Genetic regulation of dihydropyridine-sensitive calcium channels in brain may determine susceptibility to physical dependence on alcohol.
Experiments utilising rodents in vivo and cultures of adrenal cells in vitro have suggested that genetic regulation of dihydropyridine-sensitive calcium channels may be involved in dependence on alcohol. Selection of mouse lines for either a very severe ethanol-withdrawal syndrome (withdrawal seizure prone) or a very mild syndrome (withdrawal seizure resistant), has produced lines which differ very markedly in these characteristics. In these experiments, mice bred selectively for these symptoms for 26 generations, were compared for the severity of withdrawal from alcohol after inhalation of ethanol (plus injections of pyrazole) for 3 days. A proportion of animals from each line was killed before withdrawal and membranes from whole brain were analysed by radioligand binding for binding sites for [3H] nitrendipine. Mice which were withdrawal seizure prone showed a markedly greater severity of the ethanol-withdrawal syndrome, and also showed a significantly greater up-regulation of binding sites for [3H]nitrendipine with no significant difference in binding affinity. The results suggest a relationship between genetic susceptibility to dependence on alcohol and genetic regulation of neuronal calcium channels in brain.
Brennan
C H
CH
King's College, University of London, U.K.
Crabbe
J
J
Littleton
J M
JM
D000437:Alcoholism / Q000235:genetics*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D007700:Kinetics; D051379:Mice; D009568:Nitrendipine / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D015854:Up-Regulation
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D000431:Ethanol; D009568:Nitrendipine