title: Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex.
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.
authors.affiliation: Merck & Co., Inc., West Point, Pennsylvania 19486, USA. phillip_brandish@merck.com
authors.forename: Philip E
authors.initials: PE
authors.lastname: Brandish
authors.forename: Ming
authors.initials: M
authors.lastname: Su
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Holder
authors.forename: Paul
authors.initials: P
authors.lastname: Hodor
authors.forename: John
authors.initials: J
authors.lastname: Szumiloski
authors.forename: Robert R
authors.initials: RR
authors.lastname: Kleinhanz
authors.forename: Jaime E
authors.initials: JE
authors.lastname: Forbes
authors.forename: Mollie E
authors.initials: ME
authors.lastname: McWhorter
authors.forename: Sven J
authors.initials: SJ
authors.lastname: Duenwald
authors.forename: Mark L
authors.initials: ML
authors.lastname: Parrish
authors.forename: Sang
authors.initials: S
authors.lastname: Na
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Phillips
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Edward M
authors.initials: EM
authors.lastname: Scolnick
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D001714:Bipolar Disorder / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D003567:Cytidine Diphosphate Diglycerides / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D007294:Inositol / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009414:Nerve Growth Factors / Q000096:biosynthesis; D009479:Neuropeptides / Q000096:biosynthesis; D018377:Neurotransmitter Agents / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D015854:Up-Regulation / Q000235:genetics
chemical_list: C495403:Adcyap1 protein, rat; D018692:Antimanic Agents; D015415:Biomarkers; D003567:Cytidine Diphosphate Diglycerides; D009097:Multienzyme Complexes; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D001708:Biopterins; D007294:Inositol; D006899:Mixed Function Oxygenases; D014446:Tyrosine 3-Monooxygenase; C035189:peptidylglycine monooxygenase; D006136:GTP Cyclohydrolase; C003402:sapropterin; D018021:Lithium Chloride