Effects of escitalopram and paroxetine on mTORC1 signaling in the rat hippocampus under chronic restraint stress.

BACKGROUND: Recent studies have suggested that the activation of mammalian target of rapamycin (mTOR) signaling may be related to antidepressant action. Therefore, the present study evaluated whether antidepressant drugs would exert differential effects on mTOR signaling in the rat hippocampus under conditions of chronic restraint stress. Male Sprague-Dawley rats were subjected to restraint stress for 6 h/days for 21 days with either escitalopram (10 mg/kg) or paroxetine (10 mg/kg) administered after the chronic stress procedure. Western blot analyses were used to assess changes in the levels of phospho-Ser2448-mTOR, phospho-Thr37/46-4E-BP-1, phospho-Thr389-p70S6 K, phospho-Ser422-eIF4B, phospho-Ser240/244-S6, phospho-Ser473-Akt, and phospho-Thr202/Tyr204-ERK in the hippocampus. RESULTS: Chronic restraint stress significantly decreased the levels of phospho-mTOR complex 1 (mTORC1), phospho-4E-BP-1, phospho-p70S6 K, phospho-eIF4B, phospho-S6, phospho-Akt, and phospho-ERK (p < 0.05); the administration of escitalopram and paroxetine increased the levels of all these proteins (p < 0.05 or 0.01). Additionally, chronic restraint stress reduced phospho-mTORC1 signaling activities in general, while escitalopram and paroxetine prevented these changes in phospho-mTORC1 signaling activities. CONCLUSION: These findings provide further data that contribute to understanding the possible relationships among mTOR activity, stress, and antidepressant drugs.

Epigenetic modification of glucocorticoid receptor promoter I7 in maternally separated and restraint-stressed rats.

Glucocorticoid receptor (GR) promoter I7 is susceptible to epigenetic changes induced by environmental influences. Early life stress (ELS) has a persistent impact on GR expression, as well as behavior, in adult rodents via epigenetic changes of GR promoter I7. Moreover, various stressors can induce histone modifications in this region during adulthood. Thus, the present study aimed to investigate whether maternally separated (MS) rats exposed to chronic restraint stress (RS) would exhibit histone modifications of GR promoter I7 in the hippocampus. Rats were subjected to MS (3h per day) on postnatal days (PND) 1-21. Then, during adulthood (PND 56-77), the rats were exposed to RS (2h per day) followed by treatment with escitalopram (10mg/kg). The MS and RS groups exhibited significant decreases in total and exon I7 GR mRNA levels and the combination of MS and RS exerted a greater effect on these mRNA levels than either MS or RS alone. Additionally, both the MS and RS groups showed significant reductions in histone H3 acetylation at GR promoter I7 and the combination of MS and RS had a greater effect than did either MS or RS alone. Chronic escitalopram treatment ameliorated these changes. The present results indicate that postnatal MS and adult RS influence GR expression through histone modification at GR promoter I7, and that the combination of the two stressors potentiates these changes. Furthermore, epigenetic mechanisms are involved in escitalopram action.

Tianeptine induces mTORC1 activation in rat hippocampal neurons under toxic conditions.

RATIONALE: Recent studies have demonstrated that mTORC1 activation may be related to antidepressant action. However, the relationship between mTORC1 signaling activation and currently prescribed antidepressants remains unclear. OBJECTIVE: The aim of the present study was to determine whether alterations in mTORC1 signaling are observable following treatment with tianeptine under toxic conditions induced by B27 deprivation. Additionally, we investigated whether this drug affects synaptic proteins, neurite outgrowth, and spine density via mTORC1 signaling. METHODS: Using Western blotting, we measured the phosphorylation levels of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK in rat primary hippocampal neurons. Changes in BDNF, dendritic outgrowth, spine density, and synaptic proteins (PSD-95, synaptophysin, and GluR1) were measured. RESULTS: Tianeptine significantly increased the phosphorylation of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK. The increase in mTOR phosphorylation was blocked by the PI3K, MEK, and mTORC1 inhibitors. Tianeptine increased BDNF, dendritic outgrowth, spine density, and synaptic proteins; all of these effects were blocked by the mTORC1 inhibitor. CONCLUSIONS: In this study, we demonstrated that tianeptine activates the mTORC1 signaling pathway and increases dendritic outgrowth, spine density, and synaptic proteins through mTORC1 signaling under toxic conditions in rat primary hippocampal neurons.

Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus.

Early life stress (ELS) exerts long-lasting epigenetic influences on the brain and makes an individual susceptible to later depression. It is poorly understood whether ELS and subsequent adult chronic stress modulate epigenetic mechanisms. We examined the epigenetic mechanisms of the BDNF gene in the hippocampus, which may underlie stress vulnerability to postnatal maternal separation (MS) and adult restraint stress (RS). Rat pups were separated from their dams (3 h/day from P1-P21). When the pups reached adulthood (8 weeks old), we introduced RS (2 h/day for 3 weeks) followed by escitalopram treatment. We showed that both the MS and RS groups expressed reduced levels of total and exon IV BDNF mRNA. Furthermore, RS potentiated MS-induced decreases in these expression levels. Similarly, both the MS and RS groups showed decreased levels of acetylated histone H3 and H4 at BDNF promoter IV, and RS exacerbated MS-induced decreases of H3 and H4 acetylation. Both the MS and RS groups had increased MeCP2 levels at BDNF promoter IV, as well as increased HDAC5 mRNA, and the combination of MS and RS exerted a greater effect on these parameters than did RS alone. In the forced swimming test, the immobility time of the MS + RS group was significantly higher than that of the RS group. Additionally, chronic escitalopram treatment recovered these alterations. Our results suggest that postnatal MS and subsequent adult RS modulate epigenetic changes in the BDNF gene, and that these changes may be related to behavioral phenotype. These epigenetic mechanisms are involved in escitalopram action.

p11 mediates the BDNF-protective effects in dendritic outgrowth and spine formation in B27-deprived primary hippocampal cells.

BACKGROUND: p11 (S100A10) is a key regulator of depression-like behaviors and antidepressant drug response in rodent models. Recent studies suggest that p11 mediates the behavioral antidepressant action of brain-derived neurotrophic factor (BDNF) in rodents. BDNF improves neural plasticity, which is linked to the cellular actions of antidepressant drugs. In the present study, we investigated whether p11 regulated BDNF action on neural plasticity in vitro. METHODS: We generated primary hippocampal cultures. p11 expression, total dendritic length, and spine density were investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. RESULTS: B27 deprivation significantly decreased p11 expression. Treatment with BDNF significantly prevented the B27 deprivation-induced decrease in p11 levels in a concentration-dependent manner, whereas these concentrations had no effect on control cultures. B27 deprivation significantly reduced the total length of hippocampal dendrites and spine density. BDNF increased the total dendritic length and spine density in conditions with or without B27. Furthermore, p11 knockdown through small interfering RNA (siRNA) transfection blocked these effects. The overexpression of p11 in B27-deprived cells increased the total dendritic length and spine density, and treatment with BDNF potentiated these effects. LIMITATION: This study should be confirmed in animal models of depression. CONCLUSION: Taken together, our data suggest that BDNF-induced improvement in neural plasticity may depend on the regulation of p11 in hippocampal cells with B27 deprivation. These results provide evidence to strengthen the theoretical basis of a role for p11 in BDNF-induced antidepressant action.

Effects of antipsychotic drugs on the expression of synapse-associated proteins in the frontal cortex of rats subjected to immobilization stress.

