Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain
© Tyeryar et al; licensee BioMed Central Ltd. 2008
Received: 13 April 2007
Accepted: 24 January 2008
Published: 24 January 2008
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.
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.
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.
Major depression is an increasingly prevalent mood disorder that afflicts millions of people worldwide [1–3]. 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, however, that antidepressant medications generally increase the synaptic levels of the monoamine neurotransmitters serotonin, norepinephrine, and/or dopamine in discrete brain regions [6, 7]. The monoamines are then thought to activate their cognate postsynaptic receptors and modulate the activities of downstream signaling cascades to produce the antidepressive effect [5, 8–10].
Monoamine receptors coupled to diverse signaling cascades, including those mediated through adenylyl cyclase, phospholipases, and MAP Kinases [11–14]. Aspects of each signaling system have been investigated as potential downstream targets of antidepressive mechanisms with multiple and sometimes divergent findings [8, 15, 16]. As examples, acute or chronic treatment with various antidepressant compounds can lead to changes in basal or drug-induced activities of brain adenylyl cyclase [17–20], phospholipase A2 , CREB [22, 23], phosphoinositide-specific phospholipase C (PLC) [15, 24, 25], inositol phosphates (IPs) [26–29], phosphatidylinositides (PI) [29, 30], protein kinase C (PKC) [31–33], extracellular signal regulated kinase [16, 34], ion channels [35, 36], neurotrophins [37–39], and various neuropeptides [40–42]. Antidepressants can also enhance neurogenesis [43–46], modulate neuronal excitability [47–49], and alter the gene expression of various signaling components including neurotransmitter transporters, receptors, transducers, and effectors [50–53]. 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.
The PI-related observations in particular have been corroborated by clinical studies showing that depressed persons may have reduced cortical levels of the PI precursor myo-inositol [54, 55]. Moreover, oral ingestion of bolus doses of myo-inositol could elicit antidepressive responses in rodents [56, 57], and enhance the recovery of clinically depressed patients . Consistent with these findings, chronic administration of antidepressant agents has been associated with increased levels of the PIs in human platelets [29, 30]. These observations suggest that alterations in the PI signaling pathway may be implicated in the pathophysiology of depression and/or the mode of action of antidepressant agents [5, 25, 59, 60].
Several past studies examined IP signaling, but not the status of diacylglycerol (DG) production or signaling, as a potential target of disease pathology or pharmacological treatment with antidepressants [31–33]. Diacylglycerol signaling is important because this lipid is the endogenous regulator of PKC activity, and the latter is one of the indices shown to be altered in depressed persons [31–33, 61]. Moreover, PLC-stimulating receptors show differences in their capacity to generate diacylglycerol (relative to IP) from phospholipid hydrolysis [62, 63]. Therefore, to the extent that PI signaling or PKC activity may be involved in antidepressant drug action, it should be important to clarify the specific effects of the agents on diacylglycerol production as a potential basis for their therapeutic efficacy. Following our previously reported preliminary observations , we have now examined antidepressant drug effects on cellular diacylglycerol production and metabolism, including the resynthesis of the PI substrates. The results show that antidepressants belonging to diverse chemical and pharmacological classes acutely increase the formation of CDP-diacylglycerol (CDP-DG), a metabolic derivative of diacylglycerol, and that this effect does translate to enhanced resynthesis of the PIs. The latter are physiologically critical not only as substrates for PLC signaling but also as mediators in the phosphatidylinositol-3-kinase (PI3K)/Akt signaling cascades. It is conceivable, therefore, that an acute molecular action of antidepressant agents that conserves or supplements cellular PIs could ultimately contribute to the therapeutic mechanism of these medications in depression.
Chemically diverse antidepressant agents increase CDP-diacylglycerol production
Among the brain regions, the hippocampus appeared to be more sensitive (greater response magnitudes at lower concentrations), whereas the striatum gave slightly more robust (maximally attained) effects. The drug responses were statistically dose-dependent for all effective agents in each tissue, but there were noticeable differences in potency or efficacy among the compounds as shown in the data. Thus, diverse antidepressant agents can acutely induce CDP-DG synthesis in depression-relevant regions of the rat brain.
Antidepressant-induced CDP-diacylglycerol formation translates into increased PI synthesis
Effects of monoamine oxidase inhibiting agents CDP-diacylglycerol formation and PI synthesis
Psychotropic agents lacking effects on CDP-diacylglycerol accumulation in rat cerebrocortical slices. Agents were tested at multiple concentrations ranging from 0.1–300 μM. Data from up to three separate runs were normalized and pooled for analysis by One-Way ANOVA. None of these compounds showed significant or concentration-related effects on CDP-diacylglycerol.
