Differential effects of D1- and D2-like compounds on cocaine self-administration in Lewis and Fischer 344 inbred rats

J Pharmacol Exp Ther. 2001 Nov;299(2):509-18.


Genetic factors influence behavioral responses to cocaine as seen in comparisons of Lewis and Fischer 344 inbred rats. Lewis rats have lower D2-like receptor and Gi(alpha) levels in nucleus accumbens, an important area in behavioral responses to cocaine. This study assessed the effects of manipulating D2- and D1 levels pharmacologically in these strains. Experiment 1 investigated how the D2-like antagonist eticlopride (0.01-0.1 mg/kg), the D1-like antagonist SCH 23390 (0.005-0.05 mg/kg), the D2/D3 agonist quinpirole (0.001-0.1 mg/kg), and the partial D1 agonist SKF 38393 (0.1-10 mg/kg) affected responding for food under a fixed ratio 15 schedule. Quinpirole disrupted rates more readily in Lewis versus Fischer 344 rats. In experiment 2, the effects of these agents on cocaine discrimination (10 mg/kg) were examined. Quinpirole substituted and SCH 23390-attenuated cocaine discrimination in both strains. Doses of the drugs that did not disrupt responding in these experiments were tested in cocaine self-administration in experiment 3. Cocaine self-administration (0.25-1.0 mg/kg) was increased by eticlopride (0.03 mg/kg) in Lewis rats but had no effect in Fischer 344 rats, whereas SCH 23390 (0.01 mg/kg) led to greater increased cocaine self-administration in Fischer 344 versus Lewis rats. The dopamine agonists had differential effects on cocaine self-administration in the strains. Cocaine self-administration was decreased in Lewis rats and increased in Fischer 344 rats by SKF 38393 (1 mg/kg). These data show that manipulating D1- and D2-like receptor availability has strain-selective effects on the reinforcing, but not discriminative stimulus, effects of cocaine that are predicted by inherent differences in nucleus accumbens receptor populations.

Publication types

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

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / drug therapy
  • Cocaine-Related Disorders / psychology*
  • Conditioning, Operant / drug effects
  • Discrimination, Psychological / drug effects
  • Dopamine Agents / pharmacology
  • Dopamine D2 Receptor Antagonists
  • Dopamine Uptake Inhibitors / pharmacology*
  • Food
  • Male
  • Rats
  • Rats, Inbred F344
  • Rats, Inbred Lew
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / drug effects*
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / drug effects*
  • Reinforcement, Psychology
  • Self Administration
  • Species Specificity
  • Substance Abuse, Intravenous / drug therapy
  • Substance Abuse, Intravenous / psychology


  • Dopamine Agents
  • Dopamine D2 Receptor Antagonists
  • Dopamine Uptake Inhibitors
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Cocaine