Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration

Psychopharmacology (Berl). 2011 Mar;214(2):415-26. doi: 10.1007/s00213-010-2048-8. Epub 2010 Oct 20.


Rationale: 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.

Objectives: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Addictive*
  • Behavior, Animal / drug effects*
  • Central Nervous System Stimulants / administration & dosage*
  • Cocaine / administration & dosage*
  • Dopamine / metabolism*
  • Infusions, Parenteral
  • Injections, Intravenous
  • Intracellular Signaling Peptides and Proteins / administration & dosage*
  • Male
  • Microdialysis
  • Motivation / drug effects
  • Neuropeptides / administration & dosage*
  • Orexins
  • Potentiometry
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology
  • Reward
  • Self Administration
  • Signal Transduction / drug effects*
  • Time Factors
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism


  • Central Nervous System Stimulants
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins
  • Cocaine
  • Dopamine