ENVIRONMENT OF LITHIUM IN RAT BRAIN IN VIVO

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Lithium (Li) is the treatment of choice for acute manic illness and for prophylaxis in bipolar disorder. There is little agreement as to how Li exerts its clinical effects, which are presumed to originate in the intracellular space of neurons. Although relatively easy to measure, the serum Li concentration may be less than ideal for monitoring treatment, as treatment failures or neurotoxicity at nominal therapeutic serum concentrations are common. Thus, the brain concentration of Li may be a better measure of Li therapy. To elucidate the mechanisms of therapeutic action and neurotoxic effects, it is important to know the Li concentration for brain in vivo, both overall and in the intracellular and extracellular compartments. It is hypothesized that, upon reaching steady state, the overall brain concentration of Li in vivo correlates well with serum concentration in rats. It is further hypothesized that, with longer term administration (3 weeks), the overall brain concentration of Li remains constant, but the intracellular/extracellular ratio increases. A slow increase of intracellular/extracellular ratio over several seeks would be consistent with the time course of Li~s clinical effects in humans. Localized NMR spectroscopy is a powerful tool for studying biochemical processes in vivo in humans and animals. Using localized Li-7 NMR spectroscopy, the brain concentration of Li in vivo will be measured after one and three weeks of Li administration at serum concentrations in the therapeutic and toxic ranges in humans. The Li-7 spin-lattice (T1) and spin-spin (T2) relaxation times will be measured after one and three weeks. The relaxation times will provide information on ionic mobility and binding, compartmentation, and ion-tissue interactions. The T2 may yield a noninvasive estimate of the intracellular/extracellular ratio that could be extended to humans. Such studies will support development of comparable, noninvasive approaches for humans.