Role of dopamine D1 receptors in the lethal effects of cocaine and a quaternary methiodide analog

JM Witkin, AH Newman, G Nowak and JL Katz

Drug Development Group, National Institute on Drug Abuse, Baltimore, Maryland.

Acute cocaine overdose can result in convulsions and death although the mechanisms associated with this toxicity are poorly understood. The role of D1 receptors in the central and peripheral actions in cocaine were investigated by comparisons of cocaine with the stable charged cocaine analog, cocaine methiodide. Both cocaine and cocaine methiodide produced dose-related increases in lethality in male, Swiss Webster mice, with cocaine methiodide being slightly more potent than cocaine; however, only cocaine produced convulsions. Several dopamine D1 antagonists ([R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3- benzazepine] (SCH 23390), [(-)-trans-6,7,7a,8, 9,13b- hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naptho++ +-(2-1- b)azepin e (SCH 39166), 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6- methoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline HBr (A-69024), [R-(+)- 7-bromo-8-hydroxy-3- methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine] (SK F83566)) produced dose-dependent protection against the lethal effects of both compounds. Protection against cocaine methiodide-induced lethality was conferred by lower doses of the D1 antagonists than those effective against cocaine. Stereoselectivity of this effect was demonstrated by the lack of activity of the inactive enantiomer of SCH 23390. The D2 antagonist haloperidol was ineffective against either cocaine- or cocaine methiodide-induced lethality. Lethal effects of the nondopaminergic local anesthetic, lidocaine, were not influenced by prior treatment with D1 antagonists. Lethal effects of cocaine were enhanced by both centrally and peripherally acting D1 agonists but not by the D2 agonist quinpirole. Cocaine methiodide- induced lethality was also enhanced by the peripherally active DA1 agonist, fenoldopam.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 267, Issue 1, pp. 266-274, 10/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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