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

Abstract

Nitric oxide (NO), the neuromodulator/neurotransmitter formed from l-arginine by neuronal, endothelial and inducible NO synthases, is involved in numerous functions across the body, from the control of arterial blood pressure to penile erection, and at central level from energy homeostasis regulation to memory, learning and sexual behavior. The aim of this work is to review earlier studies showing that NO plays a role in erectile function and sexual behavior in the hypothalamus and its paraventricular nucleus and the medial preoptic area, and integrate these findings with those of recent studies on this matter. This revisitation shows that NO influences erectile function and sexual behavior in males and females by acting not only in the paraventricular nucleus and medial preoptic area but also in extrahypothalamic brain areas, often with different mechanisms. Most importantly, since these areas are strictly interconnected with the paraventricular nucleus and medial preoptic area, send to and receive neural projections from the spinal cord, in which sexual communication between brain and genital apparatus takes place, this review reveals that central NO participates in concert with neurotransmitters/neuropeptides to a neural circuit controlling both the consummatory (penile erection, copulation, lordosis) and appetitive components (sexual motivation, arousal, reward) of sexual behavior.

Neuroplastic changes inc‐Fos,ΔFosB,BDNF,trkB, and Arc expression in the hippocampus of male Roman rats: differential effects of sexual activity

“…Finally, this study also confirms that the hippocampus participates in a complex limbic brain circuit connecting areas such as the VTA, Acb, amygdala, and BNST to hypothalamic nuclei (PVN, mPOA) in which neurotransmitters as dopamine and excitatory amino acids, and neuropeptides as oxytocin contribute to mediate the interaction between motivational and consummatory aspects of male sexual behavior (Bratzu et al, 2019; Melis et al, 2007, 2009, 2010; Melis & Argiolas, 2011, 2021a, 2021b; Sanna et al, 2020; Sanna, Bratzu, Argiolas, & Melis, 2017; Succu et al, 2008, 2011). Noteworthy, after sexual activity, differential changes in the expression of BDNF, trkB, c‐Fos, ΔFosB, and Arc, which resemble those found in the hippocampus in this study, also occur in the VTA, Acb and mPFC of sexually naïve and experienced RHA and RLA rats (Sanna et al, 2019).…”

Dopamine, Erectile Function and Male Sexual Behavior from the Past to the Present: A Review

“…Moreover, double labelling immunohistochemistry shows also that oxytocin-labelled neuronal elements are in close proximity to tyrosine hydroxylase-labelled (dopaminergic) neurons or nitric oxide synthase-labelled cell bodies surrounded by intense vesicular glutamate transporter1-stained (glutamatergic) synapses in the bed nucleus sections in which oxytocin injections induce the above responses [ 163 ]. As discussed below ( Section 7 ), these results confirm the involvement of the bed nucleus of the stria terminalis in a complex neural circuit controlling both the consummatory (erectile function and copulatory performance) and the anticipatory phases of sexual behavior (sexual arousal and motivation) through dopaminergic, glutamatergic and oxytocinergic pathways that interconnect often reciprocally in many of the brain areas recalled above [ 100 , 101 , 102 , 161 ] ( Section 8 ).…”

“…Interestingly, dopamine D2-like receptor agonists injected into the PVN at doses that induce penile erection, also increase extracellular dopamine levels in the nucleus accumbens dialysate, being that this increase was abolished by the prior blockade of oxytocinergic receptors in the ventral tegmental area [80,155]. The latter results reveal an important interaction between the activity of incertohypothalamic and mesolimbic dopaminergic neurons that plays a role in the facilitatory effect of dopamine in erectile function and sexual behavior, and are in line with the existence of a neural circuit that participates in the control of both the anticipatory and consummatory phases of sexual behavior [80,101,102,155,161] (Sections 7 and 8).…”

“…This sexual response can take place during sexual activity and in other contexts, for instance after manipulation of the genitalia, during sleep or erotic fantasies in men, or in male rats in the presence of an inaccessible receptive female rat (non-contact erections), or after treatment with different drugs (e.g., dopamine agonists, serotonin agonists, nitric oxide donors, phosphodiesterase inhibitors, soluble guanylate cyclase activators, RhoA-Rho kinase inhibitors, etc.) and neuropeptides [e.g., adrenocorticotropin (ACTH)-melanonocyte stimulating hormone (α-MSH)-related peptides, oxytocin, hexarelin analogues, VGF related peptides and others], which act centrally or peripherally [ 83 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ]. Depending on the context in which this sexual response occurs, it is commonly accepted that different central and peripheral neural and/or humoral endocrine mechanisms may participate in the regulation of penile erections, usually in a very complex manner [ 99 , 100 ] (see Figure 1 for a simplified representation of central and peripheral neural pathways controlling penile erection and sexual behavior).…”

“…Additionally, in this case, the erectile responses of apomorphine and PD 168,077 were the first antagonized by the blockade of dopamine D 2 receptors and the second of the D 4 subtype present in the PVN and both by the blockade of oxytocin receptors in the ventral tegmental area by d(CH 2 ) 5 Tyr(Me) 2 -Orn 8 -vasotocin ( Table 7 ) [ 80 ], as found for the erectile response of oxytocin given to the ventral tegmental area [ 155 , 157 ]. As discussed below ( Section 7 ), in view of the key role of mesolimbic dopaminergic neurons in sexual motivation and reward, these findings have contributed to the hypothesis that incertohypothalamic and mesolimbic dopaminergic neurons participate with central oxytocinergic neurons that originate in the PVN and project to extrahypothalamic brain areas and glutamatergic neurons to a neural circuit that regulates the control of both the consummatory and anticipatory components of sexual behavior [ 98 , 102 , 151 , 161 ].…”