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The Journal of Neuroscience, April 15, 2003, 23(8):3106

BRIEF COMMUNICATION
Involvement of the Lateral Hypothalamic Peptide Orexin in Morphine Dependence and Withdrawal

Dan Georgescu¹, Venetia Zachariou¹, Michel Barrot^{1, 3}, Michihiro Mieda², Jon T. Willie², Amelia J. Eisch¹, Masashi Yanagisawa², Eric J. Nestler¹, and Ralph J. DiLeone¹

¹ Department of Psychiatry, and ² Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, and ³ Unité Mixte de Recherche 7519, Centre National de la Recherche Scientifique, University Louis Pasteur, 67084 Strasbourg, France

The lateral hypothalamus (LH) is implicated in the behavioral actions of drugs of abuse, but the cellular and molecular basis of this role is unclear. Recent identification of neuropeptides localized in LH neurons has allowed for more specific studies of LH function. The LH-specific peptide orexin (hypocretin) has been shown to be important in arousal and sleep regulation. However, orexin cells of the LH project broadly throughout the brain such that orexin may influence other behaviors as well. In this study, we show that orexin neurons, and not nearby LH neurons expressing melanin-concentrating hormone (MCH), have µ-opioid receptors and respond to chronic morphine administration and opiate antagonist-precipitated morphine withdrawal. cAMP response element-mediated transcription is induced in a subset of orexin cells, but not MCH cells, after exposure to chronic morphine or induction of withdrawal. Additionally, c-Fos and the orexin gene itself are induced in orexin cells in the LH during morphine withdrawal. Finally, we show that orexin knock-out mice develop attenuated morphine dependence, as indicated by a less severe antagonist-precipitated withdrawal syndrome. Together, these studies support a role for the orexin system in molecular adaptations to morphine, and demonstrate dramatic differences in molecular responses among different populations of LH neurons.

Key words: µ-opioid receptor; CREB; c-Fos; melanin-concentrating hormone; opiate withdrawal; drug addiction

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2383106-06$05.00/0

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