Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex

被引:124
作者
Dixon, JF [1 ]
Hokin, LE [1 ]
机构
[1] Univ Wisconsin, Sch Med, Dept Pharmacol, Madison, WI 53706 USA
关键词
D O I
10.1073/pnas.95.14.8363
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 V-max, as the lithium concentration was increased, whereas the K-m remained 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).
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页码:8363 / 8368
页数:6
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