Lithium Acutely Inhibits and Chronically up-Regulates and Stabilizes Glutamate Uptake by Presynaptic Nerve Endings in Mouse Cerebral Cortex

• Published in: Proceedings of the National Academy of Sciences - PNAS 1998-07, Vol.95 (14), p.8363-8368
• Main Authors: Dixon, John F., Hokin, Lowell E.
• Format: Article
• Language: English
• Subjects: Amino acid transport system XAG; Animals; Antidepressants; Antimanic agents; Biological Sciences; Bipolar Disorder - drug therapy; Blood; Brain; Cerebral Cortex - physiology; Chemical suspensions; Chlorides; Experimental procedures; Glutamic Acid - physiology; Lithium; Lithium - pharmacology; Lithium - therapeutic use; Mice; Mice, Inbred ICR; Nerve endings; Neurology; Presynaptic Terminals - physiology; Rodents; Synaptosomes; Up-Regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.14.8363

We previously reported that lithium stimulated extracellular glutamate accumulation in monkey and mouse cerebrocortical slices. We report here that this is caused by lithium-induced inhibition of glutamate uptake into the slice. Glutamate release was amplified 5-fold over inhibition of uptake. When the effects of lithium and the specific glutamate transporter inhibitors, L-trans-pyrrolidine-2,4-dicarboxylic acid and dihydrokainic acid, were plotted as glutamate accumulation vs. inhibition of glutamate uptake, the plots were superimposable. This finding strongly indicates that lithium-induced glutamate accumulation is caused entirely by inhibition of uptake. With cerebrocortical synaptosomes, inhibition of glutamate uptake was greater than in slices, suggesting that presynaptic nerve endings are the primary site of inhibition of uptake by lithium. Inhibition of uptake was caused by a progressive lowering of Vmax, as the lithium concentration was increased, whereas the Kmremained constant, indicating that lithium inhibited the capacity of the transporter but not its affinity. Chronic treatment of mice with lithium, achieving a blood level of 0.7 mM, which is on the low side of therapeutic, up-regulated synaptosomal uptake of glutamate. This would be expected to exert an antimanic effect. Lithium is a mood stabilizer, dampening both the manic and depressive phases of bipolar disorder. Interestingly, although the uptake of glutamate varied widely in individual control mice, uptake in lithium-treated mice was stabilized over a narrow range (variance in controls, 0.423; in lithium treated, 0.184).