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.
Highlights
Nitric oxide (NO), the gaseous highly diffusible compound produced from the amino acid L-arginine by NO synthases, a family of Ca2+ -calmodulin-dependent iron containing enzymes ([1,2,3,4] and references therein), has been added to the list of neurotransmitters and/or neuromodulators at the level of the peripheral and central nervous system in the 1990s [5,6,7,8,9,10,11,12]
In the paraventricular nucleus (PVN) NO is synthesized by NO synthase located in the cell bodies of oxytocinergic neurons projecting to extra-hypothalamic brain areas and mediating this sexual response
The activation of NO synthase is necessary for the induction of the sexual response induced by dopamine agonists, oxytocin, NMDA, hexarelin peptide analogues and VGFderived peptides, since penile erection does not occur when the enzyme has been previously inhibited, for instance by NO synthase inhibitors injected in the PVN
Summary
Nitric oxide (NO), the gaseous highly diffusible compound produced from the amino acid L-arginine by NO synthases, a family of Ca2+ -calmodulin-dependent iron containing enzymes (e.g., neuronal, endothelial or inducible NO synthase) ([1,2,3,4] and references therein), has been added to the list of neurotransmitters and/or neuromodulators at the level of the peripheral and central nervous system in the 1990s [5,6,7,8,9,10,11,12]. Produced NO travels as a retrograde messenger from the cell bodies in which it has been produced to the excitatory glutamatergic synapses, where guanylate cyclase is localized, activating its production of cGMP which activates the mechanisms that produce long term potentiation in the hippocampus or long-term depression in the cerebellum or vice versa, depending on the neuronal system involved [6,7,12,24] This initial picture is changing continuously, with the discovery of new modes of operation of NO ranging from local signaling to volume-type transmission across various brain regions and nuclei ([26] and references therein). This review has been prepared by considering the results of numerous published highquality studies, including those made in the authors’ laboratories, on the role of central NO in erectile function and sexual behavior in laboratory animals (mainly rats), from penile erection in males to copulation in males and females, and sexual intercourse in humans when available, in order to provide an updated picture of the most recent discoveries and to identify new possible advances that may be useful for realizing new strategies based on the modulation of central NO activity for the therapy of erectile dysfunctions and other sexual disorders
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