Hypocretin (Orexin), Dopamine, and Goal-Directed Behavior

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. I report here that in male rats, Fos-immunoreactivity (ir) in hcrt/orx neurons increases markedly during copulation and with estrous female cues, while castration produces decreases in hcrt/orx neuron cell counts and protein levels in a time course consistent with post-castration impairments in copulatory behavior. This effect was reversed by estradiol replacement. Immunolabeling for androgen (AR) and estrogen (ERα) receptors revealed no colocalization of hcrt/orx with AR and few hcrt/orx neurons expressing ERα, suggesting that hormonal regulation of hcrt/orx expression is via afferents from neurons containing those receptors. Double-immunolabeling for ERα and melanin concentrating hormone (MCH) showed no expression of this receptor in MCH cells adjacent to hcrt/orx neurons. I also demonstrate that systemic administration of the orexin-1 receptor (OX1) antagonist SB 334867 impairs copulatory behavior. One locus for hcrt/orx's pro-sexual effects may be the ventral tegmental area (VTA). I show 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.