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Open Access Research article

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 Undieh1*

Author Affiliations

1 Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA

2 Laboratory of Integrative Neuropharmacology, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA

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BMC Neuroscience 2008, 9:12  doi:10.1186/1471-2202-9-12

Published: 24 January 2008

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.