International Journal of Impotence Research (2000) 12, Suppl 4, S26±S33 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Neurotransmitters: central and peripheral mechanisms K-E Andersson1* 1Department of Clinical Pharmacology, University of Lund, Lund, Sweden Re¯exive erection initiated by recruitment of penile afferents, involves both autonomic and somatic efferents. The re¯ex is mediated at the spinal cord level, modulated by supraspinal in¯uences, and may use several transmitters. Dopamine, acetylcholine, nitric oxide, and peptides, such as oxytocin and ACTH=a-MSH, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. Peripherally, the balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa, and determines the functional state of the penis. Noradrenaline contracts both corpus cavernosum and penile vessels via stimulation of a1-adrenoceptors. The role of endothelins in the control of penile smooth muscle tone is presently unclear. Neurogenic nitric oxide (NO) is considered the most important factor for relaxation of penile vessels and corpus cavernosum. The role of other mediators, released from nerves or endothelium has not been de®nitely established. International Journal of Impotence Research (2000) 12, Suppl 4, S26±S33. Keywords: CNS pharmacology; erectile dysfunction; autonomic and somatic mechanisms Introduction Central neuromediation The central regulation of erection with processing The central mechanisms in¯uencing the erectile and integration of tactile, olfactory, auditory and response include spinal and supraspinal pathways. mental stimuli, involves many transmitters and Several regions within the central nervous system transmitter systems. This is also the case periph- may be involved.2 Much of the knowledge gained in erally, and the different steps involved in neuro- this area relates to morphological and pharmacolo- transmission, impulse propagation and intracellular gical studies in experimental animal models (eg transduction of neural signals in penile smooth rodents, primates) in which neurochemical pertur- muscles are only partly known. Re¯exive erection bations can be achieved and responses monitored in initiated by recruitment of penile afferents involves a reasonably meaningful way. For example, studies both autonomic and somatic efferents. The re¯ex is in rats have revealed that electrical stimulation of mediated at the spinal cord level and modulated the medial preoptic area,8 the paraventricular by supraspinal in¯uences, and involves several nucleus,9 or the hippocampal formation10 elicits transmitters.1±6 an erectile response. Peripherally, the balance between contractant and relaxant factors controls the degree of contrac- tion of the smooth muscle of the corpora cavernosa, and determines the functional state of the penis: Hydroxytryptamine detumescence and ¯accidity, and tumescence and erection, respectively.6,7 Below a short review is given of some of the 5-hydroxytryptamine (5-HT; serotonin) is present in transmitters=modulators believed to be involved in supraspinal as well as spinal and peripheral sites the control of erectile mechanisms centrally and believed to be involved in sexual behavior. Neurons peripherally. containing 5-HT can be found in the medullary raphe nuclei and ventral medulla reticular forma- tion, including the rostral nucleus paragigantocellu- laris. Bulbospinal neurons containing 5-HT project to the lumbar spinal cord in the rat and cat.2 Fibres immunoreactive for serotonin were largely and *Correspondence: K-E Andersson, Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, densely distributed in the dorsal horn, the dorsal Sweden. gray commissure, the sacral parasympathetic nu- E-mail: [email protected] cleus and the ventral horn. Some serotonergic ®bres Neurotransmitters in ED K-E Andersson S27 occurred in close apposition with retrogradely- lar nucleus, similar experiments have established labelled sacral preganglionic neurons and motor that D2 rather than D1 receptors primarily facilitate neurons and synapses were demonstrated at the erections.17 The mechanism of erection following ultrastructural level.11 paraventricular D2 receptor stimulation apparently 5-HT has been most strongly implicated in the involves oxytocinergic neurotransmission. In addi- spinal pharmacology of erectile function with tion, NO seems to be involved, since apomorphine participation in both sympathetic and parasympa- (given s.c.) increased NOS activity and NO produc- thetic out¯ow mechanisms. Experimental para- tion in the paraventricular nucleus.20 Both the digms in animals have indicated that 5-HT increase in NO and the erectile response to pathways exert a