Ht

1C,2C

5HTiD 5HT2

5HT3

Activate adenylate cyclase ("cAMP ♦ excitatory) Inhibit adenylate cyclase (JcAMP ♦inhibitory)

"Intracellular ca

Inhibit adenylate cyclase (JcAMP)

JcAMP JcAMP

"Phostidylinositol turnover (similar to 5HT1-B)

Similar to 5HTC1-C and linked phosphatidyl turnover

"Inflow of Na and Ca

Facilitate

Facilitate l-DOPA (+)

Apomorphine (+) Inhibit

Inhibit

(Activation of a-2 adrenoreceptor in the MPOA is associated with decrease in sexual behavior) Inhibitory (? facilitatory) 80H-DPAT (+) Inhibit (? facilitate)

Facilitatory (direct stimulation of 5HT1C and 2C causes erection) m-CPP/Trazodone (+)

Inhibit/facilitate (agonist inhibit erection but facilitate seminal emission and ejaculation) Facilitate/inhibit

Acetylcholine ACh

(somatic and Nicotinic visceral nuclei Muscarinic (Mj-M3) Act via G protein

Enkephalins mu

GABA GABAa Open C1 channel

GABAb jRelease other neurotransmitter

Oxytocin Prolactin

Facilitate

Inhibit

Morphine (+) Naloxone (-) (Inhibitory control on central oxytocinergic transmission) Inhibit

Muscimol (+) Bicuculline (-) Inhibit

Baclofen (+) Facilitate

Inhibit (inhibition of dopaminergic activity in the MPOA)

+, receptor agonist; -, receptor antagonist, l-DOPA, precursor of dopamine; apomorphine, dopamine receptor agonist; 8OH-DPAT, 8 hydroxy-2-(di-«-propyl-amino; tetralin, m-CPP, m-chlorophenylpiperazine; GABA, y-aminobutyric acid; cAMP, cyclic adenosine monophosphate; MPOA, medial pre-optic area.

tions, but higher doses micro-injected within dopaminergic neurons comprising the incer-tohypothalamic system have been shown to inhibit erections (215). Conversely, lesions within the substantia nigra (229) or the administration of dopamine antagonists at doses that do not impair motor function depress the copulatory behavior of male rats (227). The pro-erectile activity of dopaminergic neurons appears to be mediated by the release of oxytocin within the PVN and other areas along the incertohypothalamic pathway. Bilateral lesions of the PVN as well as oxytocin receptor antagonists block the apomorphine-induced erections (209,230,231). Although the exact mechanism of dopaminergic activation of oxytocinergic neurons is not clear, it likely occurs via the NOS pathway.

Serotonin (5-HT)

Seven families of 5-HT receptorsas well as several receptor subtypes (denoted by subscripts A-D) have been identified. 5-HT3 receptors are unusual because they are coupled to a cation channel, whereas the remaining 5-HT receptor families act via G proteins. There are two serotoninergic paths within the CNS. One pathway originates in the raphe nuclei and has interconnections throughout the brain, whereas the other pathway originates in the brain stem and continues caudally toward the spinal cord. Generally, serotonin acts to depress male sexual behavior. However, peripheral injection of serotonin agonists has been shown to induce tumescence in both humans and rhesus monkeys, likely by stimulation of parasympathetic pathways (232). Therefore, 5-HT compounds appear to have a central inhibitory effect but have a pro-erectile role peripherally that depends specific receptor subtypes.

Micro-injection studies using 5-HT agonists and antagonists have demonstrated that 5-HT2c agonists play a facilitative role that likely is mediated by parasympathetic targets within the spinal cord. Conversely, 5-HT1A receptors have an inhibitory effect on erection and ejaculation, as shown by systemic administration or micro-injection of agonists within the MPOA (233-237). The pro-erectile action of 5-HT may contribute to the induction of priapism in patients treated with the antidepressant trazodone as well as to the noted increase in erectile activity during REM sleep (238).

Evidence for the role of 5-HT in the control of erectile function was first noted from the alteration in sexual function after injection of serotonin within the CNS and from the discovery of areas rich in serotonergic neurons (e.g., the nPGi; refs. 234, 239-241). As mentioned previously, both facilitative and inhibitory effects have been reported in response to administration of 5-HT, depending on specific receptor subtypes and potential sites of action (242-245). Serotonergic neurons are also found within the intermediate gray matter ofthe spinal cord and innervate pudendal motor neurons (246-249). Tracing studies have shown that 78% of the ipsilateral cells (15% contralateral) in the nPGi that project to the lumbar cord are immunoreactive for 5-HT (246,248). Intrathecal injection of 5-HT inhibits the urogenital reflex in male rats; however, this is blocked by the pre-administration of the 5-HT antagonist methylsergide. Additionally, blockage of descending serotonergic inputs by intrathecal or intracerebroventricular injections of the 5-HT neurotoxin 5,7-dihydroxytryptamine allowed for the urogenital reflex in the nonsignalized male rat (250).

