Effects of dihydropyridines on the components of the ethanol withdrawal syndrome: possible evidence for involvement of potassium, as well as calcium?
Comparison was made of the ability of two dihydropyridine calcium channel antagonists, nitrendipine and felodipine, to prevent a range of signs of ethanol withdrawal. The increases in handling-induced behavior seen in mice during withdrawal from chronic ethanol treatment were prevented by administration of nitrendipine, 50 mg/kg, but not by, felodipine, 10 mg/kg, a dose that caused a similar displacement of dihydropyridine binding in central nervous system tissue, in vivo and in vitro. A higher dose of felodipine, 20 mg/kg, also had no effects. Nitrendipine, but not felodipine, prevented audiogenic seizures during the withdrawal phase. Similarly, nitrendipine prevented both the decrease in thresholds for N-methyl-DL-aspartate seizures and the increase in thresholds for convulsions due to 4-aminopyridine, which were seen during the withdrawal period, while felodipine did not alter either of these changes. Withdrawal from the ethanol chronic treatment increased the thresholds to seizures produced by intravenous aminophylline; this change was also prevented by nitrendipine. The significance of this increase in thresholds was lost after felodipine administration. In naive mice (not treated with ethanol) the doses of nitrendipine and felodipine used in the withdrawal studies were tested against the effects of convulsant drugs. Both dihydropyridines increased, to similar extents, the thresholds for seizures produced by bicuculline, pentylenetetrazol, and by N-methyl-DL-aspartate. The thresholds for aminophylline were unaltered by either dihydropyridine. In contrast, the thresholds for seizures due to 4-aminopyridine in the naive animals were not changed by felodipine, but were increased by nitrendipine. The results suggest that changes in potassium, as well as calcium, may possibly be involved in some of the stages of the ethanol withdrawal syndrome.
Watson
W P
WP
Department of Psychology, Durham University, United Kingdom.
Little
J J
JJ
D000430:Alcohol Withdrawal Delirium / Q000503:physiopathology*; D000628:Aminophylline / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D004569:Electroencephalography / Q000187:drug effects; D015736:Felodipine / Q000494:pharmacology*; D006234:Handling, Psychological; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009460:Neurologic Examination / Q000187:drug effects; D009568:Nitrendipine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011188:Potassium / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010726:Phosphodiesterase Inhibitors; D015221:Potassium Channels; D000628:Aminophylline; D009568:Nitrendipine; D015736:Felodipine; D011188:Potassium; D002118:Calcium