Inala epee Resech 2008) 20 1 £208 se Ping bmn Alig ees _(65: ‘nate con 208 $50.00 nocortins in male sexual dysfunction 1 The Center for Marital and Sexual Health of South Florida, West Palm ur involves the interrelationships between sex steroids and th central nervous system (CNS) effects and effects in the ission tomography (PET) and functional magnetic resonance etermine what areas of the brain are activated under sexual we role of various neurotransmitters, neurosteroids and other The role of CNS-acting compounds such as dopamine agonists metion is under active investigation, Melanocortins have CNS. y of bodily functions, The melanocortin agonist bremelanotide ote erections in preclinical models, and may also stimulate ty beyond their erectogonic effects. esearch (2008) 20, $11-S16; doi:10.1038/ijin 2008.17 oanatomy; neurophysiology: CNS-acting agents; melanocortins; Neuroanatomy of male sexual response alves the Sex and the brain id neuro- Sexual arousal can now be studied with such nervous sophisticated tools as PET (positron emission genitalia. tomography) and {MRI (functional magnetic reso- years in mance imaging) scanning to determine what areas of iining to the brain are activated under sexual stimulation.’ interplay Using these techniques. when sexually stimulated, roids in the activation of the right subinsular/insula region or facili- including the claustrum has been demonstrated using both {MRI and PET scanning techniques.” se, three Other brain regions that have been reported to be » first is activated during visual sexual stimuli include the orders of II not be irmaceuti- Blue Bell, right middle gyrus, right temporal gyrus, left caudate and putamen, bilateral cingulate gyri, right sonsimotor and pre-motor regions.' Other studios have shown activation of the cerebellum in response to visual erotic stimuli as well as viewing pictures of sexual partners. In addition, PET scan studies have shown differences in brain’ activation among men with normal compared with hypoactive sexual responses when viewing sexual stimuli of varying grades of intensity.’ In men with hypoactive sexual desire disorder, prolonged activation of the medial orbitofrontal cortex, which is involved in general inhibition of motivation, was seen. Men also appear to have different brain activation patterns than women in response to sexual stimuli." In this study, men displayed greater activation of the hypothalamus and amygdala compared with women overall in response to visual stimuli, Women who reported increased sexual arousal after being Preclinical effects of mela AM Shadiack! and $ Althof “Locus Pharmaceuticals, Bie Bell, PA, USA anc Beach, FL, USA ‘The neurobiology of sexual behavie neurotransmitters that resull in bo genitalia, Tools such as positron em imaging (OMRI) scanning can help d stimulation, Our understanding of t CNS-acting compounds is improving. in the treatment of male sexual dystu and peripheral roles in a wide variet ‘appears to act in the CNS to prom behaviors that facilitate sexual activi International Journal of Impotence fi Keywords: erectile dysfunction; nour bremelanotide Introduction ‘The neurobiology of sexual behavior inv interrelationships between sex steroids an transmitters that result in both central system (CNS) effects and effects in the Despite the advances made over the past 2¢ male sexual dysfunction, we are just beg) understand the incredibly intricate between neurotransmitters and neuroste tho CNS and periphery as initiators and/ tators of the sexual response cyclo. ido, or desire to engage in sexual behav second is the erectile response, whicl ultimate end-organ manifestation of motivation and arousal. Although interrel: can have arousal without desiro and vice v third major area of male sexuality is dis orgasm and ejaculation; however, this wi covered in this review. Correspondence: Dr AM Shadiack, Locus Phi cals, 4 Valley Square, 512 Township Line Road, PA 19422, USA. E-mail: ashadiack@locuspharma.com512 ut of anata al sol duction TM Stach an et presented the erotic visual stimuli showed similar activation of the hypothalamus and amygdala. This may explain why men have a greater sensitivity to visual sexual stimuli than women, In the supraspinal area, studies in animals have identified the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus, and hippocampus as important centers for sexual function and penile erection." In particular, the MPOA appears to be critical for male sexual behavior in all vertebrate species.’ The nuclei of hypothalamic neurons contain several neurotrans- milters that may be involved in penile erection, although the precise role and sequence of their activity remains to be elucidated. Neural innervation of the penis Input from the brain is relayed through descending spinal pathways to the penis through lumbar sympathetic and sacral parasympathetic outflows.” Basal antierectile tone in the flaccid state is mediated by sympathetic innervation of the pelvis, issuing from spinal segments T11 to L2." ‘The dorsolumbar spinal cord is the source of sympathetic pro-erectile pathways.” Preganglionic sympathetic fibers reach the penis via the lumbar splanchnic nerves or the paravertebral sympathetic chain, which relay ganglionic neurons in. the hypogastric plexus or in tho paravertebral sympa- thetic chain ganglia, Sympathetic postganglionic axons reach the penis through the hypogastric nerve, the paravertebral sympathetic chain and the paravertebral sympathetic chain via the pudendal nerve to the penis (Figure 1). Axons from pregan- glionic parasympathetic neurons emanate from sacral parasympathetic nuclei, establishing synapses in the pelvic plexus via the pelvic’ norve. ital tract, B, ‘dorsal Figure 1 Extrinsic innervation of the male blatider: CN, cavernous nerve: CP, celiac plex penile nerve: HN, hypogastic nerve: IMG, ‘ganglion: ISN. inforior spermatic nervo: P,'prostate: PN, pel here: PudN, pudendal nerve; SC, paravertebral sympathetic Chain; SSN, superior spermatic nerve; SV, seminal vesicles; VD, ‘as deferens, [lumbar T, thoract; and S, sacral segments ofthe Spinal cord." From Giuliano P ot al” with permission from Elsevier. ‘ert Joural of pte sah Parasympathetic postganglionic fibers reach the ponis via the cavemous nerve. Penile erection is seen when sacral cord, sacral roots, sacral nerves, the pelvic nerve or the cavernous nerve is stimu: lated. Neurobiology of sexual response ‘The central neurochemistry mediating sexual beha- viors include biogenic amines (dopamine, seroto- nin, noradrenaline and adrenaline) and_peptides (oxytocin, prolactin and melanocortins) that affect the spinal network control of penile erection." In addition, steroid hormones facilitate the sexual response process, most likely by facilitating changes in tho release or effectiveness of one or more neurotransmitters.” Dopaminergic drugs have long been known to facilitate masculine sexual behavior. Although the D2 receptor family soams to bo responsible for most of the behavioral effects of dopamine, D1 receptors also may play a role in sexual response." Rodent studies have concluded that dopamine is involved in anticipatory rather than in consummatory moti- vational sexial responses. Quail models have proposed that dopamine activates 2-2-noradrenergic Teoeptor in the MPOA.¥ Peripheral dopamine D1 and D2 receptors have beon identified in both rat and human seminal vesicles; however, the role of peripheral dopamine has not been established." In a study of human volunteers, a single dose of levodopa facilitated somatic motor responses to sexual stimuli among men, but not women," Parkinson disease patients treated with dopaminer- gic substances such as apomorphine, levodopa or bromocriptine report the occurrence of erections and increased libido or an improved sexual interest. Serotonin appears to inhibit sexual function; however, this effect is most likely subtype specifi An increase in the concentration of the primary serotonin metabolite SHIAA in the nucleus accum bens and the MPOA after ejaculation suggests thi serotonin is involved in sexual satiety."® Inhibition of the 5-H zc receptor results in decreased sexual behavior in rats and retarded ejaculation in man, whereas 5-HT 4 inhibition does not produce similar effects." However, 5-HT1a receptor effects may depend upon location of tho recoptor in the brain as well as the lovel of activation (that is, dose effect). In rats, increasing serotonin by microinjection of solective serotonin reuptake inhibitor into the lateral hypothalamic area increased the latency time of onset of copulation as well as the latency to the first ejaculation.” Other CNS-acting peptides also play a role in sexual response, Prolactin influences the sexual excitement phase.” Hyperprolactinemia in mon has been associated with a variety of effects, such as lossof libido, erectile dysfunction, gynecomastia, re- duced seminal volume and ejaculatory dysfunctioi Dopamine lowers prolactin levels and dopaminergic agents are the treatment of choice for prolactino- mas." Oxytocin is present in the paraventricular and. supraoptic nuclei of the hypothalamus." ral oxytocinergic neurons project to other areas of the brain and the spinal cord, where they are thought to influence memory, ‘learning, sexual behaviors—including penile erection and the post- orgasmic feeling of sexual satiety—as well as behaviors such as social attachment and bonding” Tho interaction between steroids and neurotrans- mitters