MAOIs that were effective in inducing CDP-DG production also showed enhanced effects on PI resynthesis (Figure 3), whereas other MAOIs that were ineffective on CDP-DG were equally ineffective in increasing PI resynthesis (data not shown). The MAOI data (Figure 3) also depict the significantly greater relative accumulation of PIs compared to the accumulation of CDP-DG, implying the conversion of CDP-DG to PI may be a dynamic or cumulative process.
We also tested a range of other psychotropic compounds in order to estimate the extent to which the CDP-DG response may characterize compounds with antidepressive activity. Neither the antipsychotic agents sulpiride, chlorpromazine and haloperidol, nor various other psychotropic compounds induced any significant effects on CDP-DG production (Table 1).
Antidepressant Agents Generally Enhance Inositol Phosphate Accumulation
Antidepressant-induced CDP-diacylglycerol formation partially depends on PI hydrolysis
Lithium is not required for antidepressant drug effects on CDP-diacylglycerol
Antidepressants elicit greater stimulation of CDP-diacylglycerol production than IP formation
Monoamine receptor agonists exert divergent effects on CDP-diacylglycerol
Various experimental approaches have been used in the past to demonstrate positive effects of select antidepressant agents on the IP arm of PI signaling cascades [15, 27, 30, 66]. The present data demonstrate for the first time that antidepressant agents could increase by several-fold the production of CDP-diacylglycerol, a crucial signaling intermediate that is both a derivative of diacylglycerol and a precursor for the biosynthesis of PIs. This effect appeared to be common across agents from diverse chemical and pharmacological classes, seeing it was obtained with the tricyclics imipramine and desipramine, the SSRIs fluoxetine and paroxetine, the atypicals maprotiline and nomifensine, and the MAO inhibitors phenelzine and hydralazine. Thus, the findings could point to a mechanism (enhanced phospholipid biosynthesis) and mediator (CDP-diacylglycerol) for the biochemical and possibly clinical effects that may be common across diverse classes of antidepressants.
Earlier studies observed that several antidepressants enhanced [3H]IP accumulation and [3H]PI labeling in rat cortical slices [27, 29]. The mechanism of this response was confounding, seeing other studies that directly assayed phospholipase C activity suggested that the drugs could stimulate or inhibit PLC-mediated PI hydrolysis [15, 24]. In the present study, the antidepressants were equally effective in enhancing CDP-DG in the presence or absence of LiCl, whereas the presence of Li+ was necessary to demonstrate the effects of the drugs on IP accumulation. This implies that the compounds do not inhibit IP breakdown (otherwise they would have substituted for Li+), and that their effects on IP accumulation is probably secondary and passive to the enhanced production of upstream CDP-DG and PI substrates.
Numerous agents acting at diverse receptor systems can enhance PI metabolism, but few such pure receptor agonists are known to exhibit an antidepressive effect in humans or animals . How then might an effect of antidepressant agents on CDP-DG and PI synthesis be associated with the antidepressive efficacy of the compounds? An attempt to address this question led to comparisons of the ratio data between the antidepressants as a group and agonists at alpha-adrenergic, 5HT2 serotonergic, and dopaminergic receptors (which are implicated in depression) as well as the muscarinic cholinergic receptor that is not known to contribute to the actions of antidepressant agents. While all these receptors are coupled to PI hydrolysis, only some 5HT2 agonists and SKF38393 have been shown to elicit antidepressive effects in rodent models [67–69]. The ratio of CDP-DG to IP components for phenylephrine and carbachol decreased, for α-methylserotonin remained unchanged, and for SKF38393 increased, with increasing concentrations of agonist. For the antidepressant agents, the ratios were not only significantly elevated, but actually increased in a concentration-dependent fashion. This was true of all classes of antidepressants examined, including the effective members among the MAO inhibitors. The similarity between the effects of SKF38393 and the antidepressants may underlie the behavioral antidepressant efficacy of the compound as previously demonstrated in the rodent model . Hence, to the extent that CDP-DG production might be relevant to depression or the mechanism of antidepressant drug action, an antidepressive agent should not merely increase PI hydrolysis, but the CDP-DG produced must exceed and probably precede the production of PI messengers.
It was noteworthy that even the SSRIs produced significant increases in each CDP-DG ratio, whereas the direct 5HT2 agonist α-methylserotonin did not. If the biological actions of the SSRIs were limited to the actions of the drugs to enhance synaptic serotonin levels, then one would expect direct serotonin receptor stimulation to elicit similar effects. This disparity should suggest that facilitation of synaptic serotonin levels may not be the sole or sufficient mechanism of action of the SSRIs. Rather, antidepressant-enhanced synaptic serotonin may work in concert with antidepressant-facilitated neurolipid biosynthesis to achieve the type and level of downstream signaling responses that may contribute to the antidepressive effect.
