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Lithium's Neural Mechanisms Uncovered
> 1/16/2008 10:32:03 AM

Lithium, an elemental salt first discovered in the early 19th century, was coincidentally found to counter various mood disorders while used as a salve for conditions like gout, and it has been used for various mood-related mental illnesses since the 1950's. Despite its near-ubiquity in the treatment of severe bipolar disorder since FDA approval in 1970, experts could not, until now, explain the precise ways in which lithium so often serves to moderate the peaks and valleys that color the daily lives of bipolar patients.

Nearly ten years ago, researchers determined that the reaction centered around the neurotransmitter glutamate, but still could not illuminate the precise path by which this change occurred. Glutamate is the brain's primary communicative agent, a chemical released by neurons in order to send coded messages to neighboring brain cells and be reabsorbed after said messages have been delivered. One of the major causes of bipolar disorder is an uneven glutamate count in the brain: too much leads to hyperactive mania and too little to depression and despondency. Researchers observed that lithium stabilizes glutamate levels, restricting them to within a very narrow range. But they could not pinpoint the process by which this change occurs, puzzled by the fact that effective lithium dosages administered to humans are usually far smaller than those required to bring about the wide-scale chemical changes mentioned above.

The newest research involving mice engineered to display excessive levels of dopamine (a faster-acting cousin to glutamate) found that, rather than directly reducing or increasing the quantity of glutamate in the brain, lithium works by disabling the signaling mechanism that allows the protein beta-arrestin 2 to facilitate the transfer of glutamate between neurons. A mediator of dopamine transmissions, beta-arrestin2 binds the neural receptor cells and the enzymes that, collectively, form the physical pathway between neurons. Study mice bred to lack beta-arrestin did not respond to the lithium doses as directly as their standard counterparts. Cells affected by lithium do not lack the required enzymes, they're simply less able to transmit them, thereby significantly tempering the dramatic glutamate swells and recessions that lead to bipolar disorder's diametrically opposed mood swing symptoms.

While the distinctions raised by this study appear minute, their implications are far greater: now that researchers understand the precise mechanism by which lithium works its apparent magic, they can focus on developing new drugs or alernative treatment methods that work by acting on the very same device. By granting experts a greater understanding of cell signaling and its regulation, this study allows for a wealth of follow-up research aimed at refining our degree of control over intercellular communication and using that knowledge to better treat any number of disorders. The largest revolution may often be traced to its humble beginnings.

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