Mechanisms of Action of Lithium in Affective Disorders: A Status Report

Waldmeier, P. C.

doi:10.1111/j.1600-0773.1990.tb02079.x

Cited by 16 publications

(27 citation statements)

References 117 publications

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“…Because of increased binding and the relatively restricted intracellular environment, cationic T 2 is expected and found to be lower intracellularly than extracellularly (23,26,28). Assuming the same holds true for Li in the brain in vivo, then biexponential behavior in a localized 7 Li MRS experiment, if observed, can be attributed to separate signals from the intra-and extracellular compartments.…”

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confidence: 93%

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confidence: 98%

“…Although 7 Li is also spin-3/2, its spin relaxation is only weakly quadrupolar (22). Intrinsic biexponential T 2 relaxation has not been clearly observed for 7 Li in biological systems (13,15). Studies on cellular systems in vitro found monoexponential T 2 behavior intracellularly for 7 Li (23)(24)(25)(26)(27).…”

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confidence: 99%

“…We have previously measured 7 Li T 2 s in vivo in rat brain using localized point-resolved spectroscopy (PRESS) (20). Because these measurements usually suffer from relatively low signal-to-noise ratio (SNR), particularly at therapeutic concentrations, monoexponential decay was assumed in the prior analysis of the T 2 data.…”

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confidence: 99%

“…Lithium-7 ( 7 Li) MR is the only technique available for measuring noninvasively the concentration of Li in the brain in vivo (13)(14)(15). We recently reported localized 7 Li MRS studies of total Li concentration and spin relaxation in rat brain in vivo (20,21).…”

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Estimating intracellular lithium in brain in vivo by localized ⁷Li magnetic resonance spectroscopy

Komoroski

Pearce

2008

Magnetic Resonance in Med

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The therapeutic mechanism of action of lithium (Li) in bipolar disorder is unknown. While Li is presumed to work intracellularly in the brain, the fraction of intracellular Li in the brain in vivo is not known. It has not yet been possible to determine, directly and noninvasively, the intra-to extracellular distribution of Li in human brain in vivo. Lithium-7 ( 7 Li) MR is the only technique available for measuring noninvasively the concentration of Li in the brain in vivo. Here the individual components of biexponential 7 Li transverse (T 2 ) relaxation in rat brain in vivo are identified with intra-and extracellular Li, and used to estimate its compartmental distribution. Intracellular T 2 was 14.6 ؎ 6.9 ms, while extracellular T 2 was 160 ؎ 52 ms in nine rats. The fraction of intracellular brain Li ranged from 37% to 75% (mean: 63 ؎ 11%). Further, the biexponential T 2 results provided the basis for estimating Li compartmental distribution from monoexponential T 2 decays using a simple linear approximation. Lithium (Li) is an elemental cation used in the treatment of bipolar disorder. Despite its widespread use in clinical settings and extensive research into its mechanisms of action, there is still little agreement as to how Li exerts its clinical effects (1,2). Because Li is a simple ion, it must be viewed differently than other psychoactive drugs, which are usually organic compounds with clear receptor binding properties. Li competes with endogenous cations and thereby affects a wide range of biochemical processes, neurotransmitter synthesis and release, and cell membranes (3). Considerable attention has been focused on the effects of Li on phosphoinositide second-messenger metabolism (4 -6). But other possible mechanisms, including the effects on G-proteins (7), Na, K-adenosine triphosphatase (8), glycogen synthase kinase-3 (6,9), and gene expression (9 -11) are under investigation. Because most biochemical processes, including phosphoinositide second-messenger metabolism, occur within the cell, it is often presumed that Li exerts its clinically relevant effects in the intracellular space of neurons in the brain. However, because low intracellular Li concentrations have been found in some in vitro cellular systems, it has been suggested that the mechanism of action may be, at least in part, extracellular (12). The typical therapeutic serum concentration is 0.6 -1.2 mM. While the overall brain concentration is generally in the same range as the serum concentration (13-15), the fraction of intracellular Li in the brain in vivo is not known. Consequently, from a mechanistic point of view, the ratio of intracellular to extracellular Li in brain in vivo is an important parameter to measure because doing so may reveal how Li exerts its therapeutic effects.NMR has been widely used to measure cationic distribution in cellular preparations. Because most alkali-metal chemical shifts are relatively insensitive to the ionic environment, the intra-and extracellular resonances typically occur at the same chemical shift...

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confidence: 93%