Vol. 285, Issue 3, 1163-1174, June 1998

Drug Discrimination in Methamphetamine-Trained Monkeys: Agonist and Antagonist Effects of Dopaminergic Drugs¹

Jennifer W. Tidey² and and Jack Bergman³

Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts

The involvement of D₁ and D₂ subtypes of dopamine receptors in behavioral effects of methamphetamine was studied in squirrel monkeys using a two-lever drug discrimination procedure. In monkeys that discriminated i.m. injections of 0.3 mg/kg methamphetamine from saline, methamphetamine (0.03-0.3 mg/kg), cocaine (0.1-1.0 mg/kg) and the selective dopamine uptake inhibitor, GBR 12909 (3.0-17.8 mg/kg) produced dose-related increases in responding on the methamphetamine-associated lever and, at the highest doses, full substitution. In contrast, the norepinephrine and serotonin uptake inhibitors, tomoxetine (1.0-17.8 mg/kg) and fluoxetine (0.3-10.0 mg/kg), respectively, did not substitute appreciably for methamphetamine. Substitution for methamphetamine also was observed with the D₁ receptor agonists, SKF 81297, SKF 82958 and dihydrexidine, and the D₂ receptor agonist, (+)-PHNO in the majority of monkeys. Lower-efficacy D₁ or D₂ agonists substituted for methamphetamine either partially (SDZ 208-911) or not at all (SKF 77434, SDZ 208-912). Pretreatment with dopamine receptor blockers [D₁ (SCH 39166, 0.1 mg/kg) or D₂ (remoxipride, 3.0 mg/kg and nemonapride, 0.003 mg/kg)] and low-efficacy agonists [D₁ (SKF 77434; 3.0 mg/kg) or D₂ (SDZ 208-911 and SDZ 208-912; 0.01-0.03 mg/kg)] antagonized the discriminative-stimulus effects of methamphetamine. In separate studies, comparable doses of each of these drugs, except SKF 77434, induced significant levels of catalepsy-associated behavior. These results support the view that both dopaminergic D₁ and D₂ mechanisms mediate the discriminative-stimulus effects of methamphetamine; further, they indicate that selected dopamine D₁ partial agonists may have antagonist actions at doses that do not produce undesirable effects associated with dopamine receptor blockade.