general inhibitory effect on male apomorphine were reduced by NOS inhibition. sexual behavior,12 although these pathways may be inhibitory or facilitatory depending upon the action of the amine at different 5-HT receptors located in the central nervous system.1,13 Noradrenaline Despite this general understanding, con¯icting reports of 5-HT agonists either enhancing or depres- Evidence for noradrenergic effects in the central sing sexual function were recognized and then neuromediation of penile erection is sparse. attributed to the action of multiple 5-HT receptors. However, the current data suggest that increased In accordance with the selective use of 5-HT nor-adrenergic activity stimulates, whereas de- receptor agonists and antagonists, components of creased noradrenergic activity inhibits, sexual male copulatory behavior were found to be dis- function.12,21,22 played variably. The sum of multiple studies suggests that 5-HT2 and 5-HT1A receptors mediate inhibitory effects on penile erection, whereas 5- HT1C receptors mediate facilitatory effects on this Gamma-amino butyric acid 14 function. Stimulation of 5-HT1C receptors in- creased circulating oxytocin,15 and nitric oxide synthase (NOS) inhibitors given by intracerebrovas- Cumulative data resulting from investigations on the role of gamma-aminobutyric acid (GABA) in penile cular administration prevented 5-HT1C-receptor mediated erectile responses,16 suggesting that both erection indicate that this neurotransmitter may function as an inhibitory modulator in the auto- oxytocin and NO were involved in the 5-HT1C- receptor mediated responses. nomic and somatic re¯ex pathways involved in Thus, 5-HT appears to serve various functions in penile erection.1 Recent investigations showed that male sexual function and likely acts as a major activation of GABA(A) receptors in the paraven- modulator of the central neuroregulatory control of tricular nucleus of the hypothalamus reduced penile erection. apomorphine-, N-methyl-D-aspartic acid (NMDA-), and oxytocin-induced penile erection and yawning in male rats.23 Dopamine Oxytocin Dopaminergic neurons have been identi®ed as traveling from the caudal hypothalamus to innervate the lumbosacral spinal cord and dopamine may Hypothalamic supraoptic and paraventricular participate in the CNS regulation of the autonomic nuclei project to spinal centers in¯uencing erectile and somatic components that produce penile function.2 The oxytocinergic spinal projections are re¯exes. Supraspinal dopaminergic neurons also more likely to in¯uence sacral autonomic rather comprise the incertohypothalamic system with than somatic out¯ow.24 Plasma oxytocin concentra- projections to the medial preoptic area and para- tions are known to be elevated in humans following ventricular nucleus. Injection of apomorphine into sexual stimulation. these central nuclei has facilitatory effects on sexual When injected into the lateral cerebral ventricle, behavior,2,17 and produces the `penile erection- the paraventricular nucleus, or hippocampus of stretching-yawning' response. laboratory animals, oxytocin is a potent inducer of Two main types of dopamine receptors, D1 and penile erection. Oxytocin receptors are believed to D2, are associated with erectile function centrally, mediate the erections, since the erectile response is with the latter perceived to predominate in this blocked by the administration of oxytocin antago- effect. In the medial preoptic area, use of selective nists and by electrolytic lesion of the paraventricu- receptor agonists has established that low levels of lar nucleus. Immunoreactive oxytocin-containing dopaminergic stimulation, via D1 receptor in parti- spinal neurons associating with sacral preganglionic cular, facilitates erections.18,19 In the paraventricu- neurons con®rmed by retrograde labelling supports International Journal of Impotence Research Neurotransmitters in ED K-E Andersson S28 the role of oxytocin in the autonomic spinal that occurs in the paraventricular nucleus during circuitry that mediates penile erection.11,25 sexual activity.31 Morphine also prevents apomor- Central oxytocin seems to be involved in the phine-, oxytocin- and NMDA-induced penile expression of penile erection induced not only by erection and yawning by inhibiting NO synthase drugs but also by sexual physiological stimuli, since activity in the paraventricular nucleus through the non-contact erections in rats were reduced dose- stimulation of opioid receptors of the m subtype.32,33 dependently by a selective oxytocin receptor antagonist, given into the lateral ventricles.26 The oxytocinergic system may be in¯uenced by Nitric oxide the