Interactions between cocaine and dopamine agonists on cardiovascular function in squirrel monkeys.
Conscious squirrel monkeys were treated i.v. with cocaine and various dopamine agonist drugs. Cocaine produced a dose-dependent increase in blood pressure, heart rate, and the rate-pressure product (RPP). The dopamine D1 receptor agonist (+/-)-6-chloro-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 82958) produced effects comparable to cocaine. The D1 agonist (+/-)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) also produced increases in blood pressure and heart rate but was much less potent than either cocaine or SKF 82958. The partial D1 agonist (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF 77434) did not significantly affect any cardiovascular parameters. The D2 agonist quinpirole slightly decreased blood pressure and increased heart rate. As such, the RPP only slightly increased. The selective dopamine uptake inhibitor 1-[2-[bis-(4-fluorphenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) produced increases in blood pressure, heart rate, and RPP, but again these effects were smaller and only seen at doses higher than cocaine. Effects similar to those with GBR 12909 were seen with the dopamine autoreceptor antagonist cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232). The combination of GBR 12909, SKF 82958, or SKF 77434 with cocaine produced effects that were clearly subadditive. The effects of quinpirole in combination with cocaine were comparable to, or lower than, those of cocaine alone on blood pressure and RPP. The effects on heart rate were additive. Only UH 232 produced additive effects with cocaine for all three measures. As dopamine agonists have been proposed as potential treatments for cocaine abuse, these results suggest that dopamine D1 agonists and uptake inhibitors can be used safely in combination with cocaine. Caution may be warranted, however, with the use of dopamine autoreceptor antagonists in the treatment of cocaine abuse.
Schindler
C W
CW
Preclinical Pharmacology Section, Behavioral Neuroscience Branch, National Institutes of Health/National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224, USA. cschindl@helix.nih.gov
Gilman
J P
JP
Bergman
J
J
Mello
N K
NK
Woosley
R L
RL
Goldberg
S R
SR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D012453:Saimiri
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003042:Cocaine