Type of Document	Dissertation
Author	Muschamp, John Whitney
URN	etd-03292007-224556
Title	Hypocretin (Orexin), Dopamine, and Goal-Directed Behavior
Degree	Doctor of Philosophy
Department	Psychology, Department of
Advisory Committee	Advisor Name Title Elaine Hull Committee Chair David Quadagno Committee Member Mohamed Kabbaj Committee Member Thomas Joiner Committee Member Zuoxin Wang Committee Member
Keywords	Hypocretin (Orexin) Reproductive Behavior Neuroendocrinology Motivated Behavior Peptides Dopamine Ventral Tegmental Area
Date of Defense	2007-03-27
Availability	unrestricted
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. 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.
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