Sexual Desire Systems & Loss of Libido [Part 2]

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.)

Conclusion

2. Excitatory Systems of Libido (cont.)

B. Norepinephrine (NE):

Norepinephrine plays a facilitatory role in regulating human sexual desire [1]. 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].

CNS norepinephrine system. It arises from the locus coeruleus (LC) and projects to several brain regions, including the medial preoptic area (mPOA) of the hypothalamus.
Brain norepinephrine system. It arises from the locus coeruleus (LC) and projects to several brain regions, including the medial preoptic area (mPOA) of the hypothalamus where sexual desire arises.

α-adrenergic receptors:

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. [3].


NE within the ventromedial hypothalamus increases sexual desire [2]. In females, Clonidine, which is an α2 agonist that reduces NE, inhibits the vaginal response to erotic stimuli and the subjective sexual arousal [6].

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 [2].


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].

β-adrenergic receptors:

It was found that centrally acting β-blockers negatively affect male and female sexual desire [7]. At the level of the pituitary, β-blockers may lower LH release in vivo [10]. 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) [11].


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 [12].


C. Histamine:

As discussed in a previous article, histamine plays a critical role in dopamine-mediated sexual functions, and libido specifically.

Histamine is excitatory to most brain regions
Histamine is excitatory to most brain regions

H1 receptors:

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 [15].


H2 receptors:

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 [16]. H2 receptors modulate Leydig cell steroidogenesis, being stimulatory in nature to sex hormone synthesis and release [17].


H3 receptors:

H3 receptors, being autoreceptors for histamine, also inhibit the release of several neurotransmitters such as acetylcholine, dopamine, norepinephrine, serotonin, glutamate and GABA [18]. 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 [26]. 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 [27]. On the other hand, progesterone inhibits mast cell secretion peripherally [28].


D. Oxytocin:

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) [2].

The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord is an important component of the neural circuits that control penile reflexes in rats, circuits that are commonly referred to as the “spinal ejaculation generator (SEG).”
The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord is an important component of the neural circuits that control penile reflexes in rats, circuits that are commonly referred to as the “spinal ejaculation generator (SEG)."

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 [23]. Oxytocin stimulates conversion of testosterone to dihydrotestostone (DHT) by 5α-reductase in various reproductive tissues [22].


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 [24].


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 [25], which can indirectly stimulate sexual desire.