Time course and genetic variation in the regulation of calcium channel antagonist binding sites in rodent tissues during the induction of ethanol physical dependence and withdrawal.
Physical dependence was induced by ethanol inhalation in male Sprague-Dawley rats and, in parallel experiments, in two lines of mice (WSR and WSP) genetically selected for differential severity of ethanol withdrawal. In dependent rats [3H]nitrendipine binding sites were significantly increased in cerebral cortex, cardiac and smooth muscle (vas deferens). Cerebral cortical membranes were the first to show an increase, the Bmax for nitrendipine binding rising sharply after 3-4 days of ethanol administration, whereas binding sites in the other tissues increased after 5-6 days. Nitrendipine binding affinity in all tissues was consistently reduced immediately preceding the rise in Bmax to a new steady state, but then returned to control values. Between 6 and 10 days of ethanol exposure there was no further increase in the Bmax for nitrendipine binding, and on removal of ethanol, the numbers of nitrendipine binding sites fell precipitously to control levels within 24 h of withdrawal. In the genetically selected mice, the up-regulation of nitrendipine binding sites in cardiac membranes was significantly greater in the WSP line. This correlates with severity of physical signs of withdrawal and parallels previous results obtained in brain. The results are consistent with an increase in the synthesis and membrane insertion of dihydropyridine sensitive calcium channel proteins in several tissues during the induction of ethanol dependence and suggest that in the brain this change may play a role in the ethanol withdrawal syndrome.
Guppy
L J
LJ
Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Crabbe
J C
JC
Littleton
J M
JM
D000430:Alcohol Withdrawal Delirium / Q000235:genetics* / Q000503:physiopathology; D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000431:Ethanol / Q000633:toxicity; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009568:Nitrendipine / Q000493:pharmacokinetics; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012641:Selection, Genetic; D013045:Species Specificity; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D015220:Calcium Channels; D000431:Ethanol; D009568:Nitrendipine