IN VIVO DISTRIBUTION OF LITHIUM IN RAT BRAIN

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Lithium (Li) is the treatment of choice for bipolar disorder, but it has an unknown mechanism of action. One approach to clarifying the origin of Li's mood stabilizing effect is to study where Li concentrates in human brain. This is based on the notion that Li would concentrate at brain sites relevant to its action. For example, if Li acts on cholinergic pathways in preference to noradrenergic pathways, higher Li concentration might be expected in cortex than in medulla, midbrain, or cerebellum. Animal studies suggest that nonuniform distribution of Li in mammalian brain, but this has been difficult to study in animals in a consistent manner by in vitro methods, or in humans in any manner. Another aspect of the "anatomy" of Li's mechanism of action is the intracellular fraction in a particular brain region, given that the presumed site of action is intracellular. Magnetic resonance (MR) imaging of the 7Li isotope is a technique for mapping the spatial distribution of Li in animal and human brain. In this proposal the quantitative distribution of Li will be measured in vivo in rat brain. The results will be compared to the distribution found for the same rat after isolation and sectioning of the frozen brain and subsequent analysis by atomic absorption spectrophotometry and in vitro 7Li NMR analysis. The MR spin relaxation time (T1 and T2) images will also be acquired to insure quantitative results, and to provide information on ion-tissue interactions and a map of the intracellular-to- extracellular concentration ratio. The results of this study will clarify the "anatomy" of Li's actions in brain and the issue of intracellular vs. extracellular concentration. These studies will serve as a prelude to future attempts to correlate Li distribution with local changes in brain biochemistry in vivo as measured by localized 31P and 1H MR spectroscopies, and similar studies in humans.