City University of New York (CUNY) CUNY Academic Works Publications and Research City College of New York 2008 Diverse Antidepressants Increase CDP-Diacylglycerol Production and Phosphatidylinositide Resynthesis in Depression-Relevant Regions of the Rat Brain Kimberly R. Tyeryar Laboratory of Integrative Neuropharmacology, University of Maryland School of Pharmacy Ashiwel S. Undieh CUNY City College Habiba OU Vongtau University of Maryland How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/cc_pubs/209 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/5633846 Diverse antidepressants increase CDP- diacylglycerol production and phosphatidylinositide resynthesis in depression- relevant regions of the rat brain ARTICLE in BMC NEUROSCIENCE · FEBRUARY 2008 Impact Factor: 2.67 · DOI: 10.1186/1471-2202-9-12 · Source: PubMed CITATIONS READS 11 26 3 AUTHORS: Kimberly Tyeryar Habiba Vongtau University of North Carolina at Chapel Hill University of Pittsburgh 10 PUBLICATIONS 305 CITATIONS 15 PUBLICATIONS 272 CITATIONS SEE PROFILE SEE PROFILE Ashiwel S Undieh Thomas Jefferson University 42 PUBLICATIONS 1,651 CITATIONS SEE PROFILE Available from: Ashiwel S Undieh Retrieved on: 04 December 2015 BMC Neuroscience BioMed Central Research article Open Access Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain Kimberly R Tyeryar2, Habiba OU Vongtau2 and Ashiwel S Undieh*1 Address: 1Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA and 2Laboratory of Integrative Neuropharmacology, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA Email: Kimberly R Tyeryar - [email protected]; Habiba OU Vongtau - [email protected]; Ashiwel S Undieh* - [email protected] * Corresponding author Published: 24 January 2008 Received: 13 April 2007 Accepted: 24 January 2008 BMC Neuroscience 2008, 9:12 doi:10.1186/1471-2202-9-12 This article is available from: http://www.biomedcentral.com/1471-2202/9/12 © 2008 Tyeryar et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Major depression is a serious mood disorder affecting millions of adults and children worldwide. While the etiopathology of depression remains obscure, antidepressant medications increase synaptic levels of monoamine neurotransmitters in brain regions associated with the disease. Monoamine transmitters activate multiple signaling cascades some of which have been investigated as potential mediators of depression or antidepressant drug action. However, the diacylglycerol arm of phosphoinositide signaling cascades has not been systematically investigated, even though downstream targets of this cascade have been implicated in depression. With the ultimate goal of uncovering the primary postsynaptic actions that may initiate cellular antidepressive signaling, we have examined the antidepressant-induced production of CDP-diacylglycerol which is both a product of diacylglycerol phosphorylation and a precursor for the synthesis of physiologically critical glycerophospholipids such as the phosphatidylinositides. For this, drug effects on [3H]cytidine-labeled CDP-diacylglycerol and [3H]inositol-labeled phosphatidylinositides were measured in response to the tricyclics desipramine and imipramine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, the atypical antidepressants maprotiline and nomifensine, and several monoamine oxidase inhibitors. Results: Multiple compounds from each antidepressant category significantly stimulated [3H]CDP-diacylglycerol accumulation in cerebrocortical, hippocampal, and striatal tissues, and also enhanced the resynthesis of inositol phospholipids. Conversely, various antipsychotics, anxiolytics, and non-antidepressant psychotropic agents failed to significantly induce CDP-diacylglycerol or phosphoinositide synthesis. Drug-induced CDP-diacylglycerol accumulation was independent of lithium and only partially dependent on phosphoinositide hydrolysis, thus indicating that antidepressants can mobilize CDP-diacylglycerol from additional pools lying outside of the inositol cycle. Further, unlike direct serotonergic, muscarinic, or α-adrenergic agonists that elicited comparable or lower effects on CDP-diacylglycerol versus inositol phosphates, the antidepressants dose-dependently induced significantly greater accumulations of CDP-diacylglycerol. Conclusion: Chemically divergent antidepressant agents commonly and significantly enhanced the accumulation of CDP-diacylglycerol. The