Noradrenaline

Noradrenergic pathways in the brain may exert an inhibitory influence on penile erection. Within the CNS, the most distinct group of noradrenergic neurons is located within the locus ceruleus. These neurons project through the dorsal noradrenergic bundles to innervate the cortex, cerebellum, and hippocampus. Additional projections travel through the ventral noradrenergic bundles to the hypothalamus, hippocampus, cerebellum, and spinal cord (251-255). Connections between the locus ceruleus and hippocampal formation play an inhibitory role on erection, as demonstrated by electrical stimulation of the locus ceruleus and micro-injection of adrenoreceptor agonists (e.g., NE) within the hippocampus in male rats (256). Additional experiments have demonstrated the presence of a-2a (a2a)- and a-2c (a2c)-adrenoreceptor subtypes in the sympathetic and parasym-pathetic preganglionic neurons controlling erection within the rat spinal cord, suggesting that these receptor subtypes play a role in the intraspinal regulation of autonomic outflow (257). a2-adrenoreceptor agonists such as clonidine inhibit erections, whereas the a2-receptor antagonist yohimbine increases sexual activity in rats but not in primates. In at least some species, this discrepancy suggests that the male sexual response is tonically inhibited by a central noradrenergic pathway (258). Furthermore, yohimbine increases sexual motivation, likely by blocking the release of NE from presynaptic a2-receptors.

Endogenous Opioid Peptides and GABA

Administration of opioid receptor agonists to the CNS inhibits—whereas opioid receptor antagonists facilitate—copulatory behavior in male rats (259). Impotence, decreased libido, anorgasmia and the ability to achieve or maintain erection are not uncommon with patients addicted to heroin or methadone (260,261). Spontaneous erections, priapism, and ejaculation occur during withdrawal from narcotics or with the administration of opiate antagonists such as naloxone (261,262). Endogenous opioid production may contribute to impotence (263).

GABA is present at high concentrations within the MPOA in male rats (264,265). This neurotransmitter likely plays an inhibitory role in the control of penile erection. Both GABAa fibers and GABAb receptors have been demonstrated in the spinal cord dorsal horn as well as in the vicinity of sacral parasympathetic and bulbocavernosi motor nuclei (265,266). Administration of GABAa agonists to the CNS reduces apomorphine- and oxytocin-induced erections, whereas GABAa receptor antagonists facilitate copulatory behavior in rats. Moreover, intrathecal injection ofthe GABAb agonist baclofen reduces or abolishes reflexic erections and preserves psychogenic erections in humans. Although the precise mechanism of action remains unknown, activation of GABAa receptors is believed to inhibit penile erection by reducing the activity of NOS within the oxcytocin-ergic neurons that mediate penile erection (267). Additionally, the cerebrospinal fluid levels of GABAA are increased several-fold during the postejaculatory interval, a time when the rats are completely refractory to sexual stimuli (268). GABA has also been shown to have a direct inhibitory effect on sacral preganglionic neurons (269,270). Therefore, it appears that GABA functions as an inhibitory neurotransmitter in the autonomic and somatic reflex pathways involved in erection.

Oxytocin

Micro-injection of oxytocin into the lateral cerebral ventricles, the PVN of the hypothalamus, or the hippocampal formation induces erection (209,230,231,271). Oxytocin-ergic neurons are found within the descending pathways from the midbrain, brain stem, and spinal autonomic centers. Following sexual activity, serum and cerebrospinal fluid levels of oxytocin are elevated (260,272), suggesting that oxytocin functions as excitatory transmitter in the control of penile erection within the hypothalamus (273). As mentioned previously, it seems that the activation of oxytocinergic neurons is mediated by the activation of NOS. Studies performed in male rats have shown a concomitant increase in NO within the PVN in rats treated with oxytocin as well as prevention of oxytocin-induced erections by NOS inhibitors (273).

Prolactin

Long-term exposure to elevated prolactin levels suppresses sexual behavior and reduced potency in men. Moreover, prolactin disrupts genital reflexes, leading to decreased frequency of erections in rats (274,275). This reduction in the number of erections is counteracted by spinal transection (276), implying that the disruption of genital reflexes occurs at a supraspinal site. Ultimately, the mechanism through which prolactin inhibits sexual behavior may originate from alterations in brain dopamine levels. Independently of these observations, prolactin may also affect reduction in testosterone levels, which in turn affect neural mechanisms.

Melanocortin System

Melanocortins (MCs) are bio-active peptides that have been shown to play a role in the neural control of penile erection. Derived from the precursor molecule proopiomelanocortin, cleavage at several sites within the prohormone results in at least eight distinct peptides. Experiments have demonstrated that intracerebroventricular administration of adrenocorticotropic and a-melanocyte hormones induces penile erection, yawning, and stretching (277). These peptides act via MC receptors, five ofwhich have been identified (MCs 1-5). These receptors are found within the CNS in key areas that regulate erection as well as in the peripheral nervous system (e.g., in the corpus cavernosum and glans penis). Receptor activation leads to an increase in cAMP through the activation of adenylate cyclase. Adrenocorticotropic hormone activates all five MC receptors, whereas a-melanocyte hormone activates all but the MC-2 receptor (278,279). Studies have shown that the pro-erectile function of MCs is mediated by the MC-3 and MC-4 receptors, although it is unclear which is the predominant receptor. Human clinical studies using subcutaneous injection of melatonin-II, a synthetic a-melanocyte hormones analog, or intranasal PT-141 have shown a pro-erectile effect in men with erectile dysfunction of psychogenic and organic origin (280,281).

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