Although CDP-DG production induced by the antidepressants may be derived from phosphoinositide breakdown, it is not impossible that the CDP-DG pool may be generated from additional endogenous sources. In an initial attempt to address this, we observed that antidepressant-mediated accumulation of [3H]CDP-DG was completely blocked by the non-specific phosphoinositide inhibitor, neomycin, in prefrontal or hippocampal tissues. Conversely, the selective PLC inhibitor U73122 could only partially decrease CDP-DG production, while it completely blocked the release of IPs. These results suggest that, while the integrity of the phosphoinositide pool is essential to the full effect of antidepressant agents on CDP-DG (based on the neomycin data), the PLC-accessible pool of phosphoinositides may not be the only source of antidepressant-mediated CDP-DG production (based on the U73122 data). It is known that neural (and other) cells maintain multiple pools of phosphoinositides not all of which may be accessible to PLC-mediated cycling. The possibility that the antidepressants could mobilize these additional reserves of PI substrates, particularly following acute or chronic metabolic depletion of the substrates, should be an interesting subject for future investigations.
A critical question that was also attempted relates to the extent to which the CDP-DG response may be specific to antidepressant agents versus other psychotropic drugs. After testing a wide range of compounds, we observed that neither the antipsychotics chlorpromazine and haloperidol, nor several other psychotropic agents were capable of inducing the degree of CDP-DG effects observed with the antidepressant agents. While this suggests that the CDP-DG effect, particularly the dose-related effect on CDP-DG/IP ratio, could reflect a characteristic property of antidepressant medications, we were equally surprised by the disparity in efficacy among the MAO inhibitors. The ineffective agents included the nonselective MAO A/B inhibitor clorgyline, and the selective MAO-B inhibitors pargyline and selegiline. At least one of these, clorgyline, is used clinically for the treatment of depression. Conversely, other MAO inhibitors, including phenelzine, hydralazine and tranylcypromine were significantly effective in inducing CDP-DG. The chemical or biological basis for this disparity among the MAOIs is still unclear. Indeed, considering the relatively marked effects of phenelzine and hydralazine, it is possible that inhibition of MAO-mediated monoamine breakdown may not be the predominant mechanism by which these compounds modulate CDP-DG signaling.
It remains to be determined how the present in vitro observations may relate to in vivo drug concentrations or behavioral effects. While all tested antidepressants generally induced significant CDP-DG or PI effects at concentrations of 1–10 μM (and as low as 0.1–0.3 μM for phenelzine and hydralazine), the in vivo concentrations or doses needed to induce comparable effects have not been determined. Nevertheless, a recent report suggests that antidepressants may induce in vivo CDP-DG or phosphoinositide effects at doses commonly used to elicit antidepressant-like behaviors in animal models . Additional studies should help to clarify these questions.
Collectively, the present data raise the speculation that depression may be associated with decreased turnover or biological efficacy of phosphoinositide-related signaling systems, possibly due to depletion of phosphoinositide substrates. Antidepressants may act by mobilizing CDP-DG to help replenish or supplement the pool of available PIs. In addition to PLC-mediated cascades, phosphatidylinositol is a key substrate for the PI3K signaling pathway . Earlier reports showed that PI3K signaling is relevant to the induction of neurogenesis or neuronal survival and plasticity [72, 73]. A recent study determined that the activity of PI3K and its downstream target, Akt, is decreased in postmortem brain tissues of depressed suicide victims . Extensive interactions or crosstalk exists among downstream mediators of the PLC and PI3K systems and other signaling pathways that have been implicated in depression. Thus, it is conceivable that an early action of antidepressant agents to enhance the mobilization of CDP-DG could lead to coordinate effects on multiple signaling systems, which might then explain the various molecular, structural, and functional effects of the drugs. The data, however, do not exclude the possibility that multiple signaling pathways, including the adenylyl cyclase pathway, may be involved in depression or the mechanism of action of antidepressant agents. Nor do the data directly address the conventional notion that antidepressive medications need be administered chronically in order to elicit a clinical effect. Additional studies also are required before a model could emerge that might relate these findings to the various theories of depression or antidepressant mechanisms. Notwithstanding these pending questions, the present CDP-DG findings demonstrate a functional biochemical response that is common across divergent antidepressant classes, is elicited within the time frame that the drug is available to the tissues, and may have a plausible role in the pathology of depression or the mechanism of action of current antidepressive agents.
