Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs.
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.
Tidey
J W
JW
Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts, USA.
Bergman
J
J
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D018663:Adrenergic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000009:adverse effects / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D004193:Discrimination Learning / Q000187:drug effects*; D018491:Dopamine Agonists / Q000009:adverse effects / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology; D010078:Oxazines / Q000009:adverse effects / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000187:drug effects*; D012453:Saimiri
D018663:Adrenergic Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004873:Ergolines; D010078:Oxazines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C058081:ecopipam; C062737:N-(2,6-dimethylergoline-8-yl)-2,2-dimethylpropanamide; C042631:naxagolide; D008694:Methamphetamine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C067114:SK&F 77434