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.
1 Fozard & Gray (1989) proposed that migraine is mediated by stimulation of 5-HT1c receptors. We have examined the interaction of two effective anti-migraine agents, ergotamine and dihydroergotamine (DHE), with these receptors. Binding (inhibition of labelling by [3H]-mesulergine) and agonist activity (phosphoinositide hydrolysis) were measured in piglet choroid plexus, a tissue rich in 5-HT1c receptors.2 The pKD for [3H]-mesulergine binding was 8.4. Ergotamine and DHE both inhibited [3H]-mesulergine binding with a pKD of 7.1. This was similar to the potency of m-chlorophenylpiperazine (m-CPP) (pKD 7.4) and rather less than that of 5-hydroxytryptamine (5-HT) (pKD 8.1).3 Both ergotamine and DHE were full agonists (pEC50s 7.5 and 7.6 respectively) with potencies similar to that of 5-HT (pEC50 7.7) and greater than that of m-CPP (pEC50 7.1). Mesulergine 1i-7M produced near-parallel rightward shifts of the concentration-response curves for all these agents of 1.8-2.2 log units, consistent with an action of the agonists at the same receptor. 4 There was no effect of prazosin, spiperone, mepyramine or atropine on the phosphoinositide hydrolysis induced by ergotamine, ruling out an action via ocl-adrenoceptors, 5-HT2, histamine H1, or muscarinic receptors.5 It is concluded that, together with 5-HT, ergotamine and DHE are the most potent 5-HT1c agonists reported so far. These findings do not support the theory that 5-HT1c receptor activation causes migraine.
1 The effects of the calcium channel blocking agent, nitrendipine, were studied on seizures in mice produced during withdrawal from chronic benzodiazepine treatment and on the development of tolerance to benzodiazepines. 2 Nitrendipine produced a dose-dependent decrease in seizure incidence, when seizures were produced by the partial inverse agonist FG7142 during withdrawal from seven days treatment with flurazepam. 3 Nitrendipine did not raise the seizure thresholds in naive mice to the full inverse agonist methyl-6,7-dimethoxy-4-ethyl-,8-carboline-3-carboxylate (DMCM), or to the y-aminobutyric acid (GABA) antagonist, 7 These results with benzodiazepines are partially in contrast with those for ethanol, where nitrendipine not only decreased ethanol withdrawal seizures when given acutely, but also prevented the development of tolerance and withdrawal signs when given concurrently with ethanol. However, they do confrm the selectivity of nitrendipine for withdrawal-induced seizures.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.