increased lordosis and midbrain 3α,5α-THP levels compared to vehicle infusions. Experiment 3: Ovx EB-primed rats were tested prior to, and 30 min after, treatmemt with acute fluoxetine (20 mg/kg, IP). Rats were then infused with 3α,5α-THP (100 ng) or vehicle to the VTA and were retested. 3α,5α-THP, but not vehicle, to the VTA reversed acute fluoxetine's inhibitory effects on lordosis. Together, these data suggest fluoxetine may alter lordosis in part through actions of 3α-THP in the midbrain.
Introduction:
Recently, the idea has emerged that on-demand use of serotonin reuptake inhibitors (SSRIs), particularly short half-life, should be equally effective in delaying ejaculation as daily SSRI treatment of premature ejaculation.
Aim:
To provide evidence that SSRI-induced ejaculation delay is mainly dependent on pharmacodynamic properties of the drug and hardly on pharmacokinetic factors, and that combined SSRI administration with specific 5-hydroxytryptamine (5-HT) receptor antagonism leads acutely to stronger ejaculation delay than acute SSRI monoadministration.
Methods:
We performed a detailed analysis of serotonin neurotransmission and reviewed animal studies with 5-HT(1A) receptor antagonists. In addition, we critically reviewed existing on-demand SSRI treatments publications and the current debate on a definition of premature ejaculation.
Main outcome measures:
Intravaginal ejaculation latency time (IELT).
Results:
Acute SSRI administration leads to only a mild or no increase of 5-HT neurotransmission and concomitant stimulation of postsynaptic 5-HT receptors. Existing on-demand SSRI treatment studies suffer from methodological insufficiencies, and the reported high-fold increases of ejaculation time contradict with neuropharmacological insights from serotonin metabolism. Animal studies show that SSRI coadministration with 5-HT(1A) receptor antagonists significantly increases the ejaculation time acutely compared to acute SSRI monoadministration.
Conclusion:
On-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment. SSRIs with a short half-life are likely leading to much less ejaculation delay than current registered SSRIs. Combined use of SSRIs with 5-HT(1A) receptor antagonists increases the likelihood of clinically relevant ejaculation delay after on-demand treatment. On-demand SSRIs with short half-life that insufficiently delay ejaculation in men with IELTs less than 1 minute should be called ejaculation-delaying drugs rather than drugs against premature ejaculation.
WIESELER FRANK, J. L., S. E. HENDRICKS AND C. H. OLSON. Multiple ejaculations and chronic fluoxetine: effects on male rat copulatory behavior. PHARMACOL BIOCHEM BEHAV 66(2) 337–342, 2000.—Male rats were treated with fluoxetine (FLX) or vehicle daily for 14 days and copulatory behavior tested on day 15. Rats were either mated to three ejaculations or to sexual exhaustion. Both standard measures and the mount bout analysis were used to evaluate the effects of the chronic FLX on male rat copulatory behavior. Only 56.25% of the animals treated with FLX achieved three ejaculations. FLX inhibited the consumatory aspect of male sexual behavior, especially the ability to achieve three ejaculations, but there was no effect on the propensity of the male to pursue the female. These differences were observed for the first three ejaculations. Analysis of the last three ejaculations in those animals that mated to exhaustion did not reveal an effect of FLX. The behavioral pattern of FLX-treated animals during the first three ejaculations resembled that observed during the last three ejaculatory series in the vehicle-treated animals that mated to exhaustion. The results are discussed in terms of the serotonergic effects on male rat sexual behavior.
Serotonin (5-HT) receptor interaction in the control of female rat lordosis behavior was examined. Ovariectomized rats, with bilateral implants in the ventromedial nucleus of the hypothalamus (VMN), were hormonally primed with 25 μg estradiol benzoate and 500 μg progesterone. Rats were infused with the 5-HT3 receptor antagonist, 3-tropanyl-indole-3 carbonylate (tropisetron; 500 ng), or were coinfused with the 5-HT3 receptor antagonist and the 5-HT2A/2C receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 500, 1500, or 2000 ng). Additional ovariectomized, hormone-primed rats received bilateral VMN infusions with the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 200 ng), or were coinfused with the 5-HT1A receptor agonist and the 5-HT3 receptor agonist, m-chlorophenyl-biguanide (mCPBG; 250, 500, or 1000 ng). Lordosis behavior was observed prior to VMN infusion, during the infusion and for 30 consecutive minutes thereafter. Tropisetron reduced the lordosis to mount (L/M) ratio in every animal investigated but the decline was attenuated by coinfusion with DOI. Similarly, the L/M ratio declined following infusion with 8-OH-DPAT and the decline was dose-dependently reduced by coinfusion with mCPBG. Only the 5-HT3 receptor agonist altered the quality of the lordosis reflex. These studies provide evidence that the effects of 5-HT on female rat lordosis behavior involve the integrated activity of at least 3 different 5-HT receptor families.
