Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration.
BACKGROUND
Recent evidence indicates that the hypocretin/orexin system participates in the regulation of reinforcement and addiction processes. For example, manipulations that decrease hypocretin neurotransmission result in disruptions of neurochemical and behavioral responses to cocaine.


OBJECTIVE
To further assess the relationship between the hypocretin system and cocaine reinforcement, the current studies used microdialysis and in vivo voltammetry to examine the effects of hypocretin 1 on cocaine-induced enhancement of dopamine signaling in the nucleus accumbens core. Fixed ratio, discrete trials, and progressive ratio self-administration procedures were also used to assess whether hypocretin 1 promotes cocaine self-administration behavior.


RESULTS
Infusions of hypocretin 1 into the ventral tegmental area increased the effects of cocaine on tonic and phasic dopamine signaling and increased the motivation to self-administer cocaine on the discrete trials and progressive ratio schedules.


CONCLUSIONS
Together with previous observations demonstrating that a hypocretin 1 receptor antagonist disrupts dopamine signaling and reduces self-administration of cocaine, the current observations further indicate that the hypocretin system participates in reinforcement processes likely through modulation of the mesolimbic dopamine system.
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA. respana@wfubmc.edu
Rodrigo A
RA
España
James R
JR
Melchior
David C S
DC
Roberts
Sara R
SR
Jones
D000704:Analysis of Variance; D000818:Animals; D016739:Behavior, Addictive; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003042:Cocaine / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D007263:Infusions, Parenteral; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage*; D008297:Male; D017551:Microdialysis; D009042:Motivation / Q000187:drug effects; D009479:Neuropeptides / Q000008:administration & dosage*; D000068797:Orexins; D011199:Potentiometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
D000697:Central Nervous System Stimulants; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D003042:Cocaine; D004298:Dopamine