Male Sprague-Dawley rats weighing 225–250 g were obtained from Zivic Laboratories (Zelienople, PA) and housed in climate-controlled facilities with a 12-h light/dark cycle for at least 3 days before use. The animals were caged in groups of three and allowed free access to food and water. Protocols for the care and use of the experimental animals were approved by the Institutional Animal Care and Use Committee and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Drugs and chemicals
Antidepressant compounds and buffer reagents were purchased from Sigma-Aldrich (St. Louis, MO). SKF38393 was a gift from the NIMH Chemical Synthesis Program (NIMH, Bethesda, US). Nomifensine was first dissolved in 0.2% tartaric acid and SKF38393 in distilled water before either drug was diluted to use concentrations in assay buffer. Other drugs were prepared fresh in HEPES bicarbonate assay buffer (HBB) . Each experiment was performed on multiple occasions using fresh preparations of drugs. Protein was assayed by the Bradford method using BioRad protein assay reagents (BioRad, Hercules, CA).
Measurement of CDP-diacylglycerol accumulation
Accumulation of CDP-diacylglycerol was measured in brain slice preparations by taking advantage of the CTP-phosphatidate transfer reaction as previously described in detail [75–77]. Briefly, male Sprague-Dawley rats weighing between 225 and 300 g were rapidly decapitated and the brains removed and rinsed in calcium-free HBB [75, 78]. Brain regions of interest, including the prefrontal cortex, hippocampus, and striatum, were quickly dissected out and 350 μm prisms prepared using a McIlwain tissue chopper . The slices were washed with calcium-free HBB and pre-incubated for 45 minutes at 37°C. Slice aliquots of approximately 300 μg protein were then incubated with 1.5 μCi of 5- [3H]cytidine (20 Ci/mmol; American Radiolabeled Chemicals, St. Louis, MO) in order to generate an endogenous pool of radiolabeled cytidine triphosphate (CTP) for feeding into the CTP:phosphatidate transfer reaction . Following addition of 5 mM LiCl, test drugs or buffer were added for a total volume of 250 μl, and incubation continued for 60 or 90 min as indicated. Reactions were terminated by addition of 1.5 ml chloroform-methanol-1M HCl (100:200:1). Formed lipids were extracted by liquid partitioning in chloroform followed by centrifugation at 1000 × g for 5 min in order to separate the liquid phases. Aliquots of the organic phase were quantitatively transferred into scintillation vials, dried at room temperature, and redissolved in Biosafe scintillation cocktail. Radioactivity in this lipid fraction was determined by liquid scintillation spectrometry; this activity corresponds to [3H]CDP-DG as previously indicated [63, 75, 79], and confirmed by us through thin layer chromatographic analysis of the reaction products (unpublished observations).
Measurement of inositol phospholipid resynthesis
Brain tissues were prepared and incubated as described above for assaying CDP-DG, except that 1.5 μCi of [3H]inositol (20 Ci/mmol; American Radiolabeled Chemicals, St. Louis, MO) was used instead of [3H]cytidine to label the slices. Following the labeling incubation, drugs were added and allowed to act for 60 or 90 min as indicated. Samples were extracted with chloroform-methanol-1M HCl (100:200:1), partitioned with chloroform into aqueous and organic phases, and aliquots of the organic phase dried and assessed for radioactivity that corresponded to the inositol phospholipids. For purposes of the present study, it was not necessary to attempt to separate the multiple phosphorylated or isomeric forms of these phospholipids. Hence, the data potentially represent the mix of phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol 4,5-bisphosphate in any of their positional isomeric forms. Based on the levels of the phospholipids present at the start of drug treatment, a subsequent decrease is seen as depletion, whereas an increase in the [3H]inositol-labeled pool of the phospholipids is considered to represent further phospholipid synthesis or resynthesis [76, 80].
Measurement of inositol phosphate accumulation
To measure the levels of IPs formed, tissues were treated exactly as in the foregoing PI synthesis assays, including the use of [3H]inositol for prelabeling of the PI pool. The 250 μl reactions were terminated by mixing the samples with 1.5 ml of chloroform – methanol – 1 M HCl (100:200:1). Following chloroform-mediated partitioning of the extracts as described , aliquots of the aqueous phase were analyzed for the content of [3H]IPs by Dowex anion exchange chromatography [65, 78]. An IP fraction was collected from the eluate and the solution converted into a gel by use of Scintisafe Gel (Fisher Scientific, Pittsburgh, PA). The amounts of IP-associated radioactivity in the samples were then measured by liquid scintillation spectrometry.
Data from the various experiments were normalized relative to the respective control or basal measurements, and then pooled for analysis. Data were tested by an appropriate analysis of variance (ANOVA) using SPSS software (SPSS, Chicago, IL, USA). Where warranted, the ANOVAs were followed by post hoc analyses using the Dunnett test to compare various treatment means to their respective controls. Statistical comparisons were considered significant at p < 0.05 or better.
This research was supported by grant #DA017614 from the US National Institutes of Health.
