AP protein is found throughout the central nervous system, said the researchers. They cited studies demonstrating that mice in which the gene is knocked out show hyperactivity and defects in their circadian (day-night) behavior--both also characteristic of humans with bipolar disorder. Also, in animals, lithium has been shown to affect such circadian behavior. The protein also has been found to affect the activity of a key neurotransmitter, dopamine, in the brain, said the researchers. What's more, they found two other genes--PAM and GCH--that are involved in producing PACAP to be upregulated in the treated brain tissue.
Brandish and his colleagues said that such findings "suggest a coordinated upregulation of genes leading to increased dopamine signaling. In the light of the recent clinical data and human genetic linkage, it is tempting to speculate that PACAP night be a therapeutic effector of lithium in bipolar disorder."
They concluded that "the data presented here warrant further investigation of PACAP signaling in the brain and of the orphan receptor GPR88 as potential new targets in bipolar disorder."
Philip E. Brandish, Ming Su, Daniel J. Holder, Paul Hodor, John Szumiloski, Robert R. Kleinhanz, Jaime E. Forbes, Mollie E. McWhorter, Sven J. Duenwald, Mark L. Parrish, Sang Na, Yuan Liu, Robert L. Phillips, John J. Renger, Sethu Sankaranarayanan, Adam J. Simon, and Edward M. Scolnick: "Regulation of Gene Expression by Lithium and Depletion of Inositol in Slices of Adult Rat Cortex"
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