Philip E. Brandish¹, Ming Su¹, Daniel J. Holder¹, Paul Hodor¹, John Szumiloski¹, Robert R. Kleinhanz², Jaime E. Forbes², Mollie E. McWhorter², Sven J. Duenwald², Mark L. Parrish², Sang Na¹, Yuan Liu¹, Robert L. Phillips¹, John J. Renger¹, Sethu Sankaranarayanan¹, Adam J. Simon¹ and Edward M. Scolnick³

¹Merck & Co., Inc., West Point, Pennsylvania 19486
²Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co. Inc., 401 Terry Avenue North, Seattle, Washington 98011
³ Present address: The Broad Institute, One Kendall Square, Cambridge, Massachusetts 02139

 

Abstract

Lithium inhibits inositol monophosphatase at therapeutically effective concentrations, and it has been hypothesized that depletion of brain inositol levels is an important chemical alteration for lithium's therapeutic efficacy in bipolar disorder. We have employed adult rat cortical slices as a model to investigate the gene regulatory consequences of inositol depletion effected by lithium using cytidine diphosphoryl-diacylglycerol as a functionally relevant biochemical marker to define treatment conditions. Genes coding for the neuropeptide hormone pituitary adenylate cyclase activating polypeptide (PACAP) and the enzyme that processes PACAP's precursor to the mature form, peptidylglycine alpha-amidating monooxygenase, were upregulated by inositol depletion. Previous work has shown that PACAP can increase tyrosine hydroxylase (TH) activity and dopamine release, and we found that the gene for GTP cyclohydrolase, which effectively regulates TH through synthesis of tetrahydrobiopterin, was also upregulated by inositol depletion. We propose that modulation of brain PACAP signaling might represent a new opportunity in the treatment of bipolar disorder.