Abstract
Chlormethiazole positively modulates the γ-aminobutyric acid (GABA)A receptor complex and is primarily used to treat certain life-threatening neurological events (e.g., refractory seizures and ethanol withdrawal syndrome). On account of several experimental and clinical studies reporting effectiveness against the toxic effects of heroin and methamphetamine, chlormethiazole was systematically tested in the present study for its effectiveness against cocaine-induced seizures and lethality in mice. The protective effects of chlormethiazole were evaluated against single, submaximal convulsive (75 mg/kg) or lethal (110 mg/kg) doses of cocaine. Chlormethiazole also was tested against the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures, and against fully developed kindled seizures. Cocaine-kindled seizures were produced by a total of five daily treatments with 60 mg/kg cocaine. The inverted-screen test was used to assess behavioral side effects of chlormethiazole. Chlormethiazole protected against acute cocaine-induced convulsions (ED50 = 7.0 mg/kg) and lethality (ED50= 21.8 mg/kg) with a robust separation [protective index (PI) = TD50/ED50 = 22.3 and 7.2, respectively] from doses producing behavioral side effects (TD50 = 156 mg/kg). Chlormethiazole suppressed the behavioral expression of cocaine-kindled seizures and prevented the development of sensitization to the convulsant effects of cocaine. It was also effective in suppressing fully developed kindled seizures. Relative to cocaine seizures in naive mice, chlormethiazole was equieffective, less potent (ED50 = 22.3 mg/kg), and had a reduced protective index (PI = 3.7) against cocaine-induced seizures in kindled mice. The protective profile and protective index of chlormethiazole were superior to those of the benzodiazepines clonazepam and diazepam, which were of limited efficacy and had low protective indices (PI = ∼1). The results of this study predict the potential utility of chlormethiazole for the treatment of life-threatening complications of cocaine abuse for which no specific treatment has yet been identified.
Footnotes
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Send reprint requests to: Maciej Gasior, M.D., Ph.D., Behavioral Pharmacology Program, Department of Psychiatry, Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill St., Belmont, MA 02178-9106. E-mail:mgasior{at}mclean.harvard.edu
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↵1 Preliminary findings of this study were presented at the American Society for Pharmacology and Experimental Therapeutics Meeting, Boston, MA, June 4–8, 2000.
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↵2 M.G. was a Visiting Fellow in the National Institutes of Health Visiting Program granted from the Fogarty International Center, Bethesda, MD. Permanent affiliation: Department of Pharmacology, Medical University School, Lublin, Poland. Current address: Department of Psychiatry, Behavioral Pharmacology Program, McLean Hospital, Harvard Medical School, Belmont, MA 02178.
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↵3 Present address: Department of Psychiatry, Johns Hopkins University, School of Medicine, Baltimore, MD 21224.
- Abbreviations:
- GABA
- γ-aminobutyric acid
- CL
- confidence limits
- PEG
- propylene glycol
- PI
- protective index
- RC
- receptor complex
- Received February 16, 2000.
- Accepted June 8, 2000.
- U.S. Government
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