Effects of chronic d-amphetamine administration on the reinforcing strength of cocaine in rhesus monkeys

Psychopharmacology (Berl). 2010 May;209(4):375-82. doi: 10.1007/s00213-010-1807-x. Epub 2010 Mar 9.


Rationale: Agonist medications have been proven effective in treating opioid and nicotine dependence; results from clinical studies suggest that the indirect dopamine agonist d-amphetamine may reduce cocaine abuse. In preclinical studies, chronic d-amphetamine treatment decreased ongoing cocaine self-administration.

Objectives: The present study extended previous results by determining effects of chronic d-amphetamine treatment on the reinforcing strength of cocaine under conditions in which access to cocaine was suspended during d-amphetamine treatment.

Methods: Daily operant conditioning sessions consisted of morning access to food pellets delivered under a 50-response fixed-ratio schedule and evening access to cocaine (0.005-0.48 mg/kg per injection, i.v.) under a progressive-ratio schedule. After responding maintained by 0.045 mg/kg per injection cocaine stabilized, self-administration sessions were suspended and d-amphetamine (0.01-0.1 mg/kg per hr, i.v.) was administered continuously for 5 days. On the following day, d-amphetamine treatment was discontinued and daily self-administration sessions resumed.

Results: Following termination of d-amphetamine treatment, food- and cocaine-maintained responding was decreased in a dose-related manner. Decreases in the reinforcing strength of cocaine were larger and lasted longer than effects on food reinforcement. However, cocaine self-administration was unaltered if 6 days elapsed between discontinuation of d-amphetamine treatment and the next cocaine self-administration session.

Conclusions: The necessity of a self-administration session in the presence of d-amphetamine suggests that the protracted decrease in cocaine self-administration may be a manifestation of behavioral tolerance. Regarding treatment of cocaine dependence, data suggest that prolonged d-amphetamine treatment may be necessary to produce a sustained reduction in the reinforcing effects of cocaine.

Publication types

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

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Central Nervous System Stimulants / administration & dosage*
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / psychology
  • Conditioning, Operant / drug effects
  • Dextroamphetamine / administration & dosage*
  • Dopamine Agonists / administration & dosage*
  • Dose-Response Relationship, Drug
  • Feeding Behavior / drug effects
  • Infusions, Intravenous
  • Injections, Intravenous
  • Macaca mulatta
  • Male
  • Reinforcement, Psychology*
  • Self Administration
  • Time Factors


  • Central Nervous System Stimulants
  • Dopamine Agonists
  • Cocaine
  • Dextroamphetamine