In vivo microdialysis was used to examine extracellular serotonin (5-HT) in the mediobasal hypothalamus (MBH) of male and female Fischer (CDF-344) rats. Females from the stages of diestrus, proestrus, and estrus were used. Additionally, ovariectomized rats, primed subcutaneously (s.c.) with estradiol benzoate or estradiol benzoate plus progesterone were examined. Extracellular 5-HT in the MBH varied with stage of the estrous cycle and with the light/dark cycle. Proestrous females had the highest microdialysate concentrations of 5-HT during the light portion of the light/dark cycle and lowest concentrations during the dark portion of the cycle. Diestrous females had the highest levels during the dark portion of the cycle, while males and estrous females showed little change between light and dark portions of the cycle. In ovariectomized rats, there was no effect of 2.5 μg or 25 μg estradiol benzoate (s.c.) on extracellular 5-HT; but the addition of 500 μg progesterone, 48 h after estrogen priming, reduced microdialysate 5-HT near the threshold for detection. In intact females and in males, reverse perfusion with 3 μM fluoxetine, a selective serotonin reuptake inhibitor (SSRI), or 2 μM methiothepin, a 5-HT receptor antagonist, increased microdialysate concentrations of 5-HT. Estrous females and males showed nearly a 4-fold increase in microdialysate 5-HT in response to fluoxetine while smaller responses were seen in diestrous and proestrous rats. In contrast, proestrous rats showed the largest response to methiothepin. Estrous females showed a delayed response to methiothepin, but there was no methiothepin-induced increase in extracellular 5-HT in males. These findings are discussed in reference to the suggestion that extracellular 5-HT in the MBH is regulated in a manner that is gender and estrous cycle dependent. The 5-HT terminal autoreceptor may exert a greater role in proestrous females; the serotonin transporter appears to play a more active role in the regulation of extracellular 5-HT in estrous females and in males.
The stimuli from a receptive female and/or copulation itself leads to the release of dopamine (DA) in at least three integrative hubs. The nigrostriatal system promotes somatomotor activity; the mesolimbic system subserves numerous types of motivation; and the medial preoptic area (MPOA) focuses the motivation onto specifically sexual targets, increases copulatory rate and efficiency, and coordinates genital reflexes. The previous (but not necessarily concurrent) presence of testosterone is permissive for DA release in the MPOA, both during basal conditions and in response to a female. One means by which testosterone may increase DA release is by upregulating nitric oxide synthase, which produces nitric oxide, which in turn increases DA release. Hormonal priming in females may also increase DA release in the MPOA, and copulatory activity may further increase DA levels in females. One of the intracellular effects of stimulation of DA D1 receptors in the MPOA of male rats may be increased expression of the immediate-early gene c-fos, which may mediate longer term responses to copulation. Furthermore, increased sexual experience led to increased immunoreactivity to Fos, the protein product of c-fos, following copulation to one ejaculation. Another intracellular mediator of DA’s effects, particularly in castrates, may be the phosphorylation of steroid receptors. Finally, while DA is facilitative to copulation, 5-HT is generally inhibitory. 5-HT is released in the LHA, but not in the MPOA, at the time of ejaculation. Increasing 5-HT in the LHA by microinjection of a selective serotonin reuptake inhibitor (SSRI) increased the latency to begin copulating and also the latency to the first ejaculation, measured from the time the male first intromitted. These data may at least partially explain the decrease in libido and the anorgasmia of people taking SSRI antidepressants. One means by which LHA 5-HT decreases sexual motivation (i.e. increases the latency to begin copulating) may be by decreasing DA release in the NAcc, a major terminal of the mesolimbic system. Thus, reciprocal changes in DA and 5-HT release in different areas of the brain may promote copulation and sexual satiety, respectively.
Serotonin (5-HT) is generally inhibitory to male rat sexual behavior. However, the 5-HT1A agonist 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), injected either systemically or into the medial preoptic area (MPOA), facilitates ejaculation. Three experiments were conducted to test the effects of 8-OH-DPAT on 5-HT and dopamine (DA) neurotransmission in the MPOA, a very important site for the control of male sexual behavior. In Experiment 1, systemically injected 8-OH-DPAT (0.4 mg/kg) decreased extracellular 5-HT levels in the MPOA as measured by in vivo microdialysis. In Experiment 2, 8-OH-DPAT (500 μM) administered directly into the MPOA via reverse dialysis increased extracellular levels of both DA and 5-HT; pretreatment with the selective 5-HT1A antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide hydrochloride (p-MPPI) failed to prevent 8-OH-DPAT's stimulatory effects on DA and 5-HT levels in the MPOA. In Experiment 3, 8-OH-DPAT (8 μg) co-injected with 5,7-dihydroxytryptamine (5,7-DHT; 6 μg) prevented neurotoxic depletion of 5-HT in the site of injection (MPOA). Because systemic and MPOA injections of 8-OH-DPAT resulted in opposite effects on extracellular 5-HT in the MPOA, yet both can facilitate ejaculation, these data suggest that moderate changes in 5-HT in the MPOA may have relatively little influence on male copulatory behavior. Instead, the facilitative effects of 8-OH-DPAT in the MPOA on male copulatory behavior may result, at least in part, from stimulatory effects of 8-OH-DPAT on DA transmission. Facilitative effects of systemic injections of 8-OH-DPAT may result from decreased 5-HT release in several sites.
