10. Pharmacology of Isoquinoline Alkaloids and Ethanol Interactions*

Very few of the more than sixty naturally-occurring isoquinoline alkaloids have been screened for pharmacological activity, although certain members of this class have known hallucinogenic and cardiovascular activity. Recently the suggestion that biosynthetic catecholamine-derived tetrahydroisoquinolines are involved in the etiology of alcoholism has stimulated research into their activity. Both salsolinol and its desmethyl analogue, 6,7-dihydroxytetrahydroisoquinoline, have been shown to exacerbate ethanol withdrawal convulsions in mice. However, the action of such isoquinolines in altering the behavioural expression of acute ethanol intoxication has not been reported. The results presented here demonstrate the ability of salsolinol and 3-carboxysalsolinol and their non-cyclised amine precursors, dopamine and L-DOPA respectively, to increase the duration of ethanol-induced narcosis in mice. The carboxylated isoquinoline was the most potent of the four compounds tested. Pretreatment with the alcohol dehydrogenase inhibitor pyrazole significantly lengthened the narcosis produced by ethanol and by both of the isoquinolineethanol combinations. Disulfiram, an inhibitor of both aldehyde dehydrogenase and dopamine-beta-hydroxylase, led to an increased sleeping time after either ethanol or L-DOPAethanol treatments, but had no effect on the isoquinoline ethanol narcosis. When carbidopa, an inhibitor of peripheral L-amino-acid decarboxylase, was administered, a significant increase in duration of narcosis following either L-DOPA or 3-carboxysalsolinol with ethanol was obtained. The results show that simple isoquinolines such as salsolinol and 3-carboxysalsolinol potentiate the narcotic effect of a single injection of ethanol and suggest that in vivo formation of such compounds may play a significant role in both acute and chronic alcoholism.