Reduced dopamine terminal function and insensitivity to cocaine following cocaine binge self-administration and deprivation

Neuropsychopharmacology. 2005 Aug;30(8):1455-63. doi: 10.1038/sj.npp.1300687.


Despite large numbers of studies describing neuroadaptations caused by chronic cocaine exposure, there remains considerable uncertainty as to whether alterations in dopamine (DA) neurotransmission are responsible for progression into an addicted state. High-intake, 24-h access cocaine self-administration (SA, 10 days) followed by an extended (7 days), but not 1 day deprivation period produces an increased motivation to SA cocaine as measured by a progressive ratio protocol. Following binge cocaine SA and deprivation, the status of DA terminals in the nucleus accumbens (NAc) was investigated using microdialysis in freely moving rats and voltammetry in brain slices. At 1 and 7 days following binge cocaine SA, baseline extracellular DA concentrations in the NAc core were decreased by 40 and 55% of control levels, in the 1 and 7 day deprivation groups, respectively. Acute cocaine (1.5 mg/kg, i.v.) administration increased extracellular DA (350%) in the NAc core of naïve animals but failed to significantly increase DA at 1 or 7 days following binge cocaine SA. The shell of the NAc showed a similar lack of effect of cocaine. Analysis of DA terminals in brain slices showed that cocaine was markedly less effective in inhibiting DA uptake at 1 and 7 days of cocaine deprivation (max effect 40% of control). Electrically stimulated DA release was decreased at 1 day and further decreased at 7 days of deprivation (67 and 49% of control, respectively). The rate of DA uptake was increased (150% of control) following binge SA, irrespective of deprivation period. Finally, presynaptic autoreceptors were subsensitive at both time points, as measured by the ability of quinpirole, a D2-like DA receptor agonist, to inhibit DA release. Thus, the NAc was hypodopaminergic and DA terminals were less sensitive to cocaine following binge cocaine SA and deprivation.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal
  • Brain Chemistry / drug effects
  • Cocaine / administration & dosage*
  • Dopamine / metabolism*
  • Dopamine Agonists / pharmacology
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • In Vitro Techniques
  • Male
  • Microdialysis / methods
  • Nucleus Accumbens / cytology
  • Presynaptic Terminals / drug effects*
  • Presynaptic Terminals / physiology
  • Quinpirole / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Self Administration / methods
  • Substance Withdrawal Syndrome / metabolism*
  • Time Factors


  • Dopamine Agonists
  • Dopamine Uptake Inhibitors
  • Quinpirole
  • Cocaine
  • Dopamine