Ovariectomized rats were hormonally primed with 10 microg estradiol benzoate or with estradiol benzoate plus 500 microg progesterone. Rats received a bilateral infusion with 200 ng of the 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1'-biphenyl-4-carboxamide hydrochloride (GR 127935), into the ventromedial nucleus of the hypothalamus (VMN), followed by a 5 min restraint or home cage experience. In estrogen-primed females that had experienced minimal handling between ovariectomy and use in the experiment, infusion with the water vehicle transiently inhibited lordosis behavior, and the 5-HT(1B/1D) receptor antagonist amplified this inhibition. There were no effects in rats hormonally primed with estrogen and progesterone. Handling for two days before the experiment reduced the effects of the infusions in estrogen-primed rats. However, when a 5 min restraint experience followed infusion with GR 127935, there was a significant decline in lordosis behavior that persisted for 10 to 15 min after the experience. Regardless of the prior experience or type of infusion, the addition of progesterone to the hormonal priming completely prevented the lordosis inhibition. These findings are consistent with prior evidence that progesterone protects against the inhibitory effects of a 5 min restraint experience on lordosis behavior. Moreover, these are the first experiments to demonstrate an inhibitory effect of a selective 5-HT(1B/1D) receptor antagonist in the VMN on lordosis behavior of estrogen primed, but not estrogen and progesterone primed, ovariectomized rats.
In an earlier study, we reported that daily fluoxetine treatment (10 mg/kg/day) rapidly disrupted estrous cyclicity and sexual receptivity in adult, regularly cycling Fischer rats. The current study was designed to investigate if comparable fluoxetine treatment would similarly affect intact, regularly cycling Sprague Dawley rats. In the first experiment, fluoxetine was injected for 24 days. After 11-14 days of daily fluoxetine treatment, 40% of the rats showed a transient disturbance of the estrous cycle with elimination of sexual receptivity. In these affected rats, reduced sexual receptivity generally preceded disruption of vaginal cyclicity. In a second experiment, a shorter exposure was used to attempt to dissociate effects of fluoxetine on behavior and estrous cyclicity. Nine days of fluoxetine treatment eliminated sexual receptivity and proceptivity (hops/darts) in 40% and 46%, respectively, of rats without altering the estrous cycle. Female rats then received a 10th fluoxetine injection 30 min prior to assessment of sexual motivation (measured with the male preference paradigm). There was no effect of fluoxetine on male preference, but fluoxetine significantly reduced the number of crossings and seconds of grooming during preference testing. Therefore, effects of fluoxetine on estrous cyclicity and behavior of Sprague Dawley female rats were smaller and required longer to develop than previously reported in Fischer female rats. These findings reinforce a probable relationship between fluoxetine's effect on sexual activity and neuroendocrine disturbances and illustrate the importance of strain selection in attempting to model human disease.
The role of serotonin in mediating hypothalamic control of sexual behavior in estrone-primed ovariectomized (OVX) rats was studied by comparing the lordotic patterns following medial preoptic (MPOA) and arcuate-ventromedial (ARC-VM) infusions of serotonin (5-HT), methysergide (MS), and vehicle. In the initial experiments, low receptivity (preinfusion receptivity: mean lordosis/mount ratio = 0.164) was maintained by priming each animal with a low dose of estrone 48 hr prior to mating. The infusion of MS in either the MPOA or ARC-VM area resulted in a significant enhancement of lordotic behavior from initial low receptivity, 5-HT infusions were found to have no statistically significant effect upon lordotic behavior. In order to corroborate the findings observed in the low preinfusion receptivity protocol, OVX rats were primed with higher doses of estrone to maintain a high level of receptivity (preinfusion receptivity: mean lordosis/mount ratio = 0.787). Using this protocol, significant depressions in lordotic behavior were observed following MPOA or ARC-VM infusions of 5-HT, It was thus proposed that serotonergic receptors within the MPOA or ARC-VM areas have inhibitory effects upon lordotic behavior. In addition to the effects of 5-HT upon estrogen-induced sexual receptivity, serotonergic influences upon luteinizing hormone-releasing hormone (LRH)-facilitated mating behavior were also evaluated. Comparisons were made between the lordotic responses following MPOA or ARC-VM infusions of vehicle, LRH, or LRH with 5-HT in OVX rats primed with low doses of estrone. The infusion of LRH into the MPOA or ARC-VM significantly enhanced lordotic behavior above vehicle levels. However, the addition of 5-HT to the LRH infusate abolished this behavioral enhancement. These findings indicated that LRH and 5-HT have opposing effects within forebrain areas known to be important for the control of lordotic behavior.
Sexually receptive female rats were infused intracranially with 500-2,000 ng 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the midbrain central gray (MCG), in the vicinity of the dorsal raphe nucleus (DRN), or directly into the DRN. When cannulae were located within the DRN, there was little evidence of change in lordosis behavior but a decrease in locomotor activity was commonly observed. In contrast, when cannulae were located anterior, ventromedial, or lateral to the DRN inhibition of lordosis behavior was rapid and robust. Both the lordosis-to-mount ratio (L/M) and the quality of the lordosis reflex were reduced following the infusion. The MCG receives lordosis-facilitating input from the ventromedial nucleus of the hypothalamus and from ascending sensory pathways and contributes information to descending motor systems involved in the lordosis response. Thus, the MCG is a critical link in the completion of the estrogen-dependent lordosis reflex. The present results suggest that 5-hydroxytryptamine1A receptors in the MCG prevent the completion of this reflex.
