Editors' ChoicePharmacology

PACAP, a New Target for Bipolar Disorder

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Science's STKE  29 Mar 2005:
Vol. 2005, Issue 277, pp. tw117
DOI: 10.1126/stke.2772005tw117

Lithium is an effective treatment for bipolar disorder, a psychiatric mood disorder. Glycogen synthase kinase 3 (GSK3) and at least two inositol phosphatases (inositol monophosphatase and inositol polyphosphate 1-phosphatase) are inhibited by lithium at therapeutic concentrations. Brandish et al. examined the gene regulatory changes that occurred in rat brain cortical slices in response to inositol depletion. Inositol depletion, resulting from lithium's inhibition of the inositol phosphatases, which decreases recycling of these sugars into inositol lipids that are involved in signaling pathways, is believed to be one mechanism of action for lithium's beneficial effects. Microarray analysis and quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis of rat brain cortical slices were performed on samples treated with lithium alone, lithium plus the muscarinic acetylcholine receptor agonist carbachol (to stimulate activity and thus deplete inositol), and lithium plus carbachol plus inositol (to provide an inositol replete sample). Genes that were regulated in the presence of carbachol and lithium and for which the regulation was reversed by the addition of inositol were counted as positive. Genes encoding proteins that had not previously been implicated in bipolar disorder and that may point to new therapeutic directions were highlighted. These included the gene encoding orphan G protein-coupled receptor (GPCR) GPR88 and the genes encoding pituitary adenylate cyclase activating polypeptide (PACAP) and one of the biosynthetic enzymes involved in PACAP processing, peptidylglycine α-amidating monooxygenase (PAM). PACAP is particularly interesting for several reasons: The gene is located near the bipolar disorder risk locus on chromosome 18. PACAP signaling regulates tyrosine hydroxylase abundance, thereby regulating dopaminergic activity. And finally, PACAP knockout mice exhibit altered behaviors consistent with a role for PACAP in circadian behavior and alterations in anxiety and activity levels. Consistent with the connection to dopaminergic signaling, Brandish et al. found that the gene encoding an enzyme involved in synthesis of a cofactor for tyrosine hydroxylase was also increased in response to inositol depletion. This analysis suggests that PACAP may be a target for development of new treatments for bipolar disorder.

P. E. Brandish, M. Su, D. J. Holder, P. Hodor, J. Szumiloski, R. R. Kleinhanz, J. E. Forbes, M. E. McWhorter, S. J. Duenwald, M. L. Parrish, S. Na, Y. Liu, R. L. Phillips, J. J. Renger, S. Sankaranarayanan, A. J. Simon, E. M. Scolnick, Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex. Neuron 45, 861-872 (2005). [Online Journal]

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