Bipolar disorder (BPD) is a devastating mental illness afflicting over 2.3 million Americans at an annual cost of over $45 billion. Its molecular origins remain unknown. It was noted in the past that sodium (Na) levels in bodily fluids of bipolar patients changed with change in mood state. Abnormal Na compartmental distribution was later confirmed in depression and mania using isotope dilution techniques. These and other observations led to the proposal that ionic imbalances arising from abnormalities in the cellular Na pump, Na,K-ATPase, were associated with BPD. Lithium (Li) is an important first-line and widely prescribed treatment for acute mania and relapse prevention in BPD. Its mechanisms of therapeutic action in BPD have not yet been sorted out. Lithium's mechanism of therapeutic action in BPD may consist of normalization of elevated intracellular Na levels, thus re-establishing normal resting membrane potential and cellular excitability. Demonstration that Li displaces intracellular Na in the brain in vivo has not been accomplished. Sodium-23 MRI, an advanced imaging technique for noninvasively probing the regional environment of Na in the brain, has the potential to demonstrate the effects of Li on brain Na. Because many bipolar patients do not respond adequately to Li treatment, there is a critical need to understand the mechanism(s) by which Li exerts its therapeutic effects. Our long-term goal is to improve our understanding of how Li impacts the brain in patients with BPD in order to provide improved therapeutic benefit. The objective of this application is to identify the effects of Li on intracelular Na in normal rat brain in vivo. Our rationale is that these effects may be relevant to Li's mechanism of action in BPD, in particular the Na,K-ATPase hypothesis. The central hypothesis of this application is that Li displaces intracellular Na into the extracellular/CSF space in norma brain. This hypothesis is supported by Preliminary Studies that show changes in 23Na MRI intensities and spin relaxation times with acute Li administration consistent with reduced intracellular and increased CSF Na in the brain in vivo. We will achieve our objective by completing the following Specific Aim: 1) Determine the effects of Li on Na compartmentation in normal rat brain in vivo as a function of Li concentration. This work is innovative because it is the first attempt to measure directly the effects of Li on brain Na in vivo. It also employs a new multinuclear, in vivo MR methodology to probe localized Na concentration using 23Na MRI and brain Li using 7Li MRS immediately thereafter. The proposed studies are significant because they will demonstrate that a key assumption of the Na,K-ATPase hypothesis of BPD is correct under certain conditions. If intracellular Na is elevated in BPD and displaced by Li, the effect of Li on 23Na MRI may be an early marker of treatment for BPD. It is critical to identify reliable markers of treatment response early in the disease course, before the long-term, recurrent illness is established. Identifying reliable markers of treatment response would dramatically improve treatment assignment, generate better response rates, and decrease the number of affective episodes.

Public Health Relevance

Lithium (Li) is an important treatment for bipolar disorder, a devastating mental illness that afflicts about 2.3 million Americans. Understanding how Li works biochemically can lead to more effective treatment. This project studies Li in brain cells in rats o understand better how it works and how it affects brain sodium.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Nadler, Laurie S
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University of Cincinnati
Schools of Medicine
United States
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