Serotonin (5-HT) receptor agonist-induced excessive grooming, penile erection and oxytocin secretion were studied in chronically cannulated freely moving rats. The 5-HT1C receptor agonist, m-chlorophenylpiperazine (m-CPP), which also binds to other 5-HT receptors, produced dose-dependent excessive grooming, penile erection and increases in circulating oxytocin concentrations. Maximal responses for excessive grooming and penile erection occurred at 0.3-0.6 mg/kg i.v. m-CPP. Higher doses (0.9-2.5 mg/kg i.v.) caused further increases in oxytocin concentrations, but attenuated both behavioral responses. All three responses to m-CPP (0.6 mg/kg) were attenuated by antagonists with high affinity for the 5-HT1C receptor site (mianserin, LY-53857 and metergoline), but not by the 5-HT2 receptor antagonist ketanserin. The 5-HT2/5-HT1C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), increased plasma oxytocin concentrations only. After ketanserin pretreatment, DOI caused penile erection and diminished the oxytocin response. All responses to DOI were blocked completely by pretreatment with LY-53857 plus ketanserin. Excessive grooming and penile erection showed significant bimodal correlations with the oxytocin response. These data suggest that stimulation of 5-HT1C receptors induces excessive grooming, penile erection and increased oxytocin secretion. Stimulation of 5-HT2 receptors causes a further increase in plasma oxytocin concentration, but inhibits both behavioral responses.
The role of serotonin (5-HT) in the modulation of sexual receptivity (lordosis) in the female rat is reviewed and reevaluated. The effects on lordosis of drug treatments that decrease or increase the activity and availability of central 5-HT are first discussed, and this is followed by an evaluation of the effects of drugs that act directly at 5-HT receptors. In order to shed light on the physiological significance of effects of serotonergic drugs on lordosis, there is also a review of what is known of changes in levels of serotonergic activity and densities of 5-HT receptors in the female rat brain that take place through the estrous cycle and in response to administration of behaviorally effective doses of gonadal steroids. Serotonin has generally been thought to have a tonic, inhibitory effect on lordosis. However, it is concluded that 5-HT can either inhibit or facilitate lordosis depending on which subtypes of central 5-HT receptors become activated. Because of a lack of consistent or compelling evidence of effects of ovarian hormones on serotonergic activity or 5-HT receptors in critical areas of the brain, it is stated that there is at present no basis to conclude that the effects of pharmacological manipulations of serotonergic activity on lordosis reflect an important, physiological role of 5-HT in the modulation of lordosis behavior in the female rat.
In the present series of experiments we compared the effect of injecting serotonin (40 micrograms/cannula), the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (5.0 micrograms/cannula), and the 5-HT1B/C agonist, trifluoromethyl-phenyl-piperazine (TFMPP) (1.0 micrograms/cannula), into the preoptic area, the nucleus accumbens and the nucleus raphe dorsalis. The dose injected was selected on the basis of dose-response curves. Injection of serotonin and TFMPP into the medial preoptic area and nucleus accumbens resulted in an inhibition of male sexual behaviour, as evidenced by an increase in the number of mounts and a prolongation of the ejaculation latency. Injection of 8-OH-DPAT into these brain areas facilitated copulatory behaviour as evidenced by a reduction in the number of mounts, intromissions and ejaculation latency. Administration of these compounds into the nucleus raphe dorsalis produced no effect, except for a prolongation of the intromission latency after serotonin. These results would suggest that at least some of the 5-HT1A receptors involved in the facilitation of male sexual behaviour are located postsynaptically in limbic brain areas that regulate male sexual behaviour. On the basis of the similarities between the inhibitory effects of serotonin and TFMPP, the present results further support the idea that endogenous serotonin acts via the stimulation of 5-HT1B receptors to inhibit male sexual behaviour.
The administration of 5-methoxy-N,N-di-methyl-tryptamine (5-MeODMT), O-2.0 mg.kg-1 SC -15 min, produced a dose-dependent facilitation of the male rat sexual behavior, as evidenced by a decrease in the number of intromissions to ejaculation and in the ejaculation latency. The effects produced by 5-MeODMT (1 mg.kg-1) were antagonized by pindolol (4 mg.kg-1 SC -30 min), but not pirenperone (0.25 mg.kg-1 SC -30 min) or metergoline (1 mg.kg-1 SC -30 min), administration. As expected, 5-HTP (25 mg.kg-1 SC -60 min) produced an increased number of mounts and intromissions to ejaculation and an increase in the ejaculation latency in benserazide (25 mg.kg-1 SC -90 min) pretreated animals. Pindolol (4 mg.kg-1) by itself produced the same effects as seen after 5-HTP administration, and the combination of these compounds produced additive effects. Betaxolol (8 mg.kg-1 SC -30 min) had no effects of its own and did not interact with 5-HTP. The results suggest that stimulation of brain 5-HT1 or 5-HT2 receptors produces facilitation and inhibition, respectively, of the male rat sexual behavior.
