Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area.
Hypocretin (orexin) and dynorphin are neuropeptides with opposing actions on motivated behavior. Orexin is implicated in states of arousal and reward, whereas dynorphin is implicated in depressive-like states. We show that, despite their opposing actions, these peptides are packaged in the same synaptic vesicles within the hypothalamus. Disruption of orexin function blunts the rewarding effects of lateral hypothalamic (LH) stimulation, eliminates cocaine-induced impulsivity, and reduces cocaine self-administration. Concomitant disruption of dynorphin function reverses these behavioral changes. We also show that orexin and dynorphin have opposing actions on excitability of ventral tegmental area (VTA) dopamine neurons, a prominent target of orexin-containing neurons, and that intra-VTA orexin antagonism causes decreases in cocaine self-administration and LH self-stimulation that are reversed by dynorphin antagonism. Our findings identify a unique cellular process by which orexin can occlude the reward threshold-elevating effects of coreleased dynorphin and thereby act in a permissive fashion to facilitate reward.
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478.
John W
JW
Muschamp
Jonathan A
JA
Hollander
Jennifer L
JL
Thompson
George
G
Voren
Linda C
LC
Hassinger
Sara
S
Onvani
Theodore M
TM
Kamenecka
Stephanie L
SL
Borgland
Paul J
PJ
Kenny
William A
WA
Carlezon
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007175:Impulsive Behavior / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins; D012201:Reward; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
C497459:Hcrtr1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D064446:Orexin Receptors; D000068797:Orexins; D004399:Dynorphins; D003042:Cocaine
addiction; kappa-opioid receptor; mood; neurotransmission; stress