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The Journal of Neuroscience, May 2, 2007, 27(18):4870-4881; doi:10.1523/JNEUROSCI.0732-07.2007

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Behavioral/Systems/Cognitive
Cannabinoids Excite Hypothalamic Melanin-Concentrating Hormone But Inhibit Hypocretin/Orexin Neurons: Implications for Cannabinoid Actions on Food Intake and Cognitive Arousal

Hao Huang,^1 * Claudio Acuna-Goycolea,^1 * Ying Li,¹ H. M. Cheng,² Karl Obrietan,² and Anthony N. van den Pol¹

¹Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, and ²Department of Neuroscience, Ohio State University, Columbus, Ohio 43210

Correspondence should be addressed to Dr. Anthony N. van den Pol, Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: anthony.vandenpol{at}yale.edu

Cannabinoids modulate energy homeostasis and decrease cognitive arousal, possibly by acting on hypothalamic neurons including those that synthesize melanin-concentrating hormone (MCH) or hypocretin/orexin. Using patch-clamp recordings, we compared the actions of cannabinoid agonists and antagonists on identified MCH or hypocretin neurons in green fluorescent protein-expressing transgenic mice. The cannabinoid type-1 receptor (CB1R) agonist R-(+)-[2,3-dihydro-5-methyl-3-(4-morpho linylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55,212,2) depolarized MCH cells and increased spike frequency; in contrast, WIN55,212,2 hyperpolarized and reduced spontaneous firing of the neighboring hypocretin cells, both results consistent with reduced activity seen with intracerebral cannabinoid infusions. These effects were prevented by AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], a CB1R antagonist, and by tetrodotoxin, suggesting no postsynaptic effect on either neuron type. In MCH cells, depolarizing WIN55,212,2 actions were abolished by the GABA_A receptor antagonist bicuculline, suggesting that the CB1R-mediated depolarization was attributable to reduced synaptic GABA release. WIN55,212,2 decreased spontaneous IPSCs, reduced the frequency but not amplitude of miniature IPSCs, and reduced electrically evoked synaptic currents in MCH cells. Glutamate microdrop experiments suggest that WIN55,212,2 acted on axons arising from lateral hypothalamus local inhibitory cells that innervate MCH neurons. In hypocretin neurons, the reduced spike frequency induced by WIN55,212,2 was attributable to presynaptic attenuation of glutamate release; CB1R agonists depressed spontaneous and evoked glutamatergic currents and reduced the frequency of miniature EPSCs. Cannabinoid actions on hypocretin neurons were abolished by ionotropic glutamate receptor antagonists. Together, these results show that cannabinoids have opposite effects on MCH and hypocretin neurons. These opposing actions could help explain the increase in feeding and reduction in arousal induced by cannabinoids.

Key words: hypothalamus; orexin; melanin-concentrating hormone; cannabinoid; feeding; arousal

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Received July 28, 2006; revised March 27, 2007; accepted March 27, 2007.

Correspondence should be addressed to Dr. Anthony N. van den Pol, Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: anthony.vandenpol{at}yale.edu

This article has been cited by other articles:

				A. D. de Kloet and S. C. Woods Endocannabinoids and Their Receptors as Targets for Obesity Therapy Endocrinology, June 1, 2009; 150(6): 2531 - 2536. [Abstract] [Full Text] [PDF]

				J. Hara, D. Gerashchenko, J. P. Wisor, T. Sakurai, X. Xie, and T. S. Kilduff Thyrotropin-Releasing Hormone Increases Behavioral Arousal through Modulation of Hypocretin/Orexin Neurons J. Neurosci., March 25, 2009; 29(12): 3705 - 3714. [Abstract] [Full Text] [PDF]

				Y. Li and A. N. van den Pol {micro}-Opioid Receptor-Mediated Depression of the Hypothalamic Hypocretin/Orexin Arousal System J. Neurosci., March 12, 2008; 28(11): 2814 - 2819. [Abstract] [Full Text] [PDF]

				H. Huang and A. N. van den Pol Rapid Direct Excitation and Long-Lasting Enhancement of NMDA Response by Group I Metabotropic Glutamate Receptor Activation of Hypothalamic Melanin-Concentrating Hormone Neurons J. Neurosci., October 24, 2007; 27(43): 11560 - 11572. [Abstract] [Full Text] [PDF]

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