Selectivity of the protective effects of dihydropyridine calcium channel antagonists against the ethanol withdrawal syndrome.
Four dihydropyridine calcium channel antagonists were compared for their ability to protect against the hyperexcitability produced in mice by withdrawal from chronic ethanol treatment and to protect against seizures due to bicuculline or pentylenetetrazol. Comparison was also made of their effects on locomotor activity, body temperature and motor co-ordination, and with the corresponding effects of the benzodiazepine, diazepam. Nitrendipine, nimodipine, nicardipine (at 50 and 10 mg/kg) and isradipine (at 10 and 4 mg/kg) decreased the withdrawal hyperexcitability, but showed no anticonvulsant action against either bicuculline or pentylenetetrazol. Diazepam (1.5 and 4 mg/kg) both protected against the withdrawal signs and decreased seizure incidence after bicuculline and pentylenetetrazol, although the latter effects were of shorter duration than those on the withdrawal signs. The four dihydropyridines decreased spontaneous locomotor activity, an effect which lasted up to 6 h. Only isradipine and diazepam had any ataxic actions at the doses tested. All the dihydropyridines had hypothermic actions, considerably shorter in duration than effects on withdrawal hyperexcitability, with little evidence of dose dependence, except for nicardipine, which had a larger, dose-related, hypothermic action. Of the four compounds, isradipine was more potent in terms of dose, but not any more selective for effectiveness against the withdrawal signs, than the other three dihydropyridines, and nicardipine was slightly less effective in protecting against the withdrawal signs. The results indicate that the anticonvulsant effects of the dihydropyridines were selective for ethanol withdrawal hyperexcitability, whereas diazepam showed no such selectivity.
Watson
W P
WP
Drug Dependence Unit, Psychology Department, Durham University, Science Laboratories, South Road, Durham DH1 3LE, UK.
Little
Hilary J
HJ
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001259:Ataxia / Q000188:drug therapy / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D001640:Bicuculline / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D003292:Convulsants; D004095:Dihydropyridines / Q000627:therapeutic use*; D000431:Ethanol / Q000009:adverse effects*; D018756:GABA Antagonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000523:psychology
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D002492:Central Nervous System Depressants; D003292:Convulsants; D004095:Dihydropyridines; D018756:GABA Antagonists; D006993:Hypnotics and Sedatives; D000431:Ethanol; D010433:Pentylenetetrazole; D001640:Bicuculline