Correlation between increases in dihydropyridine binding in vivo and behavioural signs of ethanol withdrawal in mice

Increased ligand binding to dihydropyridine receptors in the central nervous system after chronic ethanol consumption is thought to contribute to the withdrawal syndrome. Previous studies demonstrated such changes when the binding was measured in vitro, which, as the receptors are voltage-sensitive, may not accurately reflect the binding in vivo. In the present study, dihydropyridine binding was measured in vivo in mice, after intravenous administration of the radioligand. The aim was to determine whether there was any correlation between such binding and measurements of behavioural hyperexcitability at different times during the withdrawal phase and after two different methods of alcohol administration. Measurements were made of the binding in vivo of [3H]nitrendipine, at intervals after withdrawal from chronic ethanol administration, and of the severity of withdrawal as measured by response to gentle handling. An increase in the in vivo binding to [3H]nitrendipine was seen after cessation of chronic ethanol consumption by liquid diet. The binding was significantly increased at 4 h, when the behavioural changes were maximal, but not immediately after withdrawal, when the responses to handling were unchanged. By 24 h after cessation of the ethanol treatment, no differences in the binding were found, compared with control values; at this time the withdrawal hyperexcitability had ceased. When alcohol was given chronically by inhalation, the in vivo dihydropyridine binding was increased at 3 h from withdrawal of the ethanol, the time of maximal behavioural hyperexcitability, but no change was seen 30 min after withdrawal, when no changes in the ratings of behaviour were found. There was a significant positive correlation in individual mice between the ratings of handling-induced behaviour at the 3 h interval and the amount of in vivo binding. These data support the hypothesis that the sites labelled by [3H]nitrendipine play an important role in withdrawal hyperexcitability.