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

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.