Decreased plasma cholinesterase activity enhances cocaine toxicity in mice

R. S. Hoffman, G. C. Henry, P. M. Wax, R. S. Weisman, M. A. Howland, L. R. Goldfrank

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


The illicit use of cocaine continues in epidemic proportions. Despite the incidence of life-threatening complications from cocaine use, little is known of the individual determinants of cocaine toxicity. In vitro analysis demonstrating that cocaine is poorly metabolized by the serum of patients with low plasma cholinesterase (PCh) activity (succinylcholine sensitivity) led to the hypothesis that altered PCh activity might modulate cocaine toxicity. An in vivo mouse model was created to test this theory. Mice were pretreated s.c. with either parathion [a mixed plasma and red blood cell cholinesterase (RBCCh) inhibitor], tetraisopropyl pyrophosphoramide (a selective PCh inhibitor) or placebo, and cholinesterase activity was determined at 24 hr. Incremental doses of i.p. cocaine were administered in a controlled and blinded fashion, and lethality was observed. Ten mg/kg s.c. parathion produced a mean suppression of 68 ± 9 and 61 ± 8% of PCh and RBCCh activity, respectively. One mg/kg s.c. tetraisopropyl pyrophosphoramide produced a mean suppression of 78 ± 3 and 9 ± 8% of PCh and RBCCh activity, respectively. Each pretreatment produced a statistically significant increase in cocaine lethality throughout the dose-response curve. Our results suggest that PCh activity is an important determinant of cocaine toxicity. This effect appears to be independent of either RBCCh activity or manifestations of organophosphate intoxication.

Original languageEnglish (US)
Pages (from-to)698-702
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Jan 1 1992

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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