Review
Central neurophysiology and dopaminergic control of ejaculation

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Abstract

Although premature ejaculation (PE) represents the most common male sexual dysfunction, brain mechanisms controlling ejaculatory process remain poorly understood. Recently a group of neurons, identified in the lumbar spinal cord, has been proposed to constitute a spinal ejaculation generator. This key site in ejaculation control, relaying sensory inputs to the brain, is under supraspinal excitatory (medial preoptic area, paraventricular nucleus of the hypothalamus) and inhibitory (nucleus paragigantocellularis) controls. Activation of brain excitatory areas by dopamine (DA) or DA agonists being demonstrated to facilitate ejaculation, it seems particularly interesting to further understand the implication of central DA in the complex process leading to ejaculation. Moreover, the fact that dopaminergic pathways are involved in sexual behavior and that DA release in some brain regions is an important facilitator of male sexual behavior reinforces the crucial implication of DA. Clearly, a better understanding of DA incerto-hypothalamic pathways and targeting brain DA receptor subtypes mediating ejaculation (especially D3 receptors) will benefit the development of new pharmacological strategies to treat ejaculatory dysfunction including PE.

Introduction

Amongst the different physiological functions, those related to reproduction are probably the unique essential for the survival of the living species without being vital for the individual. In recent years, male sexual dysfunctions have become a more popular topic of interest in biological science. However, animal and clinical studies have mainly focused on mechanisms and pathophysiology of penile erection and erectile dysfunction, respectively, whereas the ejaculation and its dysfunctions remained poorly investigated. This is somewhat surprising, because epidemiological surveys show that disorders of ejaculation, especially premature ejaculation (PE), are the most frequently reported sexual dysfunction in men (Althof, 2006; Lewis et al., 2004). Though, in the last decade, specific spinal and supraspinal pathways implicated in ejaculation have been identified using anatomical, physiological, pharmacological or behavioral approaches. It is now crucial to better understand the neurophysiology and pharmacology related to these pathways and their involvement in the control of ejaculatory process. This will significantly benefit treatment of ejaculatory dysfunction, especially treatment focused on helping patients complaining about PE, which remains an unmet medical need, to improve their quality of life (Rowland et al., 2004).

In the past years, the emergence of encouraging results in the use of selective serotonin reuptake inhibitors (SSRIs) to delay ejaculation led to an increasing volume of research dedicated to better understand how central serotonergic system may modulate the complex processes that encompass ejaculation (Giuliano and Clement, 2005b). However, data suggest that, in addition to a direct interaction with the serotonergic system, the SSRIs’ side effects, which include a delay in ejaculation, may ensue from an inhibition of dopaminergic neurotransmission, directly on DA release or on dopaminergic receptors or indirectly via serotonergic modulation (for review, see Damsa et al., 2004). Furthermore, pro-ejaculatory effects observed after the administration of 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a classical model to accelerate ejaculation, has been reported to be blocked by the co-injection of D2-like antagonist raclopride and not by the co-injection of 5-HT1A antagonists, 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide hydrochloride (MPPI) and WAY-100635 (Clement et al., 2006; Matuszewich et al., 1999). This suggests that the effects of 8-OH-DPAT might, at least partially, be mediated by direct modulation of D2-like receptors or/and through increase in DA release in the medial preoptic area (MPOA). Taken together these data strongly support an implication of dopaminergic neurotransmission in the central control of ejaculation. It is all the more true since, in rats, D2-like agonists were demonstrated to decrease ejaculation latency and increase its frequency (Ahlenius and Larsson, 1995; Bitran et al., 1989; Foreman and Hall, 1987) as well as to manage SSRIs-induced ejaculatory dysfunction (Rosen et al., 1999). In this review we attempted to put together studies focused on the implication of central dopaminergic neurotransmission in ejaculation.

Section snippets

Central physiology of ejaculation

Ejaculation, commonly accompanied by orgasm, is the final stage of coitus in mammalian male. Ejaculation consists of two successive phases, emission and expulsion, that involve different anatomical structures. A tight coordination between sympathetic, parasympathetic, and somatic divisions of the nervous system is necessary for normal anterograde ejaculation to occur. The ejaculatory response involves sensory receptors and areas, afferent neural pathways, cerebral sensory and motor areas,

Dopaminergic control of ejaculation

Evidences for dopamine (DA) implication in the modulation of male sexual behavior were reported as early as the early 1970s, when a few studies suggested the aphrodisiac effect of l-DOPA in Parkinsonian patients and in rats (Tagliamonte et al., 1974) or showed for the first time the excitatory effect of DA receptor stimulation on male sexual behavior (Gessa and Tagliamonte, 1974). It is now well-accepted that central DA plays a key role in male sexual behavior (Damsma et al., 1992; Giuliani et

Conclusion

It was already well-accepted that DA is important for male sexual behavior. Though, in the past years, increasing numbers of studies, focusing on the better understanding of the neurophysiology/pharmacology of ejaculation, provided new insights of the physiologic events occurring during ejaculation. The central nervous system looks very promising for the development of innovative therapeutic approaches to treat ejaculatory dysfunction. The implication of central DA pathways in the regulation of

Acknowledgment

I am grateful to Pierre Clement for many helpful discussions and advices during the writing of this review.

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