Updated: Mar 31
In this part, we continue exploring the excitatory systems of sexual desire. This time, we discuss the involvement of neurotransmitters & neuropeptides such as norepinephrine, histamine, glutamate, oxytocin, and melanocortin. Without further ado, let's jump right in! Note:
For Part 1 of the article, click [here].
Table of contents:
2. Excitatory Systems of Libido (cont.)
B. Norepinephrine (NE):
Norepinephrine plays a facilitatory role in regulating human sexual desire . NE release modulates different aspects of motivation, including sexual desire, with an inverted U‐shaped curve response where an optimal NE transmission supports an optimal level of behavior. Conversely, high or low amount NE are disruptive due to inducing a state of generalized fear or a state of somnolence, respectively [1, 2].
α1-adrenergic receptor is a postsynaptic facilitatory receptor, while the α2-receptor may function as either a postsynaptic receptor or a presynaptic autoreceptor which serves to inhibit the activity of the presynaptic neuron. .
NE within the ventromedial hypothalamus increases sexual desire . In females, Clonidine, which is an α2 agonist that reduces NE, inhibits the vaginal response to erotic stimuli and the subjective sexual arousal .
In males, Clonidine decreases sexual desire and erectile function [4, 5]. Yohimbine, which acts as opposite to Clonidine (α2 antagonist), stimulates sexual desire while also stimulating autonomic penile erection through stimulating nitric oxide (NO) release, and shortening the refractory period .
Since NE follows an inverted U-shaped curve response, it was found that Yohimbine or NE at high doses inhibited sexual function altogether. Conversely, lesions of the NE neurons in the locus coeruleus (LC) increases the duration of the refractory period [1, 2].
It was found that centrally acting β-blockers negatively affect male and female sexual desire . At the level of the pituitary, β-blockers may lower LH release in vivo . Furthermore, β-adrenergic receptors are present on testicular cells and have a stimulatory effects on testosterone production [8, 9].
Effects of Sex Hormones on NE Neurotransmission:
Estradiol, and testosterone (via aromatization) stimulate gene expression of norepinephrine biosynthetic enzymes in the locus coeruleus (LC), namely tyrosine hydroxylase (TH) & dopamine beta-hydroxylase (DBH) .
Progesterone, estradiol and testosterone (via aromatization) enhance phasic, stimulus-evoked release of hypothalamic NE, which is critical for initiation of sexual desire. However, TH expression in the preoptic area and medial hypothalamus remain unchanged .
As discussed in a previous article, histamine plays a critical role in dopamine-mediated sexual functions, and libido specifically.
H1 receptors are stimulatory to tyrosine hydroxylase, long-term potentiation (LTP), NMDA receptors as well as nitric oxide (NO) [13, 14]. Furthermore, H1 receptors are upregulated by estradiol at the ventromedial hypothalamus (VMN), where they promotes sexual arousal .
The H2 antagonists, Cimetidine and Ranitidine, have been shown to cause loss of libido and erectile dysfunction, and it may partially result from reduction in uptake of testosterone . H2 receptors modulate Leydig cell steroidogenesis, being stimulatory in nature to sex hormone synthesis and release .
H3 receptors, being autoreceptors for histamine, also inhibit the release of several neurotransmitters such as acetylcholine, dopamine, norepinephrine, serotonin, glutamate and GABA . As such, it is to be expected that activation of H3 receptors would reduce sexual desire by affecting neurotransmission within the medial preoptic area (mPOA).
Effects of Sex Hormones on Histamine Neurotransmission:
Estradiol increases histamine release within the hypothalamus, leading to suppressive effects on feeding behavior and body weight . This increase in histamine by estradiol also involves the ventromedial nucleus of the hypothalamus (VMN), leading to generalized CNS arousal and facilitation of sexual desire . On the other hand, progesterone inhibits mast cell secretion peripherally .
Oxytocin is a neuropeptide which is involved in bonding, erectile function, and sexual desire. Within the mPOA, it acts to stimulate libido, whereas it stimulate erections by acting on the paraventricular nucleus (PVN) .
Chronic intranasal administration of oxytocin improves sexual parameters such as libido, erectile quality, orgasmic intensity and satiety [19, 20, 21]. Oxytocin is particularly important in stimulating female libido . Oxytocin stimulates conversion of testosterone to dihydrotestostone (DHT) by 5α-reductase in various reproductive tissues .
Intrathecal injection of oxytocin receptor antagonist not only attenuates ejaculation but also affects pre-ejaculatory behavior (i.e. libido) during normal sexual activity in rats .
