Oxytocin, Erectile Function and Sexual Behavior: Last Discoveries and Possible Advances

Abstract

A continuously increasing amount of research shows that oxytocin is involved in numerous central functions. Among the functions in which oxytocin is thought to be involved are those that play a role in social and sexual behaviors, and the involvement of central oxytocin in erectile function and sexual behavior was indeed one of the first to be discovered in laboratory animals in the 1980s. The first part of this review summarizes the results of studies done in laboratory animals that support a facilitatory role of oxytocin in male and female sexual behavior and reveal mechanisms through which this ancient neuropeptide participates in concert with other neurotransmitters and neuropeptides in this complex function, which is fundamental for the species reproduction. The second part summarizes the results of studies done mainly with intranasal oxytocin in men and women with the aim to translate the results found in laboratory animals to humans. Unexpectedly, the results of these studies do not appear to confirm the facilitatory role of oxytocin found in male and female sexual behavior in animals, both in men and women. Possible explanations for the failure of oxytocin to improve sexual behavior in men and women and strategies to attempt to overcome this impasse are considered.

Erectile Function and Sexual Behavior: A Review of the Role of Nitric Oxide in the Central Nervous System

“…but also when injected in this hypothalamic nucleus but not in surrounding structures [ 79 , 80 , 81 , 83 , 85 , 86 ] ( Table 1 ). These findings are in line with the fact that apomorphine, oxytocin and NMDA and other compounds such as hexarelin analogues, VGF related peptides and even SR 141716A, a compound that block cannabinoid receptors of the CB1 subtype, induce penile erection by activating oxytocinergic neurons whose cell bodies are located in the PVN and surrounding area, which project to extra-hypothalamic brain areas and to the spinal cord as discussed below ( Figure 2 ) ( Section 2.2.4 ) [ 53 , 54 , 55 , 56 , 57 , 73 ]. Conversely, the failure of L-NAME injected into the PVN of male rats to prevent penile erection induced by ACTH 1-24 and 5-HT 1C receptor agonists, in spite of its ability to prevent such responses when injected i.c.v., suggest that both these compounds induce penile erection by acting on NO synthase at brain sites different from the PVN with a mechanism that does not involve central oxytocinergic neurotransmission.…”

“…In fact, the activation of NO synthase is necessary for the induction of the sexual response induced by dopamine agonists, oxytocin, NMDA, hexarelin peptide analogues and VGF-derived peptides, since penile erection does not occur when the enzyme has been previously inhibited, for instance by NO synthase inhibitors injected in the PVN. Once formed, NO in the PVN activates yet unidentified intracellular targets, apparently different from guanylate cyclase (i.e., ADP-ribosyl-transferases and other iron-containing enzymes [ 4 , 12 , 26 ]), which in turn lead to the activation of oxytocinergic neurons mediating the appearance of the sexual response by releasing oxytocin in sites distant from the PVN, i.e., the ventral tegmental area, hippocampus, amygdala, ventral medulla and the spinal cord [ 40 , 53 , 54 , 56 , 57 ]. Interestingly, NO seems to act as an intracellular rather than an intercellular messenger, since penile erection is not prevented by NO scavenging from the PVN extracellular space with hemoglobin [ 96 , 97 , 103 , 104 , 143 ].…”

“…Penile erection may occur not only during sexual activity but also in other contexts, such as after simple manipulation of the genitalia, or during sleep or erotic fantasies in humans, or in male rats put in the presence of an inaccessible receptive female (non-contact erections), or after treatment with several classes of drugs (i.e., dopamine agonists, serotonin agonists, NO donors, phosphodiesterase inhibitors, soluble guanylate cyclase activators, RhoA-Rho kinase inhibitors, etc.) and neuropeptides [i.e., adrenocorticotropin (ACTH)-melanocyte stimulating hormone (α-MSH)-related peptides, oxytocin, hexarelin analogues, VGF-related peptides (produced by proteolytic cleavage of the protein VGF) and others], acting in the central nervous system or peripherally [ 16 , 40 , 54 , 55 , 56 , 57 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. Depending on the context in which penile erection occurs, it is generally accepted that different central and peripheral neural and/or humoral endocrine mechanisms may participate in the regulation of this sexual response, often in a very complex manner [ 67 ] (see Figure 1 for a schematic representation of central and peripheral neural pathways controlling erectile function and sexual behavior in mammals).…”

“…The studies reviewed above show that the activation of NO synthase in the PVN induced by the stimulation of dopamine, oxytocin and NMDA receptors, and possibly other receptors present in the PVN of male rats, leads to penile erection. Perhaps more importantly, the activation of NO synthase takes place in the PVN not only when penile erection is induced by drugs and/or peptides acting in the PVN, but also when this sexual response occurs in physiological contexts, for instance when sexually potent male rats are put in the presence of an inaccessible sexually receptive female rat (e.g., when male rats show non-contact erections) or during copulation, when in copula penile erections occur ( Table 4 ) (see also Section 2.2.3 and Section 3 ) [ 54 , 77 , 105 ]. Indeed, an increase in NO production (measured by an increase in the concentration of NO 2 − and NO 3 − ) is found in the PVN dialysate of sexually potent male rats that show non-contact erections in the presence of an inaccessible receptive female rat and during copulation [ 77 ].…”

“…Among these, the most studied are the hippocampal formation [ 46 ], the ventral tegmental area [ 47 , 48 ], the ventral subiculum of the hippocampus, the posteromedial cortical nucleus of the amygdala [ 49 , 50 , 51 ], the ventral medulla and the spinal cord [ 52 ]. In many of these areas NO exerts its sexual effects by acting in concert with other neurotransmitters and/or neuropeptides (see Section 6 and [ 53 , 54 , 55 , 56 , 57 ]). Against the role of central NO in erectile function and sexual behavior supported by the above studies, mating and penile erection are normal in neuronal NO synthase knockout mice [ 21 ], in spite of an excess of inappropriate sexual behavior and a marked increase in aggressive behavior [ 58 ].…”