TY - JOUR
T1 - Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal
AU - Georgescu, Dan
AU - Zachariou, Venetia
AU - Barrot, Michel
AU - Mieda, Michihiro
AU - Willie, Jon T.
AU - Eisch, Amelia J.
AU - Yanagisawa, Masashi
AU - Nestler, Eric J.
AU - DiLeone, Ralph J.
PY - 2003/4/15
Y1 - 2003/4/15
N2 - 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.
AB - 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.
KW - CREB
KW - Drug addiction
KW - Melanin-concentrating hormone
KW - Opiate withdrawal
KW - c-Fos
KW - μ-opioid receptor
UR - http://www.scopus.com/inward/record.url?scp=0037659189&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.23-08-03106.2003
DO - 10.1523/jneurosci.23-08-03106.2003
M3 - Article
C2 - 12716916
AN - SCOPUS:0037659189
SN - 0270-6474
VL - 23
SP - 3106
EP - 3111
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 8
ER -