Abstract
BackgroundMajor 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.ResultsMultiple 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.ConclusionChemically 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.
Highlights
Major depression is a serious mood disorder affecting millions of adults and children worldwide
Acute or chronic treatment with various antidepressant compounds can lead to changes in basal or druginduced activities of brain adenylyl cyclase [17,18,19,20], phospholipase A2 [21], CREB [22,23], phosphoinositide-specific phospholipase C (PLC) [15,24,25], inositol phosphates (IPs) [26,27,28,29], phosphatidylinositides (PI) [29,30], protein kinase C (PKC) [31,32,33], extracellular signal regulated kinase [16,34], ion channels [35,36], neurotrophins [37,38,39], and various neuropeptides [40,41,42]
Antidepressants elicit greater stimulation of CDPdiacylglycerol production than IP formation To determine if antidepressant agents exert differential effects on CDP-DG production compared to PI hydrolysis, we examined the ratios of CDP-DG production relative to the IPs (CDP-DG/IP ratio) in corresponding treatment conditions
Summary
Major depression is a serious mood disorder affecting millions of adults and children worldwide. While a number of medications is available for managing the disease symptoms, the mechanism of action of current antidepressants is not well understood [4,5] It is known, that antidepressant medications generally increase the synaptic levels of the monoamine neurotransmitters serotonin, norepinephrine, and/or dopamine in discrete brain regions [6,7]. Antidepressants can enhance neurogenesis [43,44,45,46], modulate neuronal excitability [47,48,49], and alter the gene expression of various signaling components including neurotransmitter transporters, receptors, transducers, and effectors [50,51,52,53] While these observations suggest that changes in postsynaptic signaling cascades may constitute an integral component in the mechanisms that underlie depression or its treatment with antidepressant medications, no signaling cascade has been identified that adequately explains the behavioral and clinical data
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