Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex.
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.
Brandish
Philip E
PE
Merck & Co., Inc., West Point, Pennsylvania 19486, USA. phillip_brandish@merck.com
Su
Ming
M
Holder
Daniel J
DJ
Hodor
Paul
P
Szumiloski
John
J
Kleinhanz
Robert R
RR
Forbes
Jaime E
JE
McWhorter
Mollie E
ME
Duenwald
Sven J
SJ
Parrish
Mark L
ML
Na
Sang
S
Liu
Yuan
Y
Phillips
Robert L
RL
Renger
John J
JJ
Sankaranarayanan
Sethu
S
Simon
Adam J
AJ
Scolnick
Edward M
EM
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
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