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The Journal of Neuroscience, January 11, 2006, 26(2):398-405; doi:10.1523/JNEUROSCI.2761-05.2006

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Behavioral/Systems/Cognitive
Direct Involvement of Orexinergic Systems in the Activation of the Mesolimbic Dopamine Pathway and Related Behaviors Induced by Morphine

Minoru Narita,¹ Yasuyuki Nagumo,¹ Seiko Hashimoto,¹ Michiko Narita,¹ Junaidi Khotib,¹ Mayumi Miyatake,¹ Takeshi Sakurai,² Masashi Yanagisawa,³ Tomoya Nakamachi,⁴ Seiji Shioda,⁴ and Tsutomu Suzuki¹

¹Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo 142-8501, Japan, ²Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan, ³Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, and ⁴Department of Anatomy, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan

In this study, we investigated the role of orexinergic systems in dopamine-related behaviors induced by the µ-opioid receptor agonist morphine in rodents. Extensive coexpression of tyrosine hydroxylase with orexin receptors was observed in the mouse ventral tegmental area (VTA). The levels of dopamine and its major metabolites in the nucleus accumbens were markedly increased by the microinjection of orexin A and orexin B into the VTA. The subcutaneous morphine-induced place preference and hyperlocomotion observed in wild-type mice were abolished in mice that lacked the prepro-orexin gene. An intra-VTA injection of a selective orexin receptor antagonist SB334867A [1-(2-methylbenzoxazol-6-yl)-3-[1.5]naphthyridin-4-yl urea] significantly suppressed the morphine-induced place preference in rats. Furthermore, the increased level of dialysate dopamine produced by morphine in the mouse brain was significantly decreased by deletion of the prepro-orexin gene. These findings provide new evidence that orexin-containing neurons in the VTA are directly implicated in the rewarding effect and hyperlocomotion induced by morphine through activation of the mesolimbic dopamine pathway in rodents.

Key words: orexin; opioid; morphine; reward; addiction; dependence

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Received June 24, 2004; revised November 9, 2005; accepted November 11, 2005.

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