Effects of convulsants on handling-induced convulsions in mice selected for ethanol withdrawal severity

Abstract

Withdrawal seizure-prone (WSP) mice were genetically selected to express severe handling-induced convulsions (HIC) upon cessation of chronic ethanol vapor inhalation. The HIC is a sensitive measure of CNS excitability, and the current paper compares the effects of eleven convulsant drugs on the HIC in WSP and WSR (withdrawal seizure-resistant) mice, the latter selected for minimal alcohol withdrawal HIC. If WSP and WSR mice were differentially sensitive to a subset of the tested drugs, a common mechanism of action for that subset would imply that genes influencing that mechanism were important in determining ethanol withdrawal severity. All drugs significantly enhanced HIC in WSP mice. The magnitude of enhancement was small for N-methyl-D-aspartate (NMDA), kainic acid, BAY K 8644, Ro 15-4513, and strychnine; greater enhancement in WSP mice was seen after nicotine, and the direct and indirect gamma-aminobutyric acid (GABA) antagonists bicuculline, 3-mercaptopropionic acid, picrotoxin, t-butylcyclophosphorothionate (TBPS), and pentylenetetrazol. Only two drugs, picrotoxin and pentylenetetrazol, had a marked effect on WSR mice: maximal effect of these drugs was equivalent in WSP and WSR mice. However, picrotoxin and pentylenetetrazol were more potent in WSP than in WSR mice. Three other GABA antagonists, bicuculline, 3-mercaptopropionic acid, and TBPS, had a very small effect in WSR mice: these drugs also seemed to be more potent in WSP than in WSR mice. For all other tested drugs, maximal effect in WSP mice was much greater in WSP than in WSR mice.(ABSTRACT TRUNCATED AT 250 WORDS)