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Antidepressant stimulation of CDP-diacylglycerol synthesis does not require monoamine reuptake inhibition.

Aboukhatwa MA, Undieh AS - BMC Neurosci (2010)

Bottom Line: With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished.Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues.Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Integrative Neuropharmacology, Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania, USA.

ABSTRACT

Background: Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of brain CDP-diacylglycerol synthase - the enzyme that catalyzes the physiological synthesis of CDP-diacylglycerol.

Results: Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with p-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues.

Conclusion: Antidepressants probably induce the activity of CDP-diacylglycerol synthase leading to increased production of CDP-diacylglycerol and facilitation of downstream phosphatidylinositol synthesis. Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis. Hence, the present findings should strengthen the notion that modulation of brain phosphatidylinositide signaling probably contributes to the molecular mechanism of diverse antidepressant medications.

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Effects of PCPA-induced serotonin depletion on antidepressant stimulation of CDP-diacylglycerol synthesis in brain tissue. Brain slices were prepared from the frontal cortex or hippocampus tissues of saline-injected control rats or animals that had been administered p-chlorophenylalanine (PCPA) to deplete endogenous serotonin stores. The tissue slices were labeled with [3H]cytidine and then incubated with predetermined concentrations of the antidepressant drugs fluoxetine (FLX, 100 μM), imipramine (IMI, 300 μM), or maprotiline (MAP, 100 μM). After 90 min, accumulated [3H]CDP-diacylglycerol was measured. Data were calculated as percentages relative to the respective basal accumulations in the control or PCPA group. Each bar represents the mean ± SEM (N = 6). PCPA treatment had no significant effect on basal [3H]CDP-diacylglycerol accumulation in either tissue; such basal effects being, respectively, 8194+806 v. 8555+1657 for control versus PCPA in frontal cortex, and 8026+1295 v. 8139+1642 for control versus PCPA in hippocampus. Each drug induced significant accumulations of [3H]CDP-diacylglycerol in either the control or PCPA tissues (ANOVA, p < 0.0001 for each drug). PCPA partially reduced FLX and MAP effects but did not eliminate any of the drug effects: ***p < 0.001, compared by posthoc Tukey tests.
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Figure 1: Effects of PCPA-induced serotonin depletion on antidepressant stimulation of CDP-diacylglycerol synthesis in brain tissue. Brain slices were prepared from the frontal cortex or hippocampus tissues of saline-injected control rats or animals that had been administered p-chlorophenylalanine (PCPA) to deplete endogenous serotonin stores. The tissue slices were labeled with [3H]cytidine and then incubated with predetermined concentrations of the antidepressant drugs fluoxetine (FLX, 100 μM), imipramine (IMI, 300 μM), or maprotiline (MAP, 100 μM). After 90 min, accumulated [3H]CDP-diacylglycerol was measured. Data were calculated as percentages relative to the respective basal accumulations in the control or PCPA group. Each bar represents the mean ± SEM (N = 6). PCPA treatment had no significant effect on basal [3H]CDP-diacylglycerol accumulation in either tissue; such basal effects being, respectively, 8194+806 v. 8555+1657 for control versus PCPA in frontal cortex, and 8026+1295 v. 8139+1642 for control versus PCPA in hippocampus. Each drug induced significant accumulations of [3H]CDP-diacylglycerol in either the control or PCPA tissues (ANOVA, p < 0.0001 for each drug). PCPA partially reduced FLX and MAP effects but did not eliminate any of the drug effects: ***p < 0.001, compared by posthoc Tukey tests.

Mentions: Control and serotonin-depleted tissues from the rat hippocampus or frontal cortex were tested for CDP-diacylglycerol responses to various antidepressant agents. The tissue slices were prelabeled with [3H]cytidine and then incubated with maximally effective concentrations of the antidepressant drugs fluoxetine (FLX, 100 μM), imipramine (IMI, 300 μM), or maprotiline (MAP, 100 μM); these dose selections were based on previously published studies with brain slice preparations [2,3]. While similar results were obtained in the hippocampus and frontal cortex, the results for the frontal cortex are shown in Fig. 1. Imipramine, fluoxetine, or maprotiline induced significant accumulations of CDP-diacylglycerol in the saline-pretreated control tissues as expected. Tissues depleted of serotonin also gave significant responses to the antidepressant agents, although the responses to fluoxetine in the frontal cortex and to fluoxetine and maprotiline in the hippocampus were significantly but partially (21-32%) reduced in p-chlorophenylalanine (PCPA)-pretreated tissues. The concentration and conditions of PCPA treatment in these experiments are known to result in practically complete depletion of serotonin from the tissues [7-9].


