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BJUI Mini Reviews - A Dual Physiological Character for Sexual Function: The Role of Serotonergic Receptors Show Comments PDF Print E-mail
  
Thursday, 06 March 2008

BJUI Mini Reviews - In this review, it is assumed that 5HT modulates sexual reflexes, establishing a functional connection between the involved somatic and autonomic structures.

A dual physiological character for sexual function: the role of serotonergic receptors Ion G. Motofei Carol Davila University, St. Pantelimon Hospital, Bucharest, Romania Accepted for publication 27 July 2007 distinct, opposite and positive effects on sexual function, with 5HT- 1A agonists decreasing intravaginal ejaculatory latency and erection, and 5HT- 2C agonists increasing both erection and ejaculatory latency. In this review I assume that 5HT modulates sexual reflexes, establishing a functional connection between the involved somatic and autonomic structures. The 5HT- 1A receptors are assumed to make the connection between somatic pathways and sympathetic centres while the 5HT- 2C receptors could establish the connection between somatic pathways and parasympathetic centres. Further studies will develop the cerebral sexual duality, explaining the implication of psychological factors in sexual function and the role of sexuality in psychosocial behaviour. KEYWORDS sexuality, dual, character, 5HT- 1A , 5HT- 2C , anxiety, depression Anatomically, sexual reflexes are mixed (somatic-autonomic) circuits, represented by emission (sympathetic centre and somatic afferents), expulsion (parasympathetic centre and somatic efferents) and erection (parasympathetic centre and somatic afferents). Physiologically, ejaculation has a dual autonomic mediation, consisting of two distinct and opposite autonomic centres (emission and expulsion), both with a positive contribution to the respective function. Experimentally, serotonin (5HT) has two INTRODUCTION Clinically, sexual response in normal potent men implies the following successive stages: arising of libido, erection, sexual arousal, emission, expulsion and orgasm [1,2]. From a physiological perspective, libido and sexual arousal represent the afferent part and emission-expulsion the efferent part of the cerebral ejaculatory process [3]. Ejaculatory function has (both at the spinal and cerebral level) a dual physiological character. The main dual character of sexual function is represented by the two distinct and opposite autonomic centres (sympathetic emission and parasympathetic expulsion), both with a positive contribution to the same function [4]. This dual character implies other secondary dual features for sexual function. Thus, the genital afferents are of two different types (free and encapsulated nerve endings), corresponding to the two distinct spinal ejaculatory reflexes [5]. At the cerebral level the afferents are also represented by two distinct events (libido and sexual arousal) [4,6]. Oestrogens and androgens are two antagonistic hormonal classes, with androgens modulating parasympathetic and oestrogens modulating sympathetic sexual axes, both in men and in women [4]. Finally, serotonin is a monoamine neurotransmitter which modulates two distinct, opposite and positive effects on sexual function. The 5-hydroxytriptamine (5HT)- 1A receptors decrease ejaculatory latency time and erection in male rats [7,8], while the 5HT- 2C receptors increase both erection and ejaculatory latency time [8,9]. Most probably, the serotonergic duality is linked to the reported mainly dual characteristic of sexual function. The neuroanatomical ejaculatory structures are better described at the spinal cord level. An anatomical analysis of spinal ejaculatory circuits shows some interesting aspects, suggesting the effects of serotonin on sexual function. DISTINCT (SOMATIC OR AUTONOMIC) REFLEXES AND MIXED (SOMATOAUTONOMIC) CIRCUITS Anatomical and physiological considerations divide the human nervous system into the somatic nervous system and the autonomic nervous system. The former is responsible for MOT O F E I © 2 0 07 T H E A U T H O R 5 3 2 J O U R N A L C O M P I L A T I O N © 2 0 07 B J U I N T E R N A T I O N A L the interaction of the individual with the external medium. The somatic nervous system implies somatic afferents (from somatic organs; skin, senses, etc.), somatic nervous centres (in the spinal cord/brain) and somatic efferents (to the somatic effectors; striated/ skeletal muscles). This is a pure somatic reflex arc [10]. The autonomic nervous system ensures the