Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers.
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.
Borgland
Stephanie L
SL
Ernest Gallo Clinic and Research Center, Department of Neurology, , University of California, San Francisco, San Francisco, California 94110, USA. Borgland@interchange.ubc.ca
Chang
Shao-Ju
SJ
Bowers
M Scott
MS
Thompson
Jennifer L
JL
Vittoz
Nicole
N
Floresco
Stan B
SB
Chou
Jonathan
J
Chen
Billy T
BT
Bonci
Antonello
A
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology*; D019970:Cocaine-Related Disorders / Q000517:prevention & control; D004041:Dietary Fats / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D009042:Motivation; D009287:Naphthyridines; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000502:physiology; D064446:Orexin Receptors; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000502:physiology*; D012054:Reinforcement, Psychology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D004041:Dietary Fats; C578627:Hcrtr1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea