Interaction of lithium and disulfiram in hexobarbital hypnosis: possible role of the 5-HT system.

The effects of lithium and disulfiram on the 5-hydroxytryptamine (5-HT) system and hexobarbital (HX)-induced hypnosis were studied. Treatment with lithium significantly prolonged HX hypnosis. Disulfiram, a potent inhibitor of brain aldehyde dehydrogenase, also produced a prolongation of HX hypnosis. A combination of lithium treatment for 3 days with disulfiram synergistically potentiated the HX hypnosis and reduced the brain HX levels on awakening. Furthermore, L-tryptophan loading significantly increased the HX sleeping time and reduced the brain HX level on awakening in lithium-pretreated rats, whereas it had not effect on HX hypnosis in controls rats. L-Tryptophan also potentiated HX hypnosis in disulfiram-treated rats. The combination of L-tryptophan, lithium and disulfiram caused the greatest prolongation of HX hypnosis. However, no synergism between lithium and disulfiram was observed in animals treated with lithium for 5 days. after 3 days of lithium treatment, the rate of synthesis of 5-HT was elevated, whereas it had returned to the control level after 5 days of lithium treatment. Tryptophan loading increased the rate of synthesis of 5-HT more than 2-fold in control animals. The increase in the rate of 5-HT synthesis caused by lithium was further potentiated by tryptophan loading. These results suggest that lithium and disulfiram exert their synergistic effect on HX hypnosis by acting on the 5-HT system and that an accumulation of 5-hydroxyindoleacetaldehyde, an active metabolite of 5-HT, may be responsible for the increase in the brain sensitivity to barbiturates caused by these drugs.