- Waslick BD, Kandel R, Kakouros A: Depression in children and adolescents: an overview. The many faces of depression in children and adolescents. Edited by: Shaffer D and Waslick BD. 2002, Washington DC, American Psychiatric Publishing, Inc., 1-29.
- Costello EJ, Mustillo S, Erkanli A, Keeler G, Angold A: Prevalence and development of psychiatric disorders in childhood and adolescence. Arch Gen Psychiatry. 2003, 60: 837-844. 10.1001/archpsyc.60.8.837.View ArticlePubMed
- Hasin DS, Goodwin RD, Stinson FS, Grant BF: Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry. 2005, 62: 1097-1106. 10.1001/archpsyc.62.10.1097.View ArticlePubMed
- Ciraulo DA, Tsirulnik-Barts L, Shader RI, Greenblatt DJ: Clinical pharmacology and therapeutics of antidepressants. Pharmacotherapy of depression. Edited by: Ciraulo DA and Shader RI. 2004, Totowa NJ, Humana Press, 33-119.View Article
- Taylor C, Fricker AD, Devi LA, Gomes I: Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways. Cell Signal. 2005, 17: 549-557. 10.1016/j.cellsig.2004.12.007.PubMed CentralView ArticlePubMed
- Feighner JP: Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999, 60: 4-11.View ArticlePubMed
- Frazer A: Norepinephrine involvement in antidepressant action. J Clin Psychiatry. 2000, 61: 25-30.PubMed
- Gould TD, Manji HK: Signaling networks in the pathophysiology and treatment of mood disorders. J Psychosom Res. 2002, 53: 687-697. 10.1016/S0022-3999(02)00426-9.View ArticlePubMed
- Coyle JT, Duman RS: Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron. 2003, 38: 157-160. 10.1016/S0896-6273(03)00195-8.View ArticlePubMed
- Delgado PL: How antidepressants help depression: mechanisms of action and clinical response. J Clin Psychiatry. 2004, 65: 25-30.PubMed
- De Vivo M, Maayani S: Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. J Pharmacol Exp Ther. 1986, 238: 248-253.PubMed
- De Vivo M, Maayani S: Stimulation and inhibition of adenylyl cyclase by distinct 5-hydroxytryptamine receptors. Biochem Pharmacol. 1990, 40: 1551-1558. 10.1016/0006-2952(90)90453-R.View ArticlePubMed
- Dumuis A, Sebben M, Bockaert J: Pharmacology of 5-hydroxytryptamine-1A receptors which inhibit cAMP production in hippocampal and cortical neurons in primary culture. Mol Pharmacol. 1988, 33: 178-186.PubMed
- Undie AS, Weinstock J, Sarau HM, Friedman E: Evidence for a distinct D1-like dopamine receptor that couples to activation of phosphoinositide metabolism in brain. J Neurochem. 1994, 62: 2045-2048.View ArticlePubMed
- Dwivedi Y, Agrawal AK, Rizavi HS, Pandey GN: Antidepressants reduce phosphoinositide-specific phospholipase C (PI-PLC) activity and the mRNA and protein expression of selective PLC beta 1 isozyme in rat brain. Neuropharmacology. 2002, 43: 1269-1279. 10.1016/S0028-3908(02)00253-8.View ArticlePubMed
- Fumagalli F, Molteni R, Calabrese F, Frasca A, Racagni G, Riva MA: Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain. J Neurochem. 2005, 93: 1551-1560. 10.1111/j.1471-4159.2005.03149.x.View ArticlePubMed
- Chen J, Rasenick MM: Chronic antidepressant treatment facilitates G protein activation of adenylyl cyclase without altering G protein content. J Pharmacol Exp Ther. 1995, 275: 509-517.PubMed
- Hines LM, Tabakoff B: Platelet adenylyl cyclase activity: a biological marker for major depression and recent drug use. Biol Psychiatry. 2005, 58: 955-962. 10.1016/j.biopsych.2005.05.040.View ArticlePubMed
- Odagaki Y, Garcia-Sevilla JA, Huguelet P, La Harpe R, Koyama T, Guimon J: Cyclic AMP-mediated signaling components are upregulated in the prefrontal cortex of depressed suicide victims. Brain Res. 2001, 898: 224-231. 10.1016/S0006-8993(01)02188-6.View ArticlePubMed
- Shimizu M, Nishida A, Zensho H, Yamawaki S: Chronic antidepressant exposure enhances 5-hydroxytryptamine7 receptor- mediated cyclic adenosine monophosphate accumulation in rat frontocortical astrocytes. J Pharmacol Exp Ther. 1996, 279: 1551-1558.PubMed
- Qu Y, Chang L, Klaff J, Seemann R, Rapoport SI: Imaging brain phospholipase A2-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats. Neuropsychopharmacology. 2003, 28: 1219-1226. 10.1038/sj.npp.1300177.View ArticlePubMed
- Nibuya M, Nestler EJ, Duman RS: Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci. 1996, 16: 2365-2372.PubMed