Two experiments were performed studying the effects of 8-OH-DPAT and idazoxan on sexual behaviour and ultrasonic communication of male rats. In addition, the reactions of the females towards drug-treated males were studied. 8-OH-DPAT (a very specific 5-HT1A agonist) and idazoxan (an alpha 2-adrenergic antagonist) differentially affected sexual behaviour: 8-OH-DPAT (0.1 and 0.4 mg/kg IP) markedly facilitated ejaculations, a feature indicated by decreased numbers of mounts and intromissions preceding ejaculation and a reduction in ejaculation latency. This drug concomitantly reduced the postejaculatory refractory period. Idazoxan reduced the number of intromissions before ejaculation only at the highest dose (10 mg/kg IP), but did not markedly facilitate other parameters. Both drugs markedly and dose-dependently suppressed the postejaculatory 22 kHz ultrasounds normally recorded during the postejaculatory refractory period. Ultrasound frequencies above 30 kHz first appear at the end of the absolute refractory period, even when the refractory period is shortened by 8-OH-DPAT. Idazoxan increased the number of these 30 kHz ultrasounds, whereas 8-OH-DPAT had no effect on them. No effects were observed on ultrasound production (either 22 kHz or above 30 kHz) before an ejaculation. The behaviour of the females towards 8-OH-DPAT-treated males was also affected, with the females showing more darting and lordosis before and after ejaculation, but less sitting after ejaculation. Idazoxan treatment of the males resulted in more hopping and earwiggling of the females before ejaculation. Following ejaculation, females treated with the antagonist showed more darting, hopping, earwiggling and lordosis, but sitting was decreased. It has been suggested in the rat that the emergence of ultrasounds higher than 30 kHz indicates the end of the absolute refractory period and signals to the female that the male is capable of resuming sexual activity. The significance of 22 kHz ultrasound in sexual behaviour remains puzzling because these vocalizations could be easily uncoupled from the refractory period by drugs acting via different receptor mechanisms without disturbing sexual behaviour per se. A failure to produce postejaculatory sounds appears to disinhibit (proceptive) behaviour by the females.
8-Hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) has antidepressant-like effects in rats and selectively reduces presynaptic 5-HT1A function a day after administration. In the present study, the effect of 8-OH-DPAT (1 mg/kg s.c.) pretreatment on presynaptic (raphe nuclei) and postsynaptic (frontal cortex and hippocampus) [3H]8-OH-DPAT binding was studied. Bmax values were markedly reduced in the raphe, but not in the hippocampus and frontal cortex. Kd values were unchanged. Electrical stimulation of the dorsal raphe (300 microA, 1 ms, 20 Hz, 30 min) significantly increased 5-hydroxyindoleacetic acid in the frontal cortex, but not in the amygdala or the nucleus accumbens and caused smaller increases in the rest of the brain. The increase in the frontal cortex was significantly potentiated one day after giving 8-OH-DPAT. These results confirm the ability of 8-OH-DPAT to desensitise presynaptic 5-HT1A receptors and suggest that this may lead to a loss of feedback control so that, on neuronal stimulation, the increase of 5-HT function is enhanced. This effect may underlie the antidepressant-like action of 8-OH-DPAT pretreatment, i.e. its ability to oppose restraint-induced defects in locomotion on placement in an open field one day later. A requirement of presynaptic 5-HT for this behavioural effect is consistent with its prevention by the 5-HT synthesis inhibitor parachlorophenylalanine.
Using immunohistochemical techniques, a large number of serotonergic paracrine cells were identified in the urethral mucosa of the female rat. The functional significance of these cells was investigated. A model for the study of sexual climax in the anesthetized, acutely spinalized female rat was used. In this model, distension of the urethra with saline elicits a stereotyped coordinated genital response which closely resembles the neuromuscular concomitants of sexual climax. Addition of serotonin to the urethral perfusate (10(-4)-10(-7) M) caused a dose-dependent decrease in the mechanical threshold necessary to elicit the climax-like response. This effect was blocked by a specific 5-HT3 receptor antagonist. The physiological implications of these findings are discussed.
Recent electrophysiological studies, measurements of 5-HT synthesis and in vivo voltammetry recordings of 5-HT metabolism have suggested that serotoninergic neurones in the median raphe (MR) are less sensitive to 5-HT1A autoreceptor stimulation relative to those in the dorsal raphe (DR). To further study the putative differences in regulation between ascending 5-HT projections from the raphe nuclei we have used microdialysis to measure the release of 5-HT in ventral hippocampus, globus pallidus, dorsal hippocampus, frontal cortex, nucleus accumbens and medial septum, following systemic administration of the specific 5-HT1A agonist 8-OH-DPAT. The results show that the baseline output of 5-HT was similar in each of the areas studied. While 8-OH-DPAT decreased dialysate levels of 5-HT in all areas, the inhibition of 5-HT release seen in globus pallidus was significantly less marked compared to that observed in the other five regions. The results indicate that 5-HT1A autoreceptor-mediated control of 5-HT release is functional in all of the brain areas studied, including those receiving a preferential 5-HT innervation from the DR and MR. We find little evidence in support of the idea that brain 5-HT neuronal projections are heterogenous with respect to 5-HT1A autoreceptor regulation of 5-HT release; the globus pallidus, however representing a possible exception to this.
