The role of melanocortin receptors in sexual behavior in female rats

doi:10.1054/npep.2000.0815

Neuropeptides

Volume 34, Issues 3–4, August 2000, Pages 211-215

https://doi.org/10.1054/npep.2000.0815 Get rights and content

Abstract

Earlier data have indicated that α-MSH may play a role for sexual behavior in rats. In this study we investigated the effects of MSH peptides on sexual receptivity in ovariectomized-adrenalectomized female rats, pre-treated with benzoate of estradiol, in presence of vigorous male rats. The results show that α-MSH significantly increases lordosis behavior in female rats after injections into the ventromedial nucleus. Interestingly, we have for the first time shown that γ-MSH also causes significant increase in lordosis in female rats. Furthermore, we show that HS014, an antagonist for the central MC receptors, in dose dependent manner blocks the effect of α-MSH on lordosis. The results indicate that the effects of MSH peptides on female sexual behaviour are mediated through a specific MC receptor, which could be the MC3 receptor.

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Cited by (37)

Alpha-melanocyte stimulating hormone immunoreactivity in the brain of the cichlid fish Oreochromis mossambicus
2021, Neuropeptides
Citation Excerpt :
This tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) is derived from the proteolytic cleavage of the precursor molecule, pro-opiomelanocortin (POMC) (Nakanishi et al., 1979). This peptide acts as a neurotransmitter or a neuromodulator and is shown to play diverse roles such as the regulation of skin darkening (Filadelfi and Castrucci, 1994; Höglund et al., 2000), melanogenesis (Hadley et al., 1981), immunity and anti-inflammatory responses (Luger et al., 2003), feeding (Olszewski et al., 2007; Lucas et al., 2014), color change and thermoregulation (van Eys and Peters, 1981; Cooper Jr. and Greenberg, 1992; Nilsson Sköld et al., 2013), luteinizing hormone (LH) secretion (Newman et al., 1985) and sexual behavior (Caquineau et al., 2006; Cragnolini et al., 2000) in different vertebrates. In addition, α–MSH is also released in response to stress in mammals (Khorram et al., 1985) as well as fish (Gorissen and Flik, 2016).
This study reports the distribution of a pro-opiomelanocortin-derived neuropeptide α–MSH in the brain of the cichlid fish Oreochromis mossambicus. α–MSH-ir fibres were found in the granule cell layer of the olfactory bulb, the medial olfactory tract, the pallium and the subpallium, whereas in the preoptic area of the telencephalon, few large α–MSH-ir perikarya along with extensively labeled fibres were observed close to the ventricular border. Dense network of α–MSH-ir fibres were seen in the hypothalamic areas such as the nucleus preopticus pars magnocellularis, the nucleus preopticus pars parvocellularis, the suprachiasmatic nucleus, the nucleus anterior tuberis, the paraventricular organ, the subdivisions of the nucleus recessus lateralis and the nucleus recessus posterioris. In the nucleus lateralis pars medialis, some α–MSH-ir perikarya and fibres were found along the ventricular margin. In the diencephalon, numerous α–MSH-ir fibres were detected in the nucleus posterior tuberis, the nucleus of the fasciculus longitudinalis medialis and the nucleus preglomerulosus medialis, whereas in the mesencephalon, α–MSH-ir fibres were located in the optic tectum, the torus semicircularis and the tegmentum. In the rhombencephalon, α–MSH-ir fibres were confined to the medial octavolateralis nucleus and the descending octaval nucleus. In the pituitary gland, densely packed α–MSH-ir cells were observed in the pars intermedia region. The widespread distribution of α–MSH-immunoreactivity throughout the brain and the pituitary gland suggests a role for α–MSH peptide in regulation of several neuroendocrine and sensorimotor functions as well as darkening of pigmentation in the tilapia.
Ghrelin inhibited serotonin release from hippocampal slices
2011, Peptides
Citation Excerpt :
