Comparison of the effects of the uncompetitive N-methyl-D-aspartate antagonist (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine (ADCI) with its structural analogs dizocilpine (MK-801) and carbamazepine on ethanol withdrawal seizures

K. A. Grant, L. D. Snell, Michael A Rogawski, A. Thurkauf, B. Tabakoff

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

The ability of [(±)-5-aminocarbonyl-10,11-dihydro-5H-di-benzo- [a,d]cyclohepten-5,10-imine (ADCI) and its structural analogs dizocilpine (MK-801) and carbamazepine to block ethanol withdrawal seizures was tested in mice made physically dependent upon ethanol. Three injections of either ADCI (ranging from 1.0-10.0 mg/kg), dizocilpine (ranging from 0.1-1.0 mg/kg) or carbamazepine (ranging from 17-50 mg/kg) were administered during the first 7 hr of ethanol withdrawal. The severity of ethanol withdrawal seizures was rated during the first 11 hr of withdrawal and again at 24 hr after withdrawal of ethanol. ADCI and dizocilpine suppressed the severity and occurrence of the withdrawal seizures in a dose-dependent fashion, whereas carbamazepine was ineffective in blocking the withdrawal seizures. The relative potencies of dizocilpine, ADCI and carbamazepine in suppressing ethanol withdrawal seizures corresponded with the relative potencies of the compounds in displacing [3H]dizocilpine from mouse cortical membrane preparations. These findings are consistent with the suggestion that blockade of N-methyl-D-aspartate-mediated neurotransmission is an effective treatment for decreasing ethanol withdrawal seizures. ADCI also blocked the occurrence of withdrawal-associated whole body tremors, whereas dizocilpine and carbamazepine were ineffective in blocking the tremors. The doses of ADCI, dizocilpine and carbamazepine that resulted in motor incoordination on an accelerating rotarod task were determined in groups of naive mice. Dizocilpine in doses as low as 0.3 mg/kg produced a decreased ability to remain on the rotarod, whereas ADCI up to 30 mg/kg did not affect rotarod performance. The high efficacy and low motor toxicity of ADCI indicates that this compound may be therapeutically useful for treating ethanol withdrawal seizures and other aspects of the ethanol withdrawal syndrome.

Original languageEnglish (US)
Pages (from-to)1017-1022
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume260
Issue number3
StatePublished - 1992
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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