Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal.
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 mu-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.
Georgescu
Dan
D
Department of Psychiatry, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Zachariou
Venetia
V
Barrot
Michel
M
Mieda
Michihiro
M
Willie
Jon T
JT
Eisch
Amelia J
AJ
Yanagisawa
Masashi
M
Nestler
Eric J
EJ
DiLeone
Ralph J
RJ
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D004343:Drug Implants; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006720:Homozygote; D007028:Hypothalamic Hormones / Q000096:biosynthesis; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D007763:Lac Operon; D008297:Male; D008543:Melanins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009020:Morphine / Q000008:administration & dosage; D009021:Morphine Dependence / Q000378:metabolism* / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D064446:Orexin Receptors; D000068797:Orexins; D010907:Pituitary Hormones / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D017450:Receptors, Opioid, mu / Q000096:biosynthesis; D020218:Response Elements / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000473:pathology
D002352:Carrier Proteins; D004343:Drug Implants; D007028:Hypothalamic Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D010907:Pituitary Hormones; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D017450:Receptors, Opioid, mu; C019463:melanin-concentrating hormone; D009020:Morphine