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 mM 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 degrees C. Li+ administered in vivo disappeared within 10 min from synaptosomes incubated at 37 degrees C. Li+ added in vitro at 1 mM attained a synaptosomal steady-state concentration within 30 min at 37 degrees 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 Mg2+ and hence probably partial membrane depolarization. Addition of 1 mM Li+ in vitro also caused synaptosomal Mg2+ 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+.
Lam
H R
HR
Institute of Toxicology, National Food Agency, Søborg, Denmark.
Christensen
S
S
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002412:Cations / Q000097:blood / Q000378:metabolism*; D008094:Lithium / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism; D013696:Temperature; D014018:Tissue Distribution
D002412:Cations; D009419:Nerve Tissue Proteins; D008094:Lithium