- Yamada S, Yamamoto M, Ozawa H, Riederer P, Saito T: Reduced phosphorylation of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder. J Neural Transm. 2003, 110: 671-680. 10.1007/s00702-002-0810-8.View ArticlePubMed
- Fukuda H, Nishida A, Saito H, Shimizu M, Yamawaki S: Imipramine stimulates phospholipase C activity in rat brain. Neurochem Int. 1994, 25: 567-571. 10.1016/0197-0186(94)90155-4.View ArticlePubMed
- Pacheco MA, Stockmeier C, Meltzer HY, Overholser JC, Dilley GE, Jope RS: Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain. Brain Res. 1996, 723: 37-45. 10.1016/0006-8993(96)00207-7.View ArticlePubMed
- Butler PD, Barkai AI: Agonist-stimulation of cerebral phosphoinositide turnover following long-term treatment with antidepressants. Adv Exp Med Biol. 1987, 221: 531-547.View ArticlePubMed
- Osborne NN: Tricyclic antidepressants, mianserin, and ouabain stimulate inositol phosphate formation in vitro in rat cortical slices. Neurochem Res. 1988, 13: 105-111. 10.1007/BF00973321.View ArticlePubMed
- Sanders-Bush E, Breeding M, Knoth K, Tsutsumi M: Sertraline-induced desensitization of the serotonin 5HT-2 receptor transmembrane signaling system. Psychopharmacology (Berlin). 1989, 99: 64-69. 10.1007/BF00634454.View Article
- Pandey GN, Pandey SC, Davis JM: Effect of desipramine on inositol phosphate formation and inositol phospholipids in rat brain and human platelets. Psychopharmacol Bull. 1991, 27: 255-261.PubMed
- Pandey SC, Davis JM, Schwertz DW, Pandey GN: Effect of antidepressants and neuroleptics on phosphoinositide metabolism in human platelets. J Pharmacol Exp Ther. 1991, 256: 1010-1018.PubMed
- Morishita S, Aoki S, Watanabe S: Different effect of desipramine on protein kinase C in platelets between bipolar and major depressive disorders. Psychiatry Clin Neurosci. 1999, 53: 11-15. 10.1046/j.1440-1819.1999.00479.x.View ArticlePubMed
- Morishita S, Aoki S: Effects of tricyclic antidepressants on protein kinase C activity in rabbit and human platelets in vivo. J Affect Disord. 2002, 70: 329-332. 10.1016/S0165-0327(01)00333-0.View ArticlePubMed
- Mann CD, Vu TB, Hrdina PD: Protein kinase C in rat brain cortex and hippocampus: effect of repeated administration of fluoxetine and desipramine. Br J Pharmacol. 1995, 115: 595-600.PubMed CentralView ArticlePubMed
- Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G: The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci. 2003, 23: 7311-7316.PubMed
- Shimizu M, Nishida A, Hayakawa H, Yamawaki S: Ca2+ release from inositol 1,4,5-trisphosphate-sensitive Ca2+ store by antidepressant drugs in cultured neurons of rat frontal cortex. J Neurochem. 1993, 60: 595-601. 10.1111/j.1471-4159.1993.tb03190.x.View ArticlePubMed
- Cuellar-Quintero JL, Garcia DE, Cruzblanca H: The antidepressant imipramine inhibits the M-type K+ current in rat sympathetic neurons. Neuroreport. 2001, 12: 2195-2198. 10.1097/00001756-200107200-00030.View ArticlePubMed
- Coppell AL, Pei Q, Zetterstrom TS: Bi-phasic change in BDNF gene expression following antidepressant drug treatment. Neuropharmacology. 2003, 44: 903-910. 10.1016/S0028-3908(03)00077-7.View ArticlePubMed
- Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A, Nawa H, Aloyz R, Ernfors P, Castren E: Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci. 2003, 23: 349-357.PubMed
- Xu H, Steven RJ, Li XM: Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus. Neuropsychopharmacology. 2003, 28: 53-62. 10.1038/sj.npp.1300009.View ArticlePubMed
- Wong ML, Khatri P, Licinio J, Esposito A, Gold PW: Identification of hypothalamic transcripts upregulated by antidepressants. Biochem Biophys Res Commun. 1996, 229: 275-279. 10.1006/bbrc.1996.1792.View ArticlePubMed
- Manev R, Uz T, Manev H: Fluoxetine increases the content of neurotrophic protein S100beta in the rat hippocampus. Eur J Pharmacol. 2001, 420: R1-R2. 10.1016/S0014-2999(01)00989-X.View ArticlePubMed
- Dziedzicka-Wasylewska M, Dlaboga D, Pierzchala-Koziec K, Rogoz Z: Effect of tianeptine and fluoxetine on the levels of Met-enkephalin and mRNA encoding proenkephalin in the rat. J Physiol Pharmacol. 2002, 53: 117-125.PubMed
- Duman RS, Nakagawa S, Malberg J: Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology. 2001, 25: 836-844. 10.1016/S0893-133X(01)00358-X.View ArticlePubMed