Animals were injected bilaterally in the hippocampus immediately after training in the step down test with Ghr or artificial cerebrospinal fluid (ACSF) using a 10 μl Hamilton syringe connected by Pe-10 polyethylene tubing to a 30-gage needle. ACSF composition was previously described by Cragnolini et al. [8]. The infusion volume was 0.5 μl bilaterally for the intra-hippocampal, and it was delivered over a 1 min period.
Ghrelin (Ghr) is a peptide produced peripherally and centrally. It participates in the modulation of different biological processes. In our laboratory we have shown that (a) Ghr administration, either intracerebroventricular or directly into the hippocampus enhanced memory consolidation in a step down test in rats (b) the effect of Ghr upon memory decreases in animals pretreated with a serotonin (5-HT) reuptake inhibitor, Fluoxetine, suggesting that Ghr effects in the hippocampus could be related to the availability of 5-HT. It has been demonstrated that Ghr inhibits 5-HT release from rat hypothalamic synaptosomes. Taking in mint these evidences, we studied the release of radioactive 5-HT to the superfusion medium from hippocampal slices treated with two doses of Ghr (0.3 and 3 nm/μl). Ghr inhibited significantly the 5-HT release in relation to those superfused with artificial cerebrospinal fluid (ACSF) (H = 9.48, df = 2, p ≤ 0.05). In another set of experiments, Ghr was infused into the CA1 area of hippocampus of the rats immediately after training in the step down test and the 5-HT release from slices was studied 24 h after Ghr injection showing that in this condition also the 5-HT release was inhibited (H = 11.72, df = 1, p ≤ 0.05). In conclusion, results provide additional evidence about the neurobiological bases of Ghr action in hippocampus.
An ex vivo Multi-Electrode Approach to Evaluate Endogenous Hormones and Receptor Subtype Pharmacology on Evoked and Spontaneous Neuronal Activity within the Ventromedial Hypothalamus; Translation from Female Receptivity
2010, Journal of Sexual Medicine
Citation Excerpt :
Phenylephrine (30 µM) increased SUA (584.4 ± 108.0% of control, P < 0.05, n = 5; Figure 5D). Whilst it is reported that the activation of melanocortin receptors within the VMH increases lordosis [25], evaluation of the endogenous nonselective melanocortin agonist α-MSH (10 µM) revealed no effect on EPSPs (amp 99.0 ± 2.0% of control, P > 0.05, n = 5). α-MSH (10 µM) also had no effect on SUA during the 10-minute perfusion (94.6 ± 9.6% of control, P > 0.05, n = 4).
The ventromedial hypothalamus (VMH) controls female rodent copulatory behavior, which can be modulated by injection of various compounds into the VMH.
The aim was to determine whether evoked excitatory postsynaptic potentials (EPSPs) or single-unit activity within the VMH ex vivo is a better parameter to predict lordosis.
VMH slices were placed onto a 64 microelectrode chip and spontaneous single-unit activity was recorded or slices stimulated to evoke EPSPs.
The sodium channel blocker, tetrodotoxin and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) inhibited EPSPs, confirming EPSPs were glutamatergic in origin. The GABA_A antagonist bicuculline potentiated EPSPs implying endogenous GABA tone. Single-unit activity was abolished by tetrodotoxin but unaffected by DNQX or bicuculline.
Glutamatergic neurotransmission was greatest during metestrous and following ovariectomization. The number of regions within the VMH eliciting single-unit activity was reduced following ovariectomy without changing spike frequency. Adrenergic agents increasing lordosis via the VMH in vivo, decreased glutamate neurotransmission but increased single-unit activity. Conversely, agents decreasing lordosis via the VMH increased glutamatergic neurotransmission and inhibited single-unit activity (8-OH-DPAT, [D-Ala², N-Me-Phe⁴, Gly-ol⁵]-enkephalin, corticotropin releasing factor, bicuculline). Melanocortin and pituitary adenylate cyclase-activating polypeptide agonists had no effect.
