Abstract
Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Anesthetics, Local / administration & dosage
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Animals
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Animals, Newborn
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Benzoxazoles / pharmacology
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Calcium Channel Blockers / pharmacology
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Cocaine / administration & dosage
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / pharmacology
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Dopamine / metabolism
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Dose-Response Relationship, Drug
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Drug Interactions
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Electric Stimulation / methods
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Excitatory Postsynaptic Potentials / radiation effects
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Immunohistochemistry / methods
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins / pharmacology*
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Lysine / analogs & derivatives
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Lysine / metabolism
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Male
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Motor Activity / drug effects
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Motor Activity / physiology*
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N-Methylaspartate / pharmacology
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Naphthyridines
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Neuronal Plasticity / drug effects*
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Neuronal Plasticity / physiology
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Neuronal Plasticity / radiation effects
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Neurons / drug effects*
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Neurons / physiology
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Neuropeptides / pharmacology*
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Orexins
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Patch-Clamp Techniques / methods
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Protein Kinase C / pharmacology
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Quinoxalines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Synapses / drug effects*
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Synapses / physiology
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Thionucleotides / pharmacology
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Time Factors
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Tyrosine 3-Monooxygenase / metabolism
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Urea / analogs & derivatives
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Urea / pharmacology
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Ventral Tegmental Area / cytology*
Substances
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1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
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5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione
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Anesthetics, Local
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Benzoxazoles
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Calcium Channel Blockers
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Intracellular Signaling Peptides and Proteins
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Naphthyridines
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Neuropeptides
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Orexins
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Quinoxalines
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Thionucleotides
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adenosine-3',5'-cyclic phosphorothioate
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N-Methylaspartate
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Urea
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Cyclic AMP
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Tyrosine 3-Monooxygenase
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Protein Kinase C
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biocytin
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Cocaine
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Lysine
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Dopamine