Regional and Subcellular Localization of Li + and Other Cations in the Rat Brain Following Long‐Term Lithium Administration

Rats were given LiCl in their diet (40 mmol/kg dry weight) for at least 3 months to elucidate the regional and subcellular localization of Li + in the brain as well as the effect of chronic lithium administration on the distribution of other cations. At steady‐state the mean concentrations of Li + were 0.66 mmol/kg wet weight in the whole brain and 0.52 m M in plasma. The tissue/plasma concentration ratio exceeded unity in all anatomical regions. No region showed excessive accumulation of Li + . Whole brain or regional contents of Na + or K + were unaffected by lithium treatment. Subcellular Li + localization was demonstrated in nuclear, crude mitochondrial, and microsomal fractions of whole brain homogenate. Subfractionation of the crude mitochondrial fraction revealed energy‐independent intrasynaptosomal and intramitochondrial Li + and K + localization at 0–4°C. Li + administered in vivo disappeared within 10 min from synaptosomes incubated at 37°C. Li + added in vitro at 1 m M attained a synaptosomal steady‐state concentration within 30 min at 37°C. In control rats, synaptosomal concentrations and synaptosomal/medium concentration gradients of cations paralleled their respective in vivo concentrations and gradients. Lithium treatment caused synaptosomal depletion of K + and Mg 2+ and hence probably partial membrane depolarization. Addition of 1 m M Li + in vitro also caused synaptosomal Mg 2+ depletion. The results indicate that Li + is “accumulated” in brain sediments and synaptosomes following its long‐term treatment. The estimated intracellular and intrasynaptosomal Li + concentrations are lower than predicted by passive distribution according to the Nernst equation, evidencing active extrusion of Li + .