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.
The ability of [(+-)-5-aminocarbonyl-10,11-dihydro-5H-di-benzo [a,d]cyclohepten-5,10-imine (ADCI) and its structural analogs dizocilipine (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.(ABSTRACT TRUNCATED AT 250 WORDS)
Grant
K A
KA
Section on Receptor Mechanisms, Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland.
Snell
L D
LD
Rogawski
M A
MA
Thurkauf
A
A
Tabakoff
B
B
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use*; D016291:Dizocilpine Maleate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000431:Ethanol / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000188:drug therapy*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D014202:Tremor / Q000517:prevention & control
D000927:Anticonvulsants; C071316:5-aminocarbonyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine; D002220:Carbamazepine; D000431:Ethanol; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate