dihydropyridines and Alcoholism

Prolonged ethanol administration causes upregulation of dihydropyridine-sensitive binding sites, thought to represent neuronal calcium channels, and these channels appear to play an important role in ethanol physical dependence. Dihydropyridine calcium channel antagonists, when given chronically with ethanol, prevent the development of tolerance to ethanol and the ethanol withdrawal syndrome. The upregulation of binding sites for these compounds was also prevented. Epileptiform activity has been described in isolated hippocampal slices after chronic ethanol treatment in vivo. This was prevented, stereoselectively, by the dihydropyridine calcium channel antagonist, isradipine, that did not affect the hyperexcitability produced in control slices by the GABAA antagonist, bicuculline.

Topics: Adaptation, Physiological; Alcoholism; Animals; Calcium Channel Blockers; Dihydropyridines; Electrophysiology; Ethanol; Humans; In Vitro Techniques; Substance Withdrawal Syndrome

Topics: Adrenal Medulla; Alcoholism; Animals; Calcium Channels; Cattle; Cells, Cultured; Central Nervous System; Dihydropyridines; Ethanol; Neurons; Receptors, Nicotinic; Substance Withdrawal Syndrome

This review discusses the importance of neuronal calcium currents in dependence on ethanol, barbiturates, benzodiazepines and opiates. The main sections describe the actions of ethanol on control of intracellular calcium and on calcium and calcium-dependent conductance mechanisms. In particular, the effects of both acute and chronic ethanol treatment on dihydropyridine-sensitive, voltage-dependent, calcium channels are described. The later sections cover the effects of barbiturates, benzodiazepines and opiates on these systems. The conclusions suggest that dihydropyridine calcium channel antagonists may offer a new therapeutic approach to the treatment of ethanol and opiate dependence.

Topics: Alcoholism; Animals; Barbiturates; Benzodiazepines; Binding Sites; Calcium Channels; Dihydropyridines; Ethanol; Humans; Narcotics; Neurons

Previous experiments showed that isolated hearts from ethanol-exposed rats show a marked increase in sensitivity to anoxic myocardial damage, and we suggested that this may be due to excess calcium entry through L-type voltage-operated calcium channels (L-VOCCs). To challenge this hypothesis, we investigated the effect of ethanol treatment ex vivo on a damaging stimulus, the "calcium paradox," which is associated with removal of calcium from the perfusate. Adult male Sprague-Dawley rats were exposed to intoxicating concentrations of ethanol for 6-10 days by inhalation. Isolated hearts from these animals were perfused with Krebs-Henseleit buffer by using a modified Langendorff technique, and the calcium paradox induced by a 10-min period of perfusion with calcium-free buffer, followed by reperfusion with calcium-containing buffer. Compared with controls, hearts from ethanol-exposed rats were significantly protected against myocardial damage, as shown by a marked reduction in release of intracellular proteins (lactate dehydrogenase, creatine phosphokinase, and myoglobin) during the reperfusion phase. These indices of myocardial damage were modified by the presence of the dihydropyridine (DHP) calcium channel antagonist nitrendipine (10(-6) M) and the DHP L-VOCC activator Bay K 8644 (10(-7) M) in the perfusate during the calcium paradox. Paradoxically, both drugs appeared to increase the damaging effects of calcium-free perfusion, with this effect being generally greater in the preparations from ethanol-exposed rats. As a result, the difference between these hearts and those from control rats was reduced, although a significant degree of protection against the calcium paradox remained. The results support the hypothesis that long-term exposure to ethanol in vivo produces marked alterations in the toxic effects of changes in myocardial calcium concentration. The increased sensitivity to DHP drugs of isolated hearts from ethanol-treated rats is consistent with previous experiments showing increased DHP radioligand-binding sites in these tissues.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Alcoholism; Animals; Calcium; Calcium Channel Blockers; Central Nervous System Depressants; Dihydropyridines; Ethanol; Heart; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Myocardium; Nitrendipine; Perfusion; Rats; Rats, Sprague-Dawley

This study was undertaken to investigate the biochemical events underlying the inhibitory action of ethanol on dihydropyridine-sensitive voltage-dependent Ca2+ channels in brain synaptosomes. The binding of radiolabeled dihydropyridine was used to determine functional Ca2+ channels in synaptosomes following exposure to ethanol. No effect on [3H]PN 200-110 binding was found when disrupted synaptosomal membranes were incubated with ethanol concentrations as high as 300 mM, suggesting that ethanol did not interact directly with sites on or near the Ca2+ channels. However, when intact synaptosomes were first incubated with ethanol (100 mM) at 37 degrees and then disrupted, a significant reduction in membrane binding of [3H]PN 200-110 was found. Ethanol incubation of synaptosomes at 0 degree was ineffective. It appears that metabolic processes involving intracellular factors were required in the ethanol action. In examining this possibility, [3H]PN 200-110 binding was activated by incubation of disrupted membranes with MgATP and Ca(2+)-calmodulin, and ethanol was found to inhibit the activation in a concentration-dependent manner (50-200 mM). [3H]PN 200-110 binding to membranes was also activated by incubation with MgATP and cyclic AMP-dependent protein kinase, but this activation was not inhibited by ethanol. These findings are consistent with the interpretation that ethanol acts on Ca2+ channels by inhibiting calmodulin-dependent activation of the channels.

Topics: Adenosine Triphosphate; Alcoholism; Animals; Binding Sites; Brain; Calcium Channel Blockers; Calcium Channels; Cyclic AMP; Dihydropyridines; Ethanol; Isradipine; Magnesium; Male; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Synaptosomes; Tritium

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.

Topics: Alcoholism; Animals; Brain Chemistry; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Ethanol; Female; Gene Expression Regulation; Kinetics; Mice; Nitrendipine; Seizures; Substance Withdrawal Syndrome; Up-Regulation

The density and affinity of sites labeled by the 1,4-dihydropyridines, [3H]nitrendipine and (+) [3H]PN 200-110, were not significantly different in superior frontal and parietal cortical membranes from alcoholic patients and nonalcoholic control patients. This is in contrast to the increased number of dihydropyridine receptors and increased functional activity of calcium channels reported in brain from rats treated chronically with ethanol and in neural cell lines grown in the presence of ethanol. These results indicate that 1,4-dihydropyridine-sensitive calcium channels (L type) in the brain, despite possible acute changes, are unaltered following long-term ethanol exposure in humans.

Topics: Alcoholism; Cerebral Cortex; Dihydropyridines; Humans; Isradipine; Male; Middle Aged; Nitrendipine; Oxadiazoles

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Alcoholism; Animals; Cerebral Cortex; Dihydropyridines; Hydroxydopamines; In Vitro Techniques; Inositol Phosphates; Ion Channels; Male; Muscle Contraction; Muscle, Smooth; Nitrendipine; Oxidopamine; Pyridines; Rats; Rats, Inbred Strains; Sugar Phosphates; Vas Deferens