Effects of lithium on synaptosomal Ca^{2 +} fluxes

Abstract

Lithium is the primary treatment for mania, and it has been employed as a therapeutic agent in the treatment of a number of other conditions. In spite of its widespread clinical use, the specific mechanism by which lithium acts is still not known. Because lithium bears some chemical resemblance to Ca^{2 +} and because it has been found to interfere with many Ca^{2 +}-dependent processes, we investigated the possibility that lithium can alter intracellular Ca^{2 +} homeostasis by an effect on Ca^{2 +} fluxes. When added in vitro to synaptosomes prepared from rat forebrains, lithium had no effect on ⁴⁵Ca^{2 +} influx mediated by fast or slow phase depolarization-dependent Ca^{2 +} channels or by Na⁺/Ca^{2 +} exchange. In vitro treatment with lithium also had no effect on ATP-dependent Ca^{2 +} sequestration by mitochondria or synaptosomal endoplasmic reticulum. In contrast, ⁴⁵Ca^{2 +} influx in synaptosomes prepared from rats treated chronically with lithium was increased significantly relative to controls. The fact that chronic in vivo treatment with lithium affected synaptosomal Ca^{2 +} flux whereas in vitro treatment did not is consistent with the time course of therapeutic effectiveness in man. The results suggest that lithium does not directly interact with synaptosomal Ca^{2 +} flux, but rather may influence Ca^{2 +} flux through an indirect mechanism following chronic treatment.