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 compar isons of Lewis and Fischer 344 inbred rats. Lewis rats have lower D2-like r eceptor and Gi(alpha) levels in nucleus accumbens, an important area in beh avioral responses to cocaine. This study assessed the effects of manipulati ng D2- and D1 levels pharmacologically in these strains. Experiment 1 inves tigated how the D2-like antagonist eticlopride (0.01-0.1 mg/kg), the D1-lik e 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) affecte d 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. Coc aine self-ad ministration (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 effec ts on cocaine self-administration in the strains. Cocaine self-administrati on was decreased in Lewis rats and increased in Fischer 344 rats by SKF 383 93 (1 mg/kg). These data show that manipulating D1- and D2-like receptor av ailability has strain-selective effects on the reinforcing, but not discrim inative stimulus, effects of cocaine that are predicted by inherent differe nces in nucleus accumbens receptor populations.