functioning and correlation of internal organs. The autonomic system implies autonomic afferents (from internal organs; oesophagus, stomach, heart, etc.), autonomic nervous centres (in the spinal cord/brain) and autonomic efferents (to the autonomic effectors; smooth muscles, heart, exocrine and endocrine glands). This is a pure autonomic reflex arc [11]. There are also possible mixed circuits (somatic-autonomic). The conditioned mixed circuit was described by Pavlov (cited in [12] and implies distinct anatomical structures; somatic afferents (the light), autonomic centres and autonomic efferents (gastric secretion). From a physiological approach, these circuits could imply supplementary mechanisms (neuromodulators), able to make the connection between the different involved structures (somatic afferents and the autonomic centre/response). Our current understanding shows that unconditioned mixed circuits are also possible: sensory-vegetative integration in the trigemino-pupillary reflex, emission, expulsion and erection reflexes, etc. The functional connection between somatic and autonomic components of these circuits could be made by some neurotransmitters/ neuromodulators (substance P, serotonin, etc.) [3,13]. Emission (the first reflex of ejaculation) determines the excretion of seminal fluid into the posterior urethra, while expulsion (the second reflex) eliminates this fluid to the exterior [14]. Emission is a mixed reflex and has somatic afferents (penile stimulation), an autonomic (sympathetic) spinal centre and autonomic efferents (to the prostate, vas deferens and seminal vesicles) [15]. The expulsion is also a mixed reflex, having autonomic afferents (posterior urethra), an autonomic (parasympathetic) spinal centre and somatic efferents (to bulbospongious, ischiocavernosus and pelvic floor skeletal muscles) [3,16]. Spinal erection is also a mixed circuit implying somatic (penile) afferents, an autonomic (parasympathetic) spinal centre and autonomic efferents (penile vasodilatation) [4,17]. THE ROLE OF SEROTONIN IN SEXUAL REFLEXES The 5HT- 1A agonists decrease erection and intravaginal ejaculatory latency times (IELT) in rats [7,8], while a 5HT- 2C agonist leads to an increase of both erection and IELT [8,9]. Suppose that one type of serotonin receptor has a stimulating effect on sexual function, while the other would have an inhibitory sexual effect. Serotonin is secreted by a group of neurones, diffused through certain areas of the nervous system (not limited to a single synapse) and modulates diverse populations of neurones. Consequently, when it is secreted, serotonin stimulates (most probably) both 5HT- 1A and 5HT- 2C receptors, leading to a concomitant stimulation and inhibition of sexual function. This model would be counterproductive (automatically cancelling serotonin action) so it is an improbable eventuality. Another possibility would be that both types of serotonin receptors would positively modulate sexual function. The 5HT- 1A agonists could directly favour the sympathetic emission (shortening IELT, as in premature emission after spinal cord injury) and could also indirectly decrease the opposite parasympathetic expulsion/erection centres (a decreased participation of erection and expulsion). The 5HT- 2C agonists would directly favour parasympathetic expulsion and erection (an increased erection) and consequently (indirectly) would inhibit the sympathetic (emission) centre which starts ejaculation (increased IELT). The conclusion is that serotonin positively modulates sexual function through 5HT- 1A and 5HT- 2C receptors, establishing the functional connection between the different somatic and autonomic structures of sexual circuits. The 5HT- 1B receptors (having only inhibitory sexual effects) could intervene in the period after ejaculation [18,19]. Some recent studies already suggested a possible correlation between these types of serotonin receptors. Thus, activation of lumbosacral 5HT- 2C receptors induces bursts of rhythmic activity in sympathetic nerves to the vas deferens in male rats. The 5HT- 1A receptor agonists do not elicit such a response. However, the co-administration of 5HT- 1A agonist with a 5HT- 2C agonist induces a potentiation of the vas deferens response [20]. This suggests an action of the two agonists in the lumbosacral spinal cord, with a crucial role of 5HT- 2C receptors in ejaculation [21,22]. Other authors show that mating lordosis behaviour occurs under specific physiological and environmental factors, through a dual serotonergic regulation [23]. In