Repeated cocaine modifies the mechanism by which amphetamine releases dopamine

J Neurosci. 1997 May 1;17(9):3254-61. doi: 10.1523/JNEUROSCI.17-09-03254.1997.


This study determined whether daily cocaine administration initiates a calcium requirement for the increase in extracellular dopamine produced by psychostimulants. The increase in extracellular dopamine induced by perfusion of amphetamine through a microdialysis probe in the nucleus accumbens shell was enhanced in cocaine- relative to saline-pretreated rats. The augmented portion of the amphetamine-induced increase in nucleus accumbens dopamine was abolished by the coperfusion of L- or N-type calcium channel blockers. Inhibition of calcium/calmodulin-dependent protein kinase II (CaM-KII) also prevented the augmented increase in dopamine by amphetamine, whereas inhibition of vesicular exocytosis by botulinum toxin B was ineffective. When the concentration of extracellular dopamine in the nucleus accumbens was elevated by blocking the plasmallemal dopamine transporter with GBR-12909, the augmented increase in extracellular dopamine in rats sensitized to repeated cocaine was blocked by a CaM-KII inhibitor. Pretreatment with botulinum toxin B prevented the increase in extracellular dopamine by GBR-12909 in both cocaine-pretreated and control rats. Taken together, these results demonstrate that the psychostimulant-induced enhanced increase in extracellular dopamine in the nucleus accumbens shell of cocaine-pretreated rats arises from the induction of calcium- and CaM-KII-dependent mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / pharmacology*
  • Animals
  • Behavior, Animal / drug effects*
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Male
  • Microdialysis
  • Rats
  • Rats, Sprague-Dawley


  • Amphetamine
  • Cocaine
  • Dopamine