Hypocretin (orexin) is a neuropeptide synthesized by lateral hypothalamic neurons that project widely throughout the CMS, including to regions of the brain that have been linked to the addictive actions of opioids and nicotine. Hypocretin plays a key role in activation of many brain circuits related to attention and arousal. Absence of hypocretin or its receptor results in narcolepsy, a neurological disease characterized by continued bouts of intense sleepiness during the day, both in animals and humans. Hypocretin neurons also play a role in addiction to opiates. Despite a growing interest in the role of these neurons in substance abuse, almost nothing is known about the cellular physiology of the responses of hypocretin cells to opiates. To facilitate the study of hypocretin neuron neurophysiology, transgenic mice that express GFP selectively in hypocretin neurons will be used. Whole cell patch clamp recording will be used to understand the role of dynorphin, an opioid neuropeptide cosynthesized with hypocretin. The hypothesis that hypocretin neurons are inhibited by dynorphin will be tested. Electron microscopy and immunocytochemistry will be used to study the subcellular localization of the dynorphin neuropeptide, and converging electrophysiological experiments will be used to address the hypothesis that dendrites and axons contain and release the opioid peptide, and that identified neurons postsynaptic to hypocretin axons show diverging responses to hypocretin and dynorphin. We will test the hypothesis that dynorphin receptors desensitize before hypocretin receptors, freeing postsynaptic neurons from opioid inhibition. Long term effects of the opiate morphine will be studied in brain slices after chronic morphine exposure in vitro and in vivo. The most common addictive substance is nicotine, found in tobacco. Nicotine increases general arousal, similar to the actions of hypocretin neurons. The hypothesis that nicotine has a direct action on hypocretin cells, and that long-term exposure will alter the physiology of these cells, will be tested. These experiments will provide a better understanding of the role hypocretin neurons play in the common lack of arousal and lethargic state shown by opiate users, and the arousal response to nicotine. Hypocretin neurons may thus serve as a future target for treatment of addictive drugs that alter the arousal state. Understanding the role of the endogenous opioid in hypocretin cells should also facilitate the understanding and treatment of narcolepsy. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Mitler, Merrill
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Yale University
Schools of Medicine
New Haven
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Li, Ying; Xu, Youfen; van den Pol, Anthony N (2013) Reversed synaptic effects of hypocretin and NPY mediated by excitatory GABA-dependent synaptic activity in developing MCH neurons. J Neurophysiol 109:1571-8
Zhang, Xiaobing; van den Pol, Anthony N (2013) Direct inhibition of arcuate proopiomelanocortin neurons: a potential mechanism for the orexigenic actions of dynorphin. J Physiol 591:1731-47
Zhang, Xiaobing; van den Pol, Anthony N (2012) Thyrotropin-releasing hormone (TRH) inhibits melanin-concentrating hormone neurons: implications for TRH-mediated anorexic and arousal actions. J Neurosci 32:3032-43
van den Pol, Anthony N (2012) Neuropeptide transmission in brain circuits. Neuron 76:98-115
Yao, Yang; Fu, Li-Ying; Zhang, Xiaobing et al. (2012) Vasopressin and oxytocin excite MCH neurons, but not other lateral hypothalamic GABA neurons. Am J Physiol Regul Integr Comp Physiol 302:R815-24
Huang, Hao; Xu, Youfen; van den Pol, Anthony N (2011) Nicotine excites hypothalamic arcuate anorexigenic proopiomelanocortin neurons and orexigenic neuropeptide Y neurons: similarities and differences. J Neurophysiol 106:1191-202
Liu, Meng; Blanco-Centurion, Carlos; Konadhode, RodaRani et al. (2011) Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. J Neurosci 31:6028-40
Fu, Li-Ying; van den Pol, Anthony N (2010) Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism. J Neurosci 30:10205-19
Acuna-Goycolea, Claudio; Obrietan, Karl; van den Pol, Anthony N (2010) Cannabinoids excite circadian clock neurons. J Neurosci 30:10061-6
van den Pol, Anthony N (2010) Excitatory neuromodulator reduces dopamine release, enhancing prolactin secretion. Neuron 65:147-9

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