Cocaine self-administration disrupts mesolimbic dopamine circuit function and attenuates dopaminergic responsiveness to cocaine

Eur J Neurosci. 2015 Aug;42(4):2091-6. doi: 10.1111/ejn.12970. Epub 2015 Jun 28.


Dopaminergic projections from the ventral midbrain to the nucleus accumbens (NAc) have long been implicated in encoding associations between reward availability and environmental stimuli. As such, this circuit is instrumental in guiding behaviors towards obtaining maximal rewards based on previous experience. Cocaine acts on the dopamine system to exert its reinforcing effects and it is thought that cocaine-induced dysregulation of dopamine neurotransmission contributes to the difficulty that cocaine addicts exhibit in selecting environmentally appropriate behaviors. Here we used cocaine self-administration combined with in vivo fast scan cyclic voltammetry in anesthetised rats to examine the function of the ventral tegmental area to NAc projection neurons. Over 5 days of cocaine self-administration (fixed-ratio 1; 1.5 mg/kg/injection; 40 injections/day), animals increased their rate of intake. Following cocaine self-administration, there was a marked reduction in ventral tegmental area-stimulated NAc dopamine release. Additionally, there was a decreased augmentation of stimulated dopamine overflow in response to a cocaine challenge. These findings demonstrate that cocaine induces a hypodopaminergic state, which may contribute to the inflexible drug-taking and drug-seeking behaviors observed in cocaine abusers. Additionally, tolerance to the ability of cocaine to elevate dopamine may lead to increased cocaine intake in order to overcome decreased effects, another hallmark of cocaine abuse.

Keywords: hypodopamine; in vivo; nucleus accumbens; rat; tolerance.

Publication types

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

MeSH terms

  • Animals
  • Cocaine / administration & dosage*
  • Conditioning, Operant / drug effects
  • Conditioning, Operant / physiology
  • Dopamine / metabolism*
  • Dopamine / pharmacology
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Dose-Response Relationship, Drug
  • Extracellular Fluid / drug effects
  • Extracellular Fluid / metabolism
  • Male
  • Models, Neurological*
  • Neurons / drug effects*
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Self Administration
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / metabolism*


  • Dopamine Uptake Inhibitors
  • Cocaine
  • Dopamine