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Lithium effect on the brain

Steve Mcclue Steven_Mcclue-1%notes at sb.com
Mon Jul 3 03:19:48 EST 1995

In article <DAzyzA.25K at cc.umontreal.ca>, tremblgu says...

>I am currently working on interaction between nucleic acids and lithium. Could
>someone explain how the Lithium is said to fight against manic depression? 

	One of the most popular hypotheses about the action of lithium in prophylaxis of
Bipolar Affective Disorders is that it interferes with the production of second messengers
in the brain. 
Specifically, Li has been shown to inhibit the enzyme myo-inositolmonophosphatase (IMP), a part 
of the second messenger PI (phosphatidylinositol) cycle. In this cycle, inositol-containing 
phospholipids are successively phosphorylated to produce PIP2 (PI plus 2 phosphates). A large 
family of neurotransmitters including serotonin and noradrenaline act at receptors which produce 
their intracellular second message by breaking down PIP2 into two smaller molecules, a lipid 
called diacylglycerol (DAG) and a sugar called Inositol trisphosphate (IP3). IP3 is an important 
second messenger wich can control Ca flux inside the cell.
Obviously, having broken down PIP2, the cell needs to make more of it in order to keep this 
cycle going. What happens is that IP3 is then broken down progressively to inositol 
monophosphate (IP). The enzyme IMP breaks this down one more time to inositol, which can then be 
added to DAG to make PI again. Lithium prevents this action of IMP, thus blocking the PI cycle. 
It is hypothesized that this action is relevant in the action of lithium in mania.

For more on the PI cycle, try the short review by Bob Michell, Inositol lipids in cellular 
signalling mechanisms, TIBS vol 17 pp274-276, August 1992.

More on IP3 and Calcium from Inositol trisphosphate and calcium signalling by Mike Berridge, 
Nature vol 361, pp315-325 (jan 1993).

At the moment, I can't find any references to hand that deal specifically with the lithium 
hypothesis, but those two will probably contain some leads. Hope this helps.


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