Here we present a novel, robust VMH in vitro technique that (i) is consistent with the hypothesis that glutamate via non-NMDA receptors inhibits lordosis; (ii) glutamate is under the endogenous tone of GABA and steroid hormones; (iii) inhibition of lordosis during metestrous and following ovariectomy potentiates glutamatergic neurotransmission; (iv) activation of G_q- and G_i-coupled receptors decreases and increases glutamate neurotransmission, respectively, with an inverse correlation on single-unit activity; (v) activation of G_s-coupled receptors has no direct effect on glutamate or single-unit activity; and (vi) potency, receptor subtypes and localization can be determined prior to in vivo studies. Booth C, Wayman CP, and Jackson VM. An ex vivo multi-electrode approach to evaluate endogenous hormones and receptor subtype pharmacology on evoked and spontaneous neuronal activity within the ventromedial hypothalamus; translation from female receptivity.
Neuropeptide modulation of a lumbar spinal reflex: Potential implications for female sexual function
2009, Journal of Sexual Medicine
Neuropeptides are known to modulate female receptivity. However, even though receptivity is a spinal reflex, the role of neuropeptides within the spinal cord remains to be elucidated.
The aims were to (i) investigate neuropeptides in the lumbosacral region; and (ii) determine how neuropeptides modulate glutamate release from stretch Ia fibers, touch sensation Aβ fibers and Aδ/C pain fibers.
Neuropeptide modulation of the lumbosacral dorsal-root ventral-root reflex in vitro.
Spinal cords were removed from Sprague-Dawley rats in compliance with UK Home Office guidelines. Hemisected cords were superfused with aCSF and the dorsal root (L4–S1) was stimulated to evoke glutamate release. A biphasic reflex response was evoked from the opposite ventral root consisting of a monosynaptic (Ia fibers) and polysynaptic (Aβ, Aδ/C fibers) component.
The µ opioid receptor (MOR) agonist DAMGO inhibited the monosynaptic (EC₅₀ 0.02 ± 0.02 nM) and polysynaptic area (EC₅₀ 125 ± 167 nM) but not polysynaptic amplitude. Oxytocin and corticotrophin releasing factor (CRF) inhibited the monosynaptic amplitude (EC₅₀, 1.4 ± 1.0 nM and EC₅₀ 4.3 ± 3.5 nM, respectively), polysynaptic amplitude (EC₅₀ 18.2 ± 28.0 nM and EC₅₀, 9.5 ± 13.3 nM, respectively), and area (EC₅₀ 11.6 ± 13.0 nM and EC₅₀, 2.8 ± 3.3 nM, respectively); effects that were abolished by oxytocin and CRF₁ antagonists, L-368899 and 8w. Melanocortin agonists solely inhibited the monosynaptic component, which were blocked by the MC_3/4 receptor antagonist SHU9119.
These data suggest endogenous neuropeptides are released within the lumbosacral spinal cord. Melanocortin agonists, oxytocin, CRF, and DAMGO via MC₄, oxytocin, CRF₁, and MOR inhibit glutamate release but with differing effects on afferent fiber subtypes. Melanocortins, oxytocin, CRF, and DAMGO have the ability to modulate orgasm whereas oxytocin, CRF and DAMGO can increase pain threshold. Oxytocin and CRF may dampen touch sensation. Wilson LA, Wayman CP, and Jackson MV. Neuropeptide modulation of a lumbar spinal reflex: Potential implications for female sexual function. J Sex Med **;**:**–**.
Bremelanotide: An overview of preclinical CNS effects on female sexual function
2007, Journal of Sexual Medicine
Citation Excerpt :
The role of MC receptors in the regulation of penile erection, has received increasing attention [21–23]. In female rats, α-MSH has been shown to facilitate or inhibit lordosis depending on the hormonal status of the animals [24–31]. Melanocortinergic neurons are found largely in the arcuate nucleus of the hypothalamus, and project widely throughout the hypothalamus and limbic system.
Bremelanotide is an analogue of the naturally occurring peptide α-melanocyte-stimulating hormone (α-MSH). It stimulates erection in men and male rats, and is currently in clinical trials for the treatment of erectile dysfunction.