in the CNS is still an area of active investigation.”" Steroid hormones easily cross the blood-brain barrier, where extensive steroid meta- whether originating, from outside the CNS or synthesized de novo in the brain, modulate a wide range of neurotransmitters in the brain, including GABA (-aminobutyric acid), NMDA (N-mothyl-d-aspartate}, and nicotinic, mus- carinic, sorotonin (5-HT,), kainate, glycine and sigma receptors. Nitric oxide (NO) is the pri chanism for penile erection. As reviewed elsewhere in this supplement, the endothelium of the penile vasculature is a major source of NO, and distur bances in endothelial function have been shown to be associated with erectile dysfunction of varying dogroes of severity. Neuronal NO also plays an important role in erectile function. nNOS (neuronal NO synthase) is found in cavernous nerves and their terminal end- ings within the corpora cavernosa, as well as in the nerve plexuses in the adventitia of the deep cavernous arteries and the branches of the dorsal penile nerves.”* In the CNS, the PVN contains a significant amount of NOS." Apomorphine and other dopamine agonists have been shown to increase NOS activity within oxytocinergic neurons in the PVN, and NO donors such as nitroglycerin or nitroprusside induce erections when injected into the PVN. NO also promotes the release of dopamine in the MPOA. Microinjection of an NOS inhibitor into the MPOA of sexually naive rats inhibited their ability to copulate, suggesting that NO may play both a central and a peripheral role in sexual response,” In the GNS, steroids such as androgens, estrogens and progestins interface with neurotransmitters, principally dopamine, to facilitate copulatory beha- viors.” In both men and women, this interplay occurs simultaneously in the brain’ and periphery, changing the person's desire for sexual activity as well as enhancing physiological readiness for sex. In rat studies, testosterone was found to promote increased dopamine release in the MPOA in response to the presence of a female behind a clear barrier.”* Tastosterone also appears to uprogulate NOS activity in male rats. Increased NO production ary signaling me- lets of melanocertin nasal dstuncton AM Stark ard § At leads to an increased release of dopamine in both basal and sexual contexts, ultimately resulting in greater response to sexual stimuli. Melanocortins Melanocortins are @ group of small protein mole- cules that share the same precursor molecule, POMC (proopiomelanocortin).*” These peptides include ACTH (adrenocorticotropic hormone), the melano- cyte-stimulating hormones (a-MSH, B-MSH and y-MSH), fF and y-lipotropin, and B-endorphin, In tho GNS, melanocortins may act as neurohormones or neurotransmitters, regulating numerous functions, within the neuronal systems in which they are synthesized and secreted.” It has ben proposed that melanocortins, oxytocin and dopamine use a common pathway in the CNS that involves activa- tion of NO to control erection.” Five molanocortin receptors havo been identified. that are associated with such diverse biological functions as skin pigmentation, food intake, the sloep-wake cycle and sexual response. Investiga- tions into the role of the melanocortin system on sexual response has focused on the melanocortin 3 (MC3R) and melanocortin 4 (MCAR) receptors in the CNS. There is abundant expression of both MC3R and MCAR in the brain and in poripheral_gonital sensory outputs (Figure 2).°” However, MCAR has, been shown to modulate erectile function and sexual behavior, whereas MC3R has not been shown, to have a pro-erectile effect.” MCAR is expressed in the rat and human penis, as well as in rat spinal cord, hypothalamus, brainstem and pelvic ganglion, but not in rat corpus cavernosal smooth muscle cells, In mice, administration of an MC4R agonist increased copulation, whereas knockout mice lack- ing the gene encoding for the receptor showed decreased copulatory behavior. Melanocortins and erection Preclinical work conducted indicate that melano- cortins promote erection primarily through activity in the CNS. Both ACTH and a-MSil injected into the hypothalamic periventricular region of the third vontriclo of male rats resulted in increased lovels of penile erection, as well as strotching, yawning and grooming.” However, neither caused those effects when injected into the preoptic area, the caudate nucleus or the CA1 field of the hippocampus. In a different rat model, 10min after intracorebro- ventricular administration of 2-MSH, there was a 10-fold increase in the frequency of penile erec- tions.®” Increases in erection frequencies were seen by injocting both ACTH and a-MSH directly into PVN of the hypothalamus. Blocking the MC4R with S13 ntti esac