- Malberg JE, Eisch AJ, Nestler EJ, Duman RS: Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000, 20: 9104-9110.PubMed
- Manev H, Uz T, Smalheiser NR, Manev R: Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol. 2001, 411: 67-70. 10.1016/S0014-2999(00)00904-3.View ArticlePubMed
- Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003, 301: 805-809. 10.1126/science.1083328.View ArticlePubMed
- Contreras CM, Rodriguez-Landa JF, Gutierrez-Garcia AG, Bernal-Morales B: The lowest effective dose of fluoxetine in the forced swim test significantly affects the firing rate of lateral septal nucleus neurones in the rat. J Psychopharmacol. 2001, 15: 231-236.View ArticlePubMed
- Dong J, Blier P: Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment. Psychopharmacology (Berl). 2001, 155: 52-57. 10.1007/s002130000665.View Article
- Langosch JM, Walden J: Effects of the atypical antidepressant trimipramine on neuronal excitability and long-term potentiation in guinea pig hippocampal slices. Prog Neuropsychopharmacol Biol Psychiatry. 2002, 26: 299-302. 10.1016/S0278-5846(01)00269-X.View ArticlePubMed
- Lesch KP, Manji HK: Signal-transducing G proteins and antidepressant drugs: evidence for modulation of alpha subunit gene expression in rat brain. Biol Psychiatry. 1992, 32: 549-579. 10.1016/0006-3223(92)90070-G.View ArticlePubMed
- Drigues N, Poltyrev T, Bejar C, Weinstock M, Youdim MB: cDNA gene expression profile of rat hippocampus after chronic treatment with antidepressant drugs. J Neural Transm. 2003, 110: 1413-1436. 10.1007/s00702-003-0077-8.View ArticlePubMed
- Landgrebe J, Welzl G, Metz T, van Gaalen MM, Ropers H, Wurst W, Holsboer F: Molecular characterisation of antidepressant effects in the mouse brain using gene expression profiling. J Psychiatr Res. 2002, 36: 119-129. 10.1016/S0022-3956(01)00061-9.View ArticlePubMed
- Palotas M, Palotas A, Puskas LG, Kitajka K, Pakaski M, Janka Z, Molnar J, Penke B, Kalman J: Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram. Int J Neuropsychopharmacol. 2004, 7: 401-413. 10.1017/S1461145704004493.View ArticlePubMed
- Coupland NJ, Ogilvie CJ, Hegadoren KM, Seres P, Hanstock CC, Allen PS: Decreased prefrontal Myo-inositol in major depressive disorder. Biol Psychiatry. 2005, 57: 1526-1534. 10.1016/j.biopsych.2005.02.027.View ArticlePubMed
- Barkai AI, Dunner DL, Gross HA, Mayo P, Fieve RR: Reduced myo-inositol levels in cerebrospinal fluid from patients with affective disorder. Biol Psychiatry. 1978, 13: 65-72.PubMed
- Einat H, Karbovski H, Korik J, Tsalah D, Belmaker RH: Inositol reduces depressive-like behaviors in two different animal models of depression. Psychopharmacology (Berl). 1999, 144: 158-162. 10.1007/s002130050989.View Article
- Einat H, Clenet F, Shaldubina A, Belmaker RH, Bourin M: The antidepressant activity of inositol in the forced swim test involves 5-HT(2) receptors. Behav Brain Res. 2001, 118: 77-83. 10.1016/S0166-4328(00)00314-4.View ArticlePubMed
- Levine J: Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol. 1997, 7: 147-155. 10.1016/S0924-977X(97)00409-4.View ArticlePubMed
- Manji HK, Chen G: Post-receptor signaling pathways in the pathophysiology and treatment of mood disorders. Curr Psychiatry Rep. 2000, 2: 479-489. 10.1007/s11920-000-0006-6.View ArticlePubMed
- Shelton RC: Intracellular mechanisms of antidepressant drug action. Harv Rev Psychiatry. 2000, 8: 161-174. 10.1093/hrp/8.4.161.View ArticlePubMed
- Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992, 258: 607-614. 10.1126/science.1411571.View ArticlePubMed
- Sarri E, Picatoste F, Claro E: Neurotransmitter-specific profiles of inositol phosphates in rat brain cortex: relation to the mode of receptor activation of phosphoinositide phospholipase C1. The Journal of Pharmacology and Experimental Therapeutics. 1995, 272: 77-84.PubMed
- Claro E, Fain JN, Picatoste F: Noradrenaline stimulation unbalances the phosphoinositide cycle in rat cerebral cortical slices. J Neurochem. 1993, 60: 2078-2086. 10.1111/j.1471-4159.1993.tb03492.x.View ArticlePubMed
- Tyeryar KR, Undie AS: Diverse antidepressants modulate one or more components of phosphoinositide signaling cascades in depression-relevant brain regions. Soc Neurosci Abstr. 2002, 27: 306-306.
