Orexin A/Hypocretin-1 Selectively Promotes Motivation for Positive Reinforcers

• Published in: The Journal of neuroscience Vol. 29; no. 36; pp. 11215 - 11225
• Main Authors: Borgland, Stephanie L, Chang, Shao-Ju, Bowers, M. Scott, Thompson, Jennifer L, Vittoz, Nicole, Floresco, Stan B, Chou, Jonathan, Chen, Billy T, Bonci, Antonello
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 09-09-2009; Society for Neuroscience
• Subjects: Animals; Benzoxazoles - pharmacology; Choice Behavior - drug effects; Choice Behavior - physiology; Cocaine-Related Disorders - prevention & control; Dietary Fats - administration & dosage; Dietary Fats - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - physiology; Male; Motivation; Naphthyridines; Neural Pathways - drug effects; Neural Pathways - physiology; Neuropeptides - antagonists & inhibitors; Neuropeptides - physiology; Orexin Receptors; Orexins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - physiology; Receptors, Neuropeptide - antagonists & inhibitors; Receptors, Neuropeptide - physiology; Reinforcement, Psychology; Urea - analogs & derivatives; Urea - pharmacology
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.6096-08.2009

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.