A Role for Hypocretin (Orexin) in Male Sexual Behavior

Abstract

The role of hypocretin (orexin; hcrt/orx) neurons in regulation of arousal is well established. Recently, hcrt/orx has been implicated in food reward and drug-seeking behavior. We report here that in male rats, Fos immunoreactivity (ir) in hcrt/orx neurons increases markedly during copulation, whereas castration produces decreases in hcrt/orx neuron cell counts and protein levels in a time course consistent with postcastration impairments in copulatory behavior. This effect was reversed by estradiol replacement. Immunolabeling for androgen (AR) and estrogen (ER␣) receptors revealed no colocalization of hcrt/orx with AR and few hcrt/orx neurons expressing ER␣, suggesting that hormonal regulation of hcrt/orx expression is via afferents from neurons containing those receptors. We also demonstrate that systemic administration of the orexin-1 receptor antagonist SB 334867 [N-(2-methyl-6-benzoxazolyl)-NЉ-1,5-naphthyridin-4-yl urea] impairs copulatory behavior. One locus for the prosexual effects of hcrt/orx may be the ventral tegmental area (VTA). We show here that hcrt-1/orx-A produces dose-dependent increases in firing rate and population activity of VTA dopamine (DA) neurons in vivo. Activation of hcrt/orx during copulation, and in turn, excitation of VTA DA neurons by hcrt/orx, may contribute to the robust increases in nucleus accumbens DA previously observed during male sexual behavior. Subsequent triple immunolabeling in anterior VTA showed that Fos-ir in tyrosine hydroxylase-positive neurons apposed to hcrt/orx fibers increases during copulation. Together, these data support the view that hcrt/orx peptides may act in a steroid-sensitive manner to facilitate the energized pursuit of natural rewards like sex via activation of the mesolimbic DA system.

Sexual behavior in male rodents

“…Therefore, this may be one site at which SSRI antidepressants act to inhibit sexual function. In addition, hypocretin/orexin (hcrt/orx) neurons reside in the LHA and are activated (Fos-ir) following copulation, and the numbers of hcrt/orx neurons decreased after castration (Muschamp et al, 2007). Furthermore, 5-HT inhibits hcrt/orx neurons in the LHA (Li et al, 2002).…”

“…Furthermore, 5-HT inhibits hcrt/orx neurons in the LHA (Li et al, 2002). Therefore, a possible way in which LHA 5-HT inhibits sexual behavior is by inhibiting hcrt/orx neurons, which would remove their facilitative effect on VTA DA cell firing (Muschamp et al, 2007).…”

Accumbens dopamine-acetylcholine balance in approach and avoidance

“…The hypothalamus contains motivational systems for several behaviors, including feeding [44] and mating [45]. Lateral hypothalamic outputs such as orexin cell groups may be coded for feeding, with leptin receptors [46] on some orexin cells and others for mating with inputs that are sensitive to estrogen or androgen [45].…”

Overview of orexin/hypocretin system

“…These observations indicate a strong functional interaction between the orexinergic pathways and the dopaminergic system in the mechanisms of reward and drug addiction. This interaction may underlie the hedonic control of feeding, as well as the facilitating role of orexin in male sexual behavior of rats (Muschamp et al, 2007).…”