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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.

0022-3565/98/2853-1163$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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