Abstract
Orexin A/hypocretin-1 (oxA/hcrt-1) is known to be a modulator of dopamine-dependent neuronal activity and behaviors. However, the role of this system in driving motivated behaviors remains poorly understood. Here, we show that orexin/hypocretin receptor-1 (ox/hcrt-1R) signaling is important for motivation for highly salient, positive reinforcement. Blockade of ox/hcrt-1R selectively reduced work to self-administer cocaine or high fat food pellets. Moreover, oxA/hcrt-1 strengthened presynaptic glutamatergic inputs to the ventral tegmental area (VTA) only in cocaine or high fat self-administering rats. Finally, oxA/hcrt-1-mediated excitatory synaptic transmission onto VTA neurons was not potentiated following an arousing, aversive stimulus, suggesting that oxA/hcrt-1-mediated glutamatergic synaptic transmission was potentiated selectively with highly salient positive reinforcers. These experiments provide evidence for a selective role of oxA/hcrt-1 signaling in motivation for highly salient reinforcers and may represent a unique opportunity to design novel therapies that selectively reduce excessive drive to consume positive reinforcers of high salience.
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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Animals
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Benzoxazoles / pharmacology
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Choice Behavior / drug effects
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Choice Behavior / physiology*
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Cocaine-Related Disorders / prevention & control
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Dietary Fats / administration & dosage
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Dietary Fats / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / physiology
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Male
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Motivation*
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Naphthyridines
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Neural Pathways / drug effects
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Neural Pathways / physiology
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Neuropeptides / antagonists & inhibitors
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Neuropeptides / physiology
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Orexin Receptors
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Orexins
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Rats
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Rats, Sprague-Dawley
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / physiology*
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Receptors, Neuropeptide / antagonists & inhibitors
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Receptors, Neuropeptide / physiology*
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Reinforcement, Psychology*
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Urea / analogs & derivatives
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Urea / pharmacology
Substances
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1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
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Benzoxazoles
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Dietary Fats
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Hcrtr1 protein, rat
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Intracellular Signaling Peptides and Proteins
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Naphthyridines
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Neuropeptides
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Orexin Receptors
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Orexins
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide
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Urea