Chronic dihydropyridine treatment can reverse the behavioural consequences of and prevent adaptations to, chronic ethanol treatment

Abstract

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.

The differential effects of felodipine and nitrendipine on cerebral dihydropyridine binding ex vivo and the ethanol withdrawal syndrome in mice

“…Such data serve to demonstrate the problems in trying to correlate in vivo functional changes with either in vitro or in vivo biochemical analysis. In this regard the lack of change in [3H]-isradipine binding in the ethanol-dependent mice contrasts with several reports of increases in dihydropyridine binding measured in vitro (Dolin et al, 1987;Dolin & Little, 1989;Whittington et al, 1991) but is in agreement with another report on the failure to find a significant increase in…”

“…This evidence has been obtained not only from behavioural studies showing prevention of the withdrawal syndrome by a variety of calcium antagonists (Little et al, 1986;Whittington et al, 1991), but also from neurochemical studies (Dolin et al, 1987;Whittington et al, 1991) and electrophysiological analysis of withdrawal hyperexcitability. The latter experiments have demonstrated selective and stereospecific prevention by isradipine of epileptiform activity produced by ethanol withdrawal in isolated hippocampal slices and increased dihydropyridine-sensitive calcium spikes during the withdrawal phase (Whittington et al, 1992).…”

“…They were made physically dependent on ethanol by a 14 day period of inhalation of ethanol/vapour in an inhalation chamber, at an ethanol concentration of 8 mg 1' (Green et al, 1990b;Whittington et al, 1991 Supavilai & Karobath (1984) as described in detail in Watson & Little (1994). One min following injection of [3H]-nitrendipine (4 pCi in 0.1 ml) the brain was removed and homogenized at a concentration of 20 mg tissue ml-' in ice cold Tris 4-Cl buffer.…”

“…The protective action of the drugs against the behavioural effects of the calcium channel activator, Bay K 8644, was also examined in control animals, as was the ability of the drugs to inhibit the hyperexcitability produced by handling following administration of bicuculline. The calcium antagonists, nitrendipine and felodipine, like other dihydropyridines, are both highly lipid soluble and we have previously demonstrated that nitrendipine passes the blood brain barrier (Dolin & Little, 1989;Whittington et al, 1991), while felodipine has also been recently reported to have good penetration into the brain (Rigby et al, 1991). '."…”

The effects of chronic treatment with the dihydropyridine, Bay K 8644, on hyperexcitability due to ethanol withdrawal, in vivo and in vitro

“…Nitrendipine, given concurrently with ethanol in chronic treatment, prevented the development of tolerance to ethanol (Wu et al, 1987; Dolin & Little, 1989). Nitrendipine, given chronically with ethanol, also prevented the ethanol withdrawal syndrome (Whittington et al, 1991) and decreased the electrophysiological manifestations of withdrawal described above (Whittington & Little, 1991b). These effects were considered to be responses to the continued presence of nitrendipine, rather than acute actions, as the CNS concentrations at the time of testing were too low to produce acute effects in either the tolerance studies or on the withdrawal measurements (Dolin & Little, 1989;Whittington et al, 1991).…”