The gastrin-releasing peptide (GRP) system mediates male sexual reflexes. The spinal GRP system is regulated by androgens and plays an important role in penile erection and ejaculation , which can indirectly stimulate sexual desire.
Effects of Sex Hormones on Oxytocin Neurotransmission:
Estrogen receptor α (ER-α) activation upregulates oxytocin receptor expression both in the brain and periphery , whereas ER-β activation stimulates hypothalamic oxytocin release . Oxytocin neurons of the paraventricular nucleus (PVN) and supraoptic nucleus express GPR30 receptors, and activation of those receptors stimulates oxytocin release .
The combined actions of estradiol (E2) and dihydrotestosterone (DHT) lead to upregulation of oxytocin receptors on the ventromedial hypothalamus (VMH) .
Melanocortins are neuropeptides derived from pro-opiomelanocortin (POMC). They include adrenocorticotrophic hormone (ACTH) and α-melanocyte-stimulating hormone (α-MSH), among several other neuropeptides .
MC3 & MC4 receptors are present on the hypothalamus, the limbic regions and on the reproductive tract. It has been proposed that melanocortins, oxytocin and dopamine use a common pathway in the CNS that involves activation of nitric oxide to control erection in males .
Recently, melanocortins' potential for enhancing sexual desire has been explored. It was proposed that systemic administration of Bremelanotide stimulates DA release in the mPOA through MC4 activation.
This suggests that MCs act presynaptically to increase DA release in the mPOA and such release increases libido through activating D1 receptors. Furthermore, estradiol increased α-MSH in the in the mediobasal hypothalamus of female rats .
Studies using animal models have demonstrated that pre-copulatory behaviors in female rats analogous to sexual arousal are evoked, and preliminary clinical data also suggest a role in promoting sexual desire and arousal in women [33, 34].
Glutamate is the major neurotransmitter in the central nervous system (CNS) and is extensively involved in many aspects of CNS function . Glutamate action is mediated by activation of ionotropic (NMDAR, AMPAR, KAR) and metabotropic glutamate receptors (mGluRs).
Preoptic glutamate plays a role in reproductive behavior through NMDA receptors and mGluR receptors activation . The mPOA lacks mGluR2/3 thus they are not involved in sexual functions. In contrast, mGluR5 blockade selectively inhibits sexual behavior in both appetitive and consummatory phases .
Furthermore, NMDA antagonism in the mPOA impairs copulation and the experience-induced enhancement of male sexual behavior in the rat . These findings suggest that augmented glutamate transmission in mPOA plays an important role in sexual performance, whereas attenuation of glutamate transmission in this brain region would inhibit sexual behavior.
Phasic glutamate release within the mPOA facilitates stimuli-triggered sexual responses, including sexual desire, erection, orgasm, and ejaculation. In fact, selective serotonin reuptake inhibitors (SSRIs) are proposed to impair these functions through attenuation of glutamate release within the mPOA .
Effects of Sex Hormones on Glutamate Neurotransmission:
Estradiol upregulates the expression of NMDA receptors subunit epsilon 4 in the hypothalamus through activation of ER-α receptors, and this effect is found to be essential for the normal sexual behavior in female mice . Furthermore, estradiol induces physical association of neuronal nitric oxide synthase (nNOS) with NMDA receptor in preoptic neurons .
ER-α and ER-β receptors can stimulate mGluRs to initiate intracellular signaling cascades independently of glutamate, through the caveolin proteins. Through this mechanism, estradiol has a rapid influence over all of the functions typically ascribed to G-protein coupled receptor function of mGluRs, being area specific to the hypothalamus, hippocampus, striatum, and the dorsal root ganglion .
However, the mPOA of the hypothalamus is a sexually dimorphic region and it is unknown how these effects would translate in males . It is important to note, however, that estradiol plays a critical role in male libido within the mPOA, an effect likely mediated through ER-α receptors [46, 47].
The excitatory systems of sexual desire are numerous and complex. They include several neurotransmitters, neuropeptides, neurosteroids, and hormones. Furthermore, they influence one another drastically and interact with inhibitory systems of sexual desire. Speaking of which, it was found that inhibitory systems (serotonin, GABA, galanin, endocannabinoids and β-endorphin) exert a more powerful effect on libido than excitatory systems .
What this means is that it's much easier for the brain to suppress libido than to stimulate it and it's a better idea to suppress those inhibitory systems than to stimulate the excitatory systems if one seeks to improve libido.
Part 3 will deal with discussing those inhibitory systems!
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