humans, the drugs which activate the 5HT- 2C receptors (e.g. paroxetine) delay ejaculation, and this effect can be reversed by drugs which stimulate the 5HT- 1A receptors (e.g. buspirone) [24,25]. More interpretable data are available, but most of it is obtained from different animal species, so that the results are not necessarily comparable. The administration in rats of 8-OH-DPAT (a 5HT- 1A receptor agonist) induces, in the mating behaviour test, a significant reduction in intromission frequency, IELT and interval after ejaculation. Using the mounting test with genital anaesthesia, no effect of this drug was reported. In the ex copula test this drug dramatically inhibits ejaculation and the display of penile erection [26]. These complex results might be the consequence of the fact that libido and sexual arousal (cerebral ejaculation) could be induced by the action of complex afferents, represented by an association of genital somatic afferents with psychic/sensorial impulses [4]. The studies with 8-OH-DPAT on sexual responses in male dogs (ejaculation, penile erection and pelvic thrusting behaviour) decrease the amount of ejaculated semen (depending on the dose), possibly through indirect inhibition of parasympathetic expulsion/erection centre (this drug also decreasing erectile response). However, at the highest doses, 8-OH-DPAT produces an increase in IELT, while in rats the IELT decreases [27]. Explanations for these distinct responses are required. Other studies show possible connections between serotonergic receptors and sexual hormones. Thus, in the presence of a sexually receptive female, the blood testosterone level increases in male mice; this effect is blocked by administering a 5HT- 1A receptor agonist [28,29]; the other antagonistic hormone, oestradiol, was reported to induce a desensitization of the 5HT- 1A receptors [30,31]. A D U A L P H Y S I O L O G I C A L C H A R A C T E R F O R S E X U A L F U N C T I O N © 2 0 07 T H E A U T H O R J O U R N A L C O M P I L A T I O N © 2 0 07 B J U I N T E R N A T I O N A L 5 3 3 CEREBRAL EFFECTS OF SEROTONIN Adrenaline is a mediator which intervenes in cerebral sympathetic emission and mediates the cerebral process of anxiety [4,32]. Premature ejaculation (PE) could imply a fast emission response that is an augmented intervention of adrenaline; this could explain the association of PE with anxiety. These two cerebral processes have autonomic brain centres. However, the cerebral ejaculatory afferents are somatic pathways (visual, genital stimuli, etc.); the psychosomatic afferents which induce anxiety are also somatic pathways. Consequently, serotonin could intervene at cerebral level (through 5HT- 1A receptors) to make the connection between somatic afferents and cerebral sympathetic centres (of ejaculation, anxiety). The 5HT- 1A antagonists could disfavour the connection between somatic afferents and the autonomic centres of emission and anxiety. These drugs delay ejaculation (both in normal potent men and in men with PE) and decrease anxiety [33,34]. The 5HT- 2C agonists lead to an increase of both erection and IELT, perhaps connecting somatic afferents to the parasympathetic cerebral centres. The 5HT- 2C receptors could also modulate depression, a parasympathetic process [35]. The 5HT- 2C antagonists could disfavour the connection between psychosomatic afferents and the autonomic centres of depression; these drugs are being used to treat (decrease) depressive moods [36]. The 5HT- 1A agonists could directly favour anxiety and disfavour (indirectly) depression, while the 5HT- 2C agonists would directly favour depression and disfavour (indirectly) anxiety, i.e., an unbalance between 5HT- 1A and 5HT- 2C receptors will lead to anxiety or depression. Interestingly, the drugs which re-establish the equilibrium between these receptor types are effective for treating anxiety and depression, even those acting antagonistically. Thus, tianeptine, a selective serotonin-reuptake enhancer, has strong antidepressant and anxiolytic properties; this drug decreases the amount of synaptic serotonin and thus decreases the stimulation of both 5HT- 1A and 5HT- 2C receptors [37]. An antagonist drug moclobemide, that blocks the decomposition of serotonin, is also used to treat depression and social anxiety; this drug increases the synaptic serotonin amounts and thus stimulates both 5HT- 1A and 5HT- 2C receptors [38]. Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) is an illegal drug that acts as an indirect monoaminergic agonist, stimulating the release and inhibiting the reuptake of serotonin [39]. The administration of MDMA in a single dose leads to moderately to profoundly increases desire and satisfaction, and a delayed orgasm, which is perceived as more intense (5HT- 1A and 5HT- 2C ), while erection decreases in 40% of the subjects (5HT-1 B receptors) [40]. Abstinent previously regular MDMA users have a reduced level of serotonin and serotonin transporter density, and associated loss of sexual interest and pleasure [41]. PREMATURE EJACULATION While serotonin modulates/facilitates the autonomic reflexes/sexual responses (leading at best to a faster response), the sympathetic and parasympathetic centres mediate the sexual response directly (thus triggering the fastest responses). Consequently, PE (a constant ‘fastest response’) would be a consequence of sympatho- parasympathetic disturbances [42] more than serotonergic disturbances [21]. Published data sustain this point of view for the cause of PE. Thus, during the administration of 5HT- 1A receptor agonists in control rats and in rats with impaired sexual behaviour, there were moderate (flesinoxan) to severe (8-OH-DPAT) decreases in latency to first ejaculation. PE occurred during the first ejaculation series with 8-OHDPAT, but not during flesinoxan treatment nor in the second ejaculation series with 8-OHDPAT [43]. CONCLUSIONS Ejaculation has a dual character at the spinal cord level and consists of two distinct, mixed and opposite autonomic circuits. Serotonin might make the connection between somatic and autonomic components of these circuits, becoming in time autonomic unconditioned reflexes. The presented model for spinal serotonin action could be extrapolated to the cerebral level. The emission and expulsion phases of cerebral ejaculation are mixed autonomic reflexes. Both afferents of these two phases are represented by somatic stimuli. The somatic impulses become autonomic stimuli under hormonal modulation and could also become afferents for autonomic centres under cerebial neuromodulation. At the cerebral level the action of serotonin is more complex, presenting a unique positive and double-negative modulation of three distinct autonomic centres. Four psycho-neuro-endocrine and four psychosomatic axes could be described in humans. Therefore, further studies are needed for a complete understanding of serotonin effects, for both sexual and psychological functions. CONFLICT OF INTEREST None declared. 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Depression and associated sleep disturbances: patient benefits with agomelanine. Eur Neuropsychopharmacol 2006; 16: 639–43 37 Sonawalla S, Chakraborty N, Parikh R. Treatment of major depression and anxiety with the selective serotonin re-uptake enhancer tianeptine in the outpatient psychiatric care setting of India. J Indian Med Assoc 2003; 101: 116– 24 38 Bonnet U. Moclobemide: therapeutic use and clinical studies. CNS Drug Rev 2003; 9: 97–140 39 Medina KL, Shear PK, Corcoran K. Ecstasy (MDMA) exposure and neuropsychological functioning: a polydrug perspective. J Int Neuropsychol Soc 2005; 11: 753–65 40 Zemishlany Z, Aizenberg D, Weizman A. Subjective effects of MDMA (‘Ecstasy’) on human sexual function. Eur Psychiatry 2001; 16: 127–30 41 Parrott AC. Human psychopharmacology of ecstasy (MDMA): a review of 15 years of empirical research. Hum Psychopharmacol 2001; 16: 557–77 42 Motofei IG. The neurobiological approach to premature ejaculation. J Urol 2003; 170: 929 43 Haensel SM, Slob AK. Flesinoxan: a prosexual drug for male rats. Eur J Pharmacol 1997; 330: 1–9 Correspondence: Ion G. Motofei, Str. Tarnita, Nr. 14, Sect. 3, Bucharest, Romania. e-mail: <script language='JavaScript' type='text/javascript'> <!-- var prefix = 'ma' + 'il' + 'to'; var path = 'hr' + 'ef' + '='; var addy20709 = 'igmotofei' + '@'; addy20709 = addy20709 + 'yahoo' + '.' + 'com'; document.write( '<a ' + path + '\'' + prefix + ':' + addy20709 + '\'>' ); document.write( addy20709 ); document.write( '<\/a>' ); //-->\n </script><script language='JavaScript' type='text/javascript'> <!-- document.write( '<span style=\'display: none;\'>' ); //--> </script>This email address is being protected from spam bots, you need Javascript enabled to view it <script language='JavaScript' type='text/javascript'> <!-- document.write( '</' ); document.write( 'span>' ); //--> </script> Abbreviations: 5HT, 5-hydroxytriptamine; IELT, intravaginal ejaculatory latency time; PE, premature ejaculation; MDMA, methylenedioxymethamphetamine.

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