Modulation of cocaine's discriminative stimulus effects by dopamine D(1) agonists in rhesus monkeys.
Dopamine (DA) D(1) agonists are classified as high- or low-efficacy on the basis of in vitro functional measures as compared to DA. In monkeys self-administering cocaine, high-efficacy D(1) agonists have been shown to have reinforcing effects, while low-efficacy agonists do not. However, the relationship between D(1) agonist efficacy and cocaine-like discriminative stimulus effects, particularly in rhesus monkeys, is not clear. The present study investigated the discriminative stimulus effects of a high- (SKF 81297) and a low-efficacy (SKF 38393) D(1) agonist in rhesus monkeys (n=4) trained to discriminate cocaine from saline using a two-lever drug discrimination procedure. In a second experiment, the effects of agonist pretreatments, as well as pretreatment with a D(1) antagonist, on cocaine's discriminative stimulus effects were evaluated. SKF 81297 (0.01-1.7 mg/kg) fully substituted for cocaine in three of four animals (> 80% cocaine-appropriate responding), while SKF 38393 (0.3-10 mg/kg) occasioned < 50% cocaine-appropriate responding in all subjects. When given as a pretreatment, neither agonist altered cocaine's discriminative stimulus effects at the doses tested. In contrast, the D(1) antagonist SCH 23390 attenuated cocaine's discriminative stimulus effects. These results indicate that D(1) agonists have cocaine-like discriminative stimulus effects in rhesus monkeys that are consistent with their in vitro efficacies. However, when given in combination with cocaine, D(1) agonist efficacy does not appear to be a major factor in modifying cocaine's discriminative stimulus effects.
Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA.
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D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000502:physiology
D001552:Benzazepines; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C067113:SK&F 81297; D003042:Cocaine