To review the effects of bremelanotide, an analogue of the naturally occurring peptide α-MSH, on the preclinical indices of sexual desire in female rats, and where in the brain these actions may occur.
Appetitive sexual behaviors, such as solicitations, hops and darts, and pacing, were assessed along with consummatory behaviors such as lordosis. The involvement of brain regions was assessed following direct administration to the region, by the stimulation of molecular markers of neural activation, and using microdialysis to examine extracellular fluid for different neurotransmitters.
Using a model that allows ovariectomized, hormone-primed female rats to control the timing of sexual encounters with males, we tested the ability of bremelanotide to increase appetitive (proceptive) and/or consummatory sexual behaviors.
Bremelanotide dramatically and selectively increased measures of solicitation in female rats, without altering pacing or lordosis, following both peripheral (subcutaneous) administration or infusions directly into the lateral ventricles or medial preoptic area (mPOA), but not the ventromedial hypothalamus. The mPOA is critical for the display of appetitive sexual behaviors in females and males of a variety of species. Peripheral administration of bremelanotide activates the mPOA and other hypothalamic and limbic regions of the brain involved in sexual behavior, and may work by activating dopamine terminals in the mPOA.
To the extent that solicitations indicate the desire of female rats to engage in sexual activity, bremelanotide appears to possess the behavioral, pharmacological, and neuroanatomical specificity required of a drug in the treatment of hypoactive sexual desire disorders. Pfaus J, Giuliano F, and Gelez H. Bremelanotide: An overview of preclinical CNS effects on female sexual function.
The melanocortin agonist, melanotan II, enhances proceptive sexual behaviors in the female rat
2006, Pharmacology Biochemistry and Behavior
Melanocortins have been reported to play a role in the control of both male and female sexual behavior. The present study examined the effects of melanotan-II (MT-II), a cyclic peptide analogue of alpha-melanocyte stimulating hormone on appetitive and consummatory aspects of female sexual behavior, including aspects of sexual proceptivity (solicitations, hops and darts, ear wiggling, pacing) and receptivity (lordosis). One group of ovariectomized Long-Evans rats (n = 7) was primed subcutaneously with estradiol benzoate (EB) and progesterone (P) (10 μg and 500 μg respectively) and another group (n = 7) with EB (10 μg) and oil (EB alone). Paced mating tests were performed with sexually experienced males in unilevel chambers, which were bisected by a Plexiglas divider containing three holes, through which only the female could pass. MT-II (1 and 3 mg/kg) or saline was injected intravenously 10 min before each 30-min paced mating test. Each female received the 3 treatments. In females primed with EB + P both doses of MT-II increased the number of hops and darts and ear wiggling significantly, but did not alter pacing or lordosis. With EB alone, no effect of MT-II was observed on any of the parameters measured. These results suggest that P can interact with MT-II to increase proceptive behaviors. Because hops and darts are essentially solicitations, made in close proximity to the male, that indicate a desire on the part of females to receive mounts and intromissions, these data suggest that activation of melanocortin receptors may represent a promising mode of action for the treatment of women with hypoactive sexual desire.

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Regular ArticleThe role of melanocortin receptors in sexual behavior in female rats

Abstract

Neuroscience and Biobehaviour

Cell

Biochemistry and Biophysical Research Communication,

Biochemistry and Biophysical Research Communication,

Cell

Biochemical and Biophysical Research Communication

Brain Research,

substituted MSH analogues for the melanocortin receptors, Peptides

European Journal of Pharmacology