Antidepressant stimulation of CDP-diacylglycerol synthesis does not require monoamine reuptake inhibition.

Aboukhatwa MA, Undieh AS - BMC Neurosci (2010)

Effects of PCPA-induced serotonin depletion on antidepressant stimulation of CDP-diacylglycerol synthesis in brain tissue. Brain slices were prepared from the frontal cortex or hippocampus tissues of saline-injected control rats or animals that had been administered p-chlorophenylalanine (PCPA) to deplete endogenous serotonin stores. The tissue slices were labeled with [3H]cytidine and then incubated with predetermined concentrations of the antidepressant drugs fluoxetine (FLX, 100 μM), imipramine (IMI, 300 μM), or maprotiline (MAP, 100 μM). After 90 min, accumulated [3H]CDP-diacylglycerol was measured. Data were calculated as percentages relative to the respective basal accumulations in the control or PCPA group. Each bar represents the mean ± SEM (N = 6). PCPA treatment had no significant effect on basal [3H]CDP-diacylglycerol accumulation in either tissue; such basal effects being, respectively, 8194+806 v. 8555+1657 for control versus PCPA in frontal cortex, and 8026+1295 v. 8139+1642 for control versus PCPA in hippocampus. Each drug induced significant accumulations of [3H]CDP-diacylglycerol in either the control or PCPA tissues (ANOVA, p < 0.0001 for each drug). PCPA partially reduced FLX and MAP effects but did not eliminate any of the drug effects: ***p < 0.001, compared by posthoc Tukey tests.
© Copyright Policy - open-access
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Figure 1: Effects of PCPA-induced serotonin depletion on antidepressant stimulation of CDP-diacylglycerol synthesis in brain tissue. Brain slices were prepared from the frontal cortex or hippocampus tissues of saline-injected control rats or animals that had been administered p-chlorophenylalanine (PCPA) to deplete endogenous serotonin stores. The tissue slices were labeled with [3H]cytidine and then incubated with predetermined concentrations of the antidepressant drugs fluoxetine (FLX, 100 μM), imipramine (IMI, 300 μM), or maprotiline (MAP, 100 μM). After 90 min, accumulated [3H]CDP-diacylglycerol was measured. Data were calculated as percentages relative to the respective basal accumulations in the control or PCPA group. Each bar represents the mean ± SEM (N = 6). PCPA treatment had no significant effect on basal [3H]CDP-diacylglycerol accumulation in either tissue; such basal effects being, respectively, 8194+806 v. 8555+1657 for control versus PCPA in frontal cortex, and 8026+1295 v. 8139+1642 for control versus PCPA in hippocampus. Each drug induced significant accumulations of [3H]CDP-diacylglycerol in either the control or PCPA tissues (ANOVA, p < 0.0001 for each drug). PCPA partially reduced FLX and MAP effects but did not eliminate any of the drug effects: ***p < 0.001, compared by posthoc Tukey tests.
Mentions: Control and serotonin-depleted tissues from the rat hippocampus or frontal cortex were tested for CDP-diacylglycerol responses to various antidepressant agents. The tissue slices were prelabeled with [3H]cytidine and then incubated with maximally effective concentrations of the antidepressant drugs fluoxetine (FLX, 100 μM), imipramine (IMI, 300 μM), or maprotiline (MAP, 100 μM); these dose selections were based on previously published studies with brain slice preparations [2,3]. While similar results were obtained in the hippocampus and frontal cortex, the results for the frontal cortex are shown in Fig. 1. Imipramine, fluoxetine, or maprotiline induced significant accumulations of CDP-diacylglycerol in the saline-pretreated control tissues as expected. Tissues depleted of serotonin also gave significant responses to the antidepressant agents, although the responses to fluoxetine in the frontal cortex and to fluoxetine and maprotiline in the hippocampus were significantly but partially (21-32%) reduced in p-chlorophenylalanine (PCPA)-pretreated tissues. The concentration and conditions of PCPA treatment in these experiments are known to result in practically complete depletion of serotonin from the tissues [7-9].

Bottom Line: With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished.Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues.Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Integrative Neuropharmacology, Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania, USA.

ABSTRACT

Background: Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of brain CDP-diacylglycerol synthase - the enzyme that catalyzes the physiological synthesis of CDP-diacylglycerol.

Results: Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with p-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues.

Conclusion: Antidepressants probably induce the activity of CDP-diacylglycerol synthase leading to increased production of CDP-diacylglycerol and facilitation of downstream phosphatidylinositol synthesis. Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis. Hence, the present findings should strengthen the notion that modulation of brain phosphatidylinositide signaling probably contributes to the molecular mechanism of diverse antidepressant medications.

Show MeSH
Related in: MedlinePlus