title: Differential effects of D1- and D2-like compounds on cocaine self-administration in Lewis and Fischer 344 inbred rats.
abstract: 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.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Hew Haven, Connecticut, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Haile
authors.forename: T A
authors.initials: TA
authors.lastname: Kosten
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D015259:Dopamine Agents / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005502:Food; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000187:drug effects*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013045:Species Specificity; D015819:Substance Abuse, Intravenous / Q000188:drug therapy / Q000523:psychology
chemical_list: D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003042:Cocaine