The local application of 5-HT (0-40 micrograms side-1) into the nucleus accumbens was found to inhibit male rat sexual behavior, as evidenced by an increase in number of mounts and intromissions preceding ejaculation and in time to ejaculation. There were no effects on male rat sexual behavior after similar 5-HT injections into other striatal areas, including the dorsolateral, the ventromedial and the posterior neostriatum, as well as the olfactory tubercle. The same groups of animals were also scored for motor activity and body posture after the injection of 5-HT, and only animals injected into the nucleus accumbens showed a statistically significant decrease in motor activity and an increase in the display of a flat body posture. 8-OH-DPAT (0-5 micrograms side-1), injected into the nucleus accumbens, produced a facilitation of the male rat sexual behavior, as evidenced by a decrease in number of mounts and intromissions to ejaculation, as well as in the postejaculatory interval. 8-OH-DPAT injections into the nucleus accumbens produced a decrease in motor activity and an increase in the per cent animals with a flat body posture. Injections into the olfactory tubercle had no effects on the sexual behavior or on the motor activity, whereas the per cent flat body posture was increased. Local application of 8-OH-DPAT (0-5 micrograms) into the median raphe nucleus, facilitated male rat sexual behavior, as evidenced by a decrease in number of intromissions preceding ejaculation and in time to ejaculation. The same doses of 8-OH-DPAT injected into the dorsal raphe had no effects on the sexual behavior. In an additional experiment, 3 groups of animals were injected with 5-HT (40 micrograms) or 8-OH-DPAT (5 micrograms) into the nucleus accumbens, the dorsal and the median raphe nuclei and thereafter observed for treadmill performance. No statistically significant effects were found after injections in any of these brain areas. The present results strongly suggest an inhibitory role of ventral forebrain 5-HT in the mediation of male rat sexual behavior. The facilitation produced by 8-OH-DPAT is possibly due to a blockade of 5-HT2 receptors. Facilitation by 8-OH-DPAT of the male rat copulatory performance after median raphe injections is probably due to stimulation of 5-HT1A autoreceptors in this brainstem region. In contrast to their opposite effects on sexual behavior, both compounds produced a decrease in motor activity and an increased display of flat body posture after accumbens injections.(ABSTRACT TRUNCATED AT 250 WORDS)
Although many different types of compounds have been tested for 5-hydroxytryptamine1A (5-HT1A) binding affinity, much remains to be learned about the structural requirements associated with 5-HT1A agonism, partial agonism, and antagonism. The present study uses the forskolin-stimulated adenylate cyclase (FSC) assay as a functional screen in rat hippocampal membranes to examine structure-activity relationships for a series of enantiomers of novel analogs of the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The findings illustrate that there can be large enantiomeric differences in intrinsic activity at the 5-HT1A receptor, independent of enantiomeric effects on binding affinity. Generally, for each enantiomeric pair exhibiting stereoselective 5-HT1A binding, the enantiomer with the higher affinity also displayed the greater amount of 5-HT1A intrinsic activity in the FSC assay. Interestingly, the enantiomers of 8-OH-DPAT itself displayed stereoselective differences in intrinsic activity but not 5-HT1A affinity. Several of the compounds, namely (S)-UH-301, (2R,3R)-CM-12, and (1S,2R)-LEA-146, may have potential as prototypes for selective 5-HT1A antagonists, and (S)-UH-301 itself may be useful as a selective 5-HT1A antagonist. The FSC data presented here are in good agreement with reported measures of in vivo 5-HT1A activity, which were in part the basis of a recently proposed model for the 5-HT1A pharmacophore [J. Med. Chem. 34: 497-510 (1991)].
In order to establish whether the 5-HT1A or the 5HT1B agonists, 8-OH-DPAT or TFMPP, produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving: (a) the serotonin synthesis or release; (b) the stimulation of presynaptic receptors, or (c) the stimulation of somatodendritic receptors, three series of experiments were performed. The administration of the serotonin synthesis inhibitor, p-chlorophenylalanine (p-CPA, 300 mg/kg x 3 days), facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP (0.5 mg/kg) or 8-OH-DPAT (0.5 mg/kg), respectively. The icv or the intraraphé administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels. In lesioned animals TFMPP (0.5 mg/kg) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency. The inhibitory effect of this drug on mounting behaviour was not observed in 5,7-DHT treated rats. In lesioned animals 8-OH-DPAT (0.5 mg/kg) produced the same facilitatory effect. Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8-OH-DPAT in copulation. All data further support the idea that endogenous serotonin acts via the stimulation of 5-HT1B receptors to induce its inhibitory effects on masculine sexual behaviour.
A preparation for the study of sexual function in anesthetized spinal male and female rats is discussed. Urethral stimulation in males elicited penile erection, ejaculation, and rhythmic contractions of the striated perineal muscles. In females, vaginal and uterine contractions and rhythmic contractions of the perineal muscles were elicited. These responses show many similarities to responses seen during sexual climax in unanesthetized humans and animals. This response, which we refer to as the urethrogenital reflex, is unaffected in either sex by gonadectomy. We determined that the urethrogenital reflex is produced by a spinal pattern generator and is under tonic descending inhibition from the brain stem. We conclude that this preparation may be a valuable model for experimental study of the neural mechanisms of sexual function in both sexes.
