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

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)

Genetic components of ethanol responses.

A powerful technique for determining the role of a particular neurotransmitter in mediating a response to ethanol (EtOH) is the analysis of selectively bred lines of animals. Lines selected for sensitivity and resistance to an EtOH effect differ principally in gene frequencies for genes affecting the selected response. Hence, other differences between the lines are likely due to pleiotropic actions of those genes. We discuss behavioral pharmacological experiments in two sets of selected lines. Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mouse lines were selected for severe and minimal handling-induced convulsions (HIC), respectively, after withdrawal from chronic EtOH inhalation. The HIC is also elevated after acute administration of low doses of convulsant drugs. WSP mice were found to be more sensitive than WSR mice to many such drugs. There was no apparent specificity of such effects to any particular neurotransmitter system. Thus, genetic determination of a behavioral response to EtOH in this case cannot be traced to the influence of a single neurotransmitter system. COLD and HOT mice were selectively bred to show severe and mild hypothermia, respectively, after acute EtOH administration. COLD mice are also more sensitive to a number of other alcohols, barbiturates, and other general central nervous system depressants. When tested for sensitivity to a number of drugs with specific effects on neurotransmitter systems, COLD and HOT mice did not differ in sensitivity to drugs affecting dopaminergic, alpha-adrenergic, or nicotinic acetylcholinergic systems. COLD mice were more sensitive, however, to opioid and serotonergic drugs. Thus, analysis of these selected lines was successful in identifying particular neurotransmitters which may be important in EtOH-induced hypothermia.