Chronic dihydropyridine treatment can reverse the behavioural consequences of and prevent adaptations to, chronic ethanol treatment.
1. Chronic treatment with the dihydropyridine calcium channel antagonist, nitrendipine, given concurrently with ethanol, prevented the ethanol withdrawal syndrome in mice, even though the chronic nitrendipine treatment was stopped 24 h or 48 h before the withdrawal testing. 2. This effect was seen in two strains of mice with different methods of ethanol administration. Nitrendipine was effective when given for two weeks but not after only two days' treatment. 3. Two other dihydropyridine calcium antagonists, nimodipine and PN 200-110, given chronically with ethanol, also prevented the withdrawal syndrome. The tests were again made 24 h after the last administration of dihydropyridine. 4. The chronic nitrendipine treatment also prevented the rise in the number of central dihydropyridine binding sites that occurs on chronic ethanol administration. 5. Chronic administration of nitrendipine alone did not cause any withdrawal behaviour. 6. Chronic nitrendipine treatment did not affect the seizure threshold to bicuculline in mice that were not given ethanol. 7. Whole brain concentration measurements showed that the effects were not due to residual nitrendipine in the CNS at the time of withdrawal testing or to differences in central ethanol concentrations during the treatment. 8. It is suggested that the results provide evidence for a functional role for dihydropyridine-sensitive calcium channels in ethanol dependence.
Whittington
M A
MA
Pharmacology Department, Medical School, University Walk, Bristol.
Dolin
S J
SJ
Patch
T L
TL
Siarey
R J
RJ
Butterworth
A R
AR
Little
H J
HJ
D000223:Adaptation, Psychological / Q000187:drug effects*; D000280:Administration, Inhalation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D017275:Isradipine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009553:Nimodipine / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D000431:Ethanol; D009553:Nimodipine; D009568:Nitrendipine; D001640:Bicuculline; D017275:Isradipine