Systemic administration of the 5HT1A receptor agonist, 8-OH-DPAT, consistently decreases the threshold of ejaculatory behavior and enhances some aspects of arousal. Previous findings by others demonstrated the in copula ejaculatory behavior effect using intrathecal (IT) injection at the level of the lumbosacral spinal cord, but the dose used was in the range that produced results systemically. This study aimed at a) a more comprehensive study of the sexual effects of 8-OH-DPAT and b) use of IT doses of 8-OH-DPAT below those effective when administered systemically. The ex copula genital reflex test showed severe inhibition. At doses of 5 micrograms or more, significant inhibition of the percentage of rats displaying ejaculation occurred, and the two highest doses also significantly reduced the percentage of rats displaying erection. In the in copula mating test, 20 and 80 micrograms IT 8-OH-DPAT, significantly reduced ejaculation latency, intromission frequency and intercopulatory interval. Copulatory plugs, collected at the highest dose only, showed a trend towards weight reduction. We conclude that the facilitation of ejaculatory behavior and some measure of arousal by 8-OH-DPAT can be mediated directly via the lumbosacral spinal cord. An hypothesis for explaining the inhibitory effect on ejaculation ex copula is presented, but the inhibitory effect on erectile reflexes is without interpretation.
Different 5‐hydroxytryptamine (5‐HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5‐HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction between different 5‐HT receptor subtypes was studied.
Hypothermia and hypoactivity in mice induced by the 5‐HT 1A ‐agonist 8‐hydroxy‐dipropylaminotetralin (8‐OH‐DPAT) could be attenuated by the preferential 5‐HT 1C ‐agonists MK 212, 1‐(meta‐chlorophenyl)‐piperazine (mCPP) and m‐trifluoromethyl phenyl piperazine (TFMPP), and by the mixed 5‐HT 2/1C ‐agonist 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI). The mixed 5‐HT 1A/1B ‐agonist CGS 12066B at 10 mg kg ⁻¹ potentiated hypothermia and had no effect on hypoactivity.
Forepaw treading in rats induced by the 5‐HT 1A ‐agonist 8‐OH‐DPAT was attenuated by the 5‐HT 1C ‐agonists MK 212 and mCPP. The 5‐HT 1C ‐agonist TFMPP had a bimodal effect: at low doses (> 1 mg kg ⁻¹ ) it potentiated, and at higher doses (> 2.2 mg kg ⁻¹ ) it attenuated forepaw treading. the mixed 5‐HT 2/1C ‐agonist DOI produced 5‐HT 2 ‐related behaviours and potentiated 8‐OH‐DPAT‐induced forepaw treading. This indicates an attenuating effect of 5‐HT 1C ‐receptor activation and a potentiating effect of 5‐HT 2 ‐receptor activation. CGS 12066B had no effect in this respect.
Head shakes in rats induced by DOI could be attenuated by 8‐OH‐DPAT, TFMPP, mCPP and MK 212. The ID 50 s were 0.03, 0.7, 0.1 and 2 mg kg ⁻¹ , respectively. This suggests that a 5‐HT 2 ‐receptor‐mediated effect may be attenuated by activation of 5‐HT 1A ‐ or 5‐HT 1C ‐receptors. CGS 12066B attenuated the head shake response but only at 10 mg kg ⁻¹ .
The results suggest that interactions exist between the different 5‐HT receptor subtype‐mediated events. Therefore, care is needed in drawing conclusions from functional measurements when compounds have more or less equal affinities for more than one 5‐HT‐receptor subtype.
Peripheral administrations of TFMPP (0.2- 1 mg/kg) or MCPP (1 mg/kg) facilitated lordosis behavior in female rats treated with estradiol benzoate, and had no effects in females primed with estradiol benzoate and progesterone. In contrast, TFMPP (1 mg/kg) and MCPP (1 mg/kg) inhibited copulatory behavior in male rats. It is concluded that there are sex differences in the effects of TFMPP and MCPP on copulatory behavior in the rat. Moreover, it is suggested that the effects of these drugs on copulatory behavior may be mediated by activation of 5-HT1B and/or 5-HT1C receptors, or by blockade of activity at 5-HT3 receptors.
Drug-induced penile erections (PE) were initially suggested to be 5-HT1B receptor mediated. However, since the discovery of the 5-HT1C receptor a number of compounds, considered to be 5-HT1B selective, appear to bind more strongly to the 5-HT1C receptor and this prompted a re-evaluation of the receptor subtype involved in PE induction. PE could be induced by the 5-HT agonists mCPP (0.22-2.2 mg/kg), TFMPP (0.46-1.0 mg/kg) and MK 212 (0.1-1.0 mg/kg). The 5-HT agonist DOI (0.022-0.22 mg/kg) did not induce PE in placebo-pretreated rats but in rats pretreated with various 5-HT2 antagonists it did. These compounds have in common a strong affinity for the 5-HT1C receptor, mCPP (0.46 mg/kg)-induced PE could be antagonized by the 5-HT antagonists metergoline, cyproheptadine, mesulergine, mianserin, ritanserin and ketanserin. Their ED50S were 0.04, 0.4, 0.03, 0.06, 0.4 and 2 mg/kg, respectively. The potency of both the agonists to induce, and the antagonists to inhibit, PE was found to be dependent on their selectivity for the 5-HT1C receptor versus the 5-HT2 receptor. Spiperone (0.1-1.0 mg/kg) and GR 38032F (1-10 mg/kg) did not antagonise mCPP-induced PE. 8-OH-DPAT and 5MeODMT counteracted mCPP (0.46 mg/kg)-induced PE. Their ED50S were 0.03 and 0.4 mg/kg, respectively. DOI counteracted mCPP induced PE only at doses above 1 mg/kg, whereas CGS 12066B (1.0-10 mg/kg) was inactive. The results suggest that PE are induced by activation of the 5-HT1C receptor and are functionally inhibited by activation of 5-HT1A or 5-HT2 receptors.