latter is not only a derived product of phosphoinositide hydrolysis but is also a crucial intermediate in the biosynthesis of several signaling substrates. Hence, altered CDP-diacylglycerol signaling might be implicated in the pathophysiology of depression or the mechanism of action of diverse antidepressant medications. Page 1 of 18 (page number not for citation purposes) BMC Neuroscience 2008, 9:12 http://www.biomedcentral.com/1471-2202/9/12 Background Several past studies examined IP signaling, but not the sta- Major depression is an increasingly prevalent mood disor- tus of diacylglycerol (DG) production or signaling, as a der that afflicts millions of people worldwide [1-3]. While potential target of disease pathology or pharmacological a number of medications is available for managing the treatment with antidepressants [31-33]. Diacylglycerol disease symptoms, the mechanism of action of current signaling is important because this lipid is the endog- antidepressants is not well understood [4,5]. It is known, enous regulator of PKC activity, and the latter is one of the however, that antidepressant medications generally indices shown to be altered in depressed persons [31- increase the synaptic levels of the monoamine neurotrans- 33,61]. Moreover, PLC-stimulating receptors show differ- mitters serotonin, norepinephrine, and/or dopamine in ences in their capacity to generate diacylglycerol (relative discrete brain regions [6,7]. The monoamines are then to IP) from phospholipid hydrolysis [62,63]. Therefore, to thought to activate their cognate postsynaptic receptors the extent that PI signaling or PKC activity may be and modulate the activities of downstream signaling cas- involved in antidepressant drug action, it should be cades to produce the antidepressive effect [5,8-10]. important to clarify the specific effects of the agents on diacylglycerol production as a potential basis for their Monoamine receptors coupled to diverse signaling cas- therapeutic efficacy. Following our previously reported cades, including those mediated through adenylyl cyclase, preliminary observations [64], we have now examined phospholipases, and MAP Kinases [11-14]. Aspects of antidepressant drug effects on cellular diacylglycerol pro- each signaling system have been investigated as potential duction and metabolism, including the resynthesis of the downstream targets of antidepressive mechanisms with PI substrates. The results show that antidepressants multiple and sometimes divergent findings [8,15,16]. As belonging to diverse chemical and pharmacological examples, acute or chronic treatment with various antide- classes acutely increase the formation of CDP-diacylglyc- pressant compounds can lead to changes in basal or drug- erol (CDP-DG), a metabolic derivative of diacylglycerol, induced activities of brain adenylyl cyclase [17-20], phos- and that this effect does translate to enhanced resynthesis pholipase A2 [21], CREB [22,23], phosphoinositide-spe- of the PIs. The latter are physiologically critical not only as cific phospholipase C (PLC) [15,24,25], inositol substrates for PLC signaling but also as mediators in the phosphates (IPs) [26-29], phosphatidylinositides (PI) phosphatidylinositol-3-kinase (PI3K)/Akt signaling cas- [29,30], protein kinase C (PKC) [31-33], extracellular sig- cades. It is conceivable, therefore, that an acute molecular nal regulated kinase [16,34], ion channels [35,36], neuro- action of antidepressant agents that conserves or supple- trophins [37-39], and various neuropeptides [40-42]. ments cellular PIs could ultimately contribute to the ther- Antidepressants can also enhance neurogenesis [43-46], apeutic mechanism of these medications in depression. modulate neuronal excitability [47-49], and alter the gene expression of various signaling components including Results neurotransmitter transporters, receptors, transducers, and Chemically diverse antidepressant agents increase CDP- effectors [50-53]. While these observations suggest that diacylglycerol production changes in postsynaptic signaling cascades may constitute Diacylglycerol released from phospholipid breakdown is an integral component in the mechanisms that underlie normally rapidly phosphorylated to produce phospha- depression or its treatment with antidepressant medica- tidic acid. In the presence of [3H]cytidine-labeled CTP, tions, no signaling