- Undie AS, Friedman E: Stimulation of a dopamine D1 receptor enhances inositol phosphates formation in rat brain. J Pharmacol Exp Ther. 1990, 253: 987-992.PubMed
- Pandey GN, Dwivedi Y, Kumari R, Janicak PG: Protein kinase C in platelets of depressed patients. Biol Psychiatry. 1998, 44: 909-911. 10.1016/S0006-3223(97)00535-0.View ArticlePubMed
- Lucki I, Singh A, Kreiss DS: Antidepressant-like behavioral effects of serotonin receptor agonists. Neurosci Biobehav Rev. 1994, 18: 85-95. 10.1016/0149-7634(94)90039-6.View ArticlePubMed
- Cryan JF, Lucki I: Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine(2C) receptors. J Pharmacol Exp Ther. 2000, 295: 1120-1126.PubMed
- D'Aquila PS, Collu M, Pani L, Gessa GL, Serra G: Antidepressant-like effect of selective dopamine D1 receptor agonists in the behavioural despair animal model of depression. Eur J Pharmacol. 1994, 262: 107-111. 10.1016/0014-2999(94)90033-7.View ArticlePubMed
- Tyeryar KR, Undie AS: Tandem regulation of phosphoinositide signaling and acute behavioral effects induced by antidepressant agents in rats. Psychopharmacology (Berl). 2007, 193: 271-282. 10.1007/s00213-007-0784-1.View Article
- Downes CP, Carter AN: Phosphoinositide 3-kinase: a new effector in signal transduction?. Cell Signal. 1991, 3: 501-513. 10.1016/0898-6568(91)90027-R.View ArticlePubMed
- Daw MI, Bortolotto ZA, Saulle E, Zaman S, Collingridge GL, Isaac JT: Phosphatidylinositol 3 kinase regulates synapse specificity of hippocampal long-term depression. Nat Neurosci. 2002, 5: 835-836. 10.1038/nn903.View ArticlePubMed
- Edstrom A, Ekstrom PA: Role of phosphatidylinositol 3-kinase in neuronal survival and axonal outgrowth of adult mouse dorsal root ganglia explants. J Neurosci Res. 2003, 74: 726-735. 10.1002/jnr.10686.View ArticlePubMed
- Hsiung SC, Adlersberg M, Arango V, Mann JJ, Tamir H, Liu KP: Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. J Neurochem. 2003, 87: 182-194. 10.1046/j.1471-4159.2003.01987.x.View ArticlePubMed
- Undie AS: Relationship between dopamine agonist stimulation of inositol phosphate formation and cytidine diphosphate-diacylglycerol accumulation in brain slices. Brain Res. 1999, 816: 286-294. 10.1016/S0006-8993(98)01076-2.View ArticlePubMed
- Panchalingam S, Undie AS: SKF83959 exhibits biochemical agonism by stimulating phosphoinositide hydrolysis and [35S]GTPgS binding in rat and monkey brain. Neuropharmacology. 2001, 40: 826-837. 10.1016/S0028-3908(01)00011-9.View ArticlePubMed
- Godfrey PP: Potentiation by lithium of CMP-phosphatidate formation in carbachol-stimulated rat cerebral-cortical slices and its reversal by myo-inositol. Biochem J. 1989, 258: 621-624.PubMed CentralView ArticlePubMed
- Undie AS, Friedman E: Selective dopaminergic mechanism of dopamine and SKF38393 stimulation of inositol phosphate formation in rat brain. Eur J Pharmacol. 1992, 226: 297-302. 10.1016/0922-4106(92)90046-X.View ArticlePubMed
- Stubbs EB, Agranoff BW: Lithium enhances muscarinic receptor-stimulated CDP-diacylglycerol formation in inositol-depleted SK-N-SH neuroblastoma cells. J Neurochem. 1993, 60: 1292-1299. 10.1111/j.1471-4159.1993.tb03289.x.View ArticlePubMed
- Billah MM, Michell RH: Stimulation of the breakdown and resynthesis of phosphatidylinositol in rat hepatocytes by angiotensin, vasopressin and adrenaline. Biochem Soc Trans. 1978, 6: 1033-1035.View ArticlePubMed
This article is published under license to 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.