It has long been assumed that the brainstem exerts a tonic descending inhibitory influence on spinal sexual reflexes, but the source of this inhibition is unknown. Sexual responses (penile erection and ejaculatory movements) were elicited in anesthetized male rats using urethral stimuli. Using brainstem transections and electrolytic and neurotoxic lesions, we have identified a group of neurons in the paragigantocellular reticular nucleus in the ventral medulla which mediates this descending inhibition. Correlative neuroanatomical studies indicate that the inhibition is mediated via a direct projection to pelvic efferent neurons and interneurons. These results promise new approaches to the treatment of human sexual disorders.
Male rat sexual behavior was examined in a variety of tests following a single acute IP injection of the serotonin1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT). The objective was to determine the effects of 5-HT1A receptor stimulation on the components of sexual behavior (arousal/motivation, erection and ejaculation) using this prototypical 5-HT1A ligand. In the ex copula genital reflex test, DPAT dramatically inhibited ejaculation and the display of penile erections. When examined in the mating behavior test, DPAT caused a significant reduction in intromission frequency (IF), ejaculation latency (EL), intercopulatory intervals (ICI) and postejaculatory interval (PEI). The decrease in IF and EL indicated a lowering of the behavioral-ejaculatory threshold, while the reduction in ICI and PEI indicated a stimulation of two aspects of sexual arousal. Further tests, however, revealed complexities. Using the mounting test (with genital anesthesia) as an assessment of sexual arousal, no effect of DPAT was found. Collection and examination of the coagulated ejaculates resulting from mating (copulatory plugs) provided evidence of an impairment in ejaculation, as a result of DPAT treatment. The data suggests that 5-HT1A receptor stimulation lowers the behavioral-ejaculatory threshold despite inhibition of ejaculation in and ex copula; as well as stimulating specific aspects of sexual arousal. It remains to be determined whether the effects on arousal were either due to nonselectivity as currently believed or because 5-HT1A receptor stimulation affects alpha 2-adrenoceptor activity by some as yet undefined mechanism; and as a result modulates sexual arousal.
We determined the minimum number of hours per day of testosterone (T) exposure required to activate male sexual behavior, and correlated these changes with the temporal parameters of androgen receptor occupation. For the first part of the study, castrated Long-Evans male rats received two 10 mm T-filled Silastic capsules in open flank pouches for 4, 8, 12, 16, 18, 21, or 24 hours per day over a 10 day period. Tests for male sexual behavior were conducted on days 2-3, 4-5, 7-8, and 9-10 of T treatment. A significantly higher proportion of males receiving 21 or 24 hr of daily T exposure mounted, intromitted and ejaculated compared to groups with daily T exposures of 18 hr or less. In the second part of this study we assessed whether it was necessary to maintain high levels of androgen receptor occupation during the 21-24 hr exposure period in order to activate male sexual behavior. Cell nuclear androgen receptor occupation was measured in HPAS (combined hypothalamus, preoptic area, amygdala and septum) of rats receiving 12, 21, or 24 hr of T exposure. In all three groups, nuclear androgen receptor occupation was high at the time of capsule removal, and fell significantly by 3 hr following T capsule removal. By 6 hr after T capsule removal, androgen receptor binding had fallen to castrate levels. These results demonstrate that, although relatively brief (less than or equal to 18 hr/day) exposures to testosterone can activate mounts and intromissions, significantly more responses are found in males receiving at least 21 hr of T exposure per day.(ABSTRACT TRUNCATED AT 250 WORDS)
The study investigated the possible involvement of serotonin in the medial preoptic area in the regulation of sexual behavior of male rats. Injection of serotonin in the medial preoptic area resulted in an inhibition, whereas cyproheptadine (a serotonin antagonist) produced a slight facilitation, of male sexual behavior.
The effects of m-chlorophenylpiperazine (MCPP), a serotonin agonist, on spontaneous and evoked neural firing in nerves supplying the penis and bladder were examined in the urethan-anesthetized rat. MCPP (0.1-10 mg/kg iv) elicited, after a 2- to 4-min delay, an increase in spontaneous firing in cavernous nerves but no detectable firing in bladder nerves. The cavernous nerve firing was accompanied by an increase in intracavernous pressure and a depression of rhythmic bladder activity. Administration of ganglionic-blocking agents or transection of peripheral nerves revealed that the cavernous nerve discharge was mediated by activation of pre-ganglionic cholinergic pathways in the pelvic nerve. The effects of MCPP were noted in intact as well as in acute and chronic spinal rats and were prevented by the administration of the serotonin (5-HT) antagonist, metergoline (3 mg/kg im). These data indicate that pharmacological activation of 5-HT receptors, possibly of the 5-HT1B subtype, can facilitate the sacral preganglionic outflow to the penis and inhibit bladder activity.