Behavioral effects of selective dopaminergic compounds in rats discriminating cocaine injections.
The involvement of dopamine receptor subtypes in the discriminative stimulus effects of cocaine was evaluated by the ability of a series of compounds selective for D1 or D2 dopamine receptors to produce discriminative stimulus effects comparable to cocaine. Male, Sprague-Dawley rats were trained to discriminate 10 mg/kg of cocaine HCI from saline in a two-lever discrimination procedure. Inhibitors of catecholamine and serotonin reuptake (GBR 12909, WIN 35,428 and mazindol), d-amphetamine, and the nonselective dopamine agonist, apomorphine, produced dose-dependent increases in cocaine-appropriate responding and fully substituted for cocaine. Cocaine methiodide, a charged, quaternary cocaine analog, did not substitute for cocaine. Neither pentobarbital, haloperidol nor SCH 23390 produced cocaine-like behavioral activity. Both D1- and D2-selective agonists with diverse structures partially substituted for cocaine, producing from 40 to 80% cocaine-appropriate responses. The D1 agonists studied were SKF 38393 and stereoisomers, SKF 75670 and CY 208-243. Dihydrexidine, a full D1 agonist for induction of adenylate cyclase activity, also only partially substituted for cocaine. The peripherally acting D1 agonist, fenoldopam, produced predominantly saline-appropriate responding that was unrelated to dose. The D2 agonists tested were pergolide, quinpirole, (-)-NPA, RU 24213, N-0434 and N-0437. The D2 antagonist haloperidol did not block the discriminative stimulus effects of cocaine. In contrast, the D1 antagonist SCH 23390 reduced the discriminative stimulus effects of cocaine by a maximum of 50%. These results suggest that both D1 and D2 receptors may play a role in the discriminative stimulus effects of cocaine but that stimulation of either dopamine receptor subtype alone is not sufficient.
Drug Development Group, National Institute on Drug Abuse Addiction Research Center, Baltimore, Maryland.
J M
JM
Witkin
D E
DE
Nichols
P
P
Terry
J L
JL
Katz
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*
D001552:Benzazepines; D015259:Dopamine Agents; D011954:Receptors, Dopamine; D003042:Cocaine