The present study examined the effects of antipsychotic drugs on the expression of synapse-associated proteins in the frontal cortex of rats with and without immobilization stress. Rats were subjected to immobilization stress 6h/day for 3 weeks. The effects of atypical antipsychotic drugs, olanzapine and aripiprazole, on expression of serine(9)-phosphorylated GSK-3ß, ß-catenin, BDNF, PSD-95, and synaptophysin were determined by Western blotting. A typical antipsychotic drug, haloperidol, was used for comparison. Immobilization stress significantly decreased the expression of these proteins in the frontal cortex. Chronic administration of olanzapine and aripiprazole significantly attenuated the immobilization stress-induced decrease in the levels of these proteins, whereas haloperidol had no such effect. Additionally, olanzapine and aripiprazole significantly increased levels of phosphorylated GSK-3ß under normal conditions without stress, and aripiprazole also increased BDNF levels under this condition. These results indicate that olanzapine and aripiprazole, and, haloperidol, differentially regulate the levels of synapse-associated proteins in the rat frontal cortex. These findings may contribute to explain the neurobiological basis of how olanzapine and aripiprazole up-regulated synapse-associated proteins.

Effects of mood-stabilizing drugs on dendritic outgrowth and synaptic protein levels in primary hippocampal neurons.

OBJECTIVES: Mood-stabilizing drugs, such as lithium (Li) and valproate (VPA), are widely used for the treatment of bipolar disorder, a disease marked by recurrent episodes of mania and depression. Growing evidence suggests that Li exerts neurotrophic and neuroprotective effects, leading to an increase in neural plasticity. The present study investigated whether other mood-stabilizing drugs produce similar effects in primary hippocampal neurons. METHODS: The effects of the mood-stabilizing drugs Li, VPA, carbamazepine (CBZ), and lamotrigine (LTG) on hippocampal dendritic outgrowth were examined. Western blotting analysis was used to measure the expression of synaptic proteins - that is, brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), neuroligin 1 (NLG1), ß-neurexin, and synaptophysin (SYP). To determine neuroprotective effects, we used a B27-deprivation cytotoxicity model which causes hippocampal cell death upon removal of B27 from the culture medium. RESULTS: Li (0.5-2.0 mM), VPA (0.5-2.0 mM), CBZ (0.01-0.10 mM), and LTG (0.01-0.10 mM) significantly increased dendritic outgrowth. The neurotrophic effect of Li and VPA was blocked by inhibition of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, and protein kinase A signaling; the effects of CBZ and LTG were not affected by inhibition of these signaling pathways. Li, VPA, and CBZ prevented B27 deprivation-induced decreases in BDNF, PSD-95, NLG1, ß-neurexin, and SYP levels, whereas LTG did not. CONCLUSIONS: These results suggest that Li, VPA, CBZ, and LTG exert neurotrophic effects by promoting dendritic outgrowth; however, the mechanism of action differs. Furthermore, certain mood-stabilizing drugs may exert neuroprotective effects by enhancing synaptic protein levels against cytotoxicity in hippocampal cultures.

Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons.

Recent studies suggest that ketamine produces antidepressant actions via stimulation of mammalian target of rapamycin (mTOR), leading to increased levels of synaptic proteins in the prefrontal cortex. Thus, mTOR activation may be related to antidepressant action. However, the mTOR signalling underlying antidepressant drug action has not been well investigated. The aim of the present study was to determine whether alterations in mTOR signalling were observed following treatment with antidepressant drugs, using ketamine as a positive control. Using Western blotting, we measured changes in the mTOR-mediated proteins and synaptic proteins in rat hippocampal cultures. Dendritic outgrowth was determined by neurite assay. Our findings demonstrated that escitalopram, paroxetine and tranylcypromine significantly increased levels of phospho-mTOR and its down-stream regulators (phospho-4E-BP-1 and phospho-p70S6K); fluoxetine, sertraline and imipramine had no effect. All drugs tested increased up-stream regulators (phospho-Akt and phospho-ERK) levels. Increased phospho-mTOR induced by escitalopram, paroxetine or tranylcypromine was significantly blocked in the presence of specific PI3K, MEK or mTOR inhibitors, respectively. All drugs tested also increased hippocampal dendritic outgrowth and synaptic proteins levels. The mTOR inhibitor, rapamycin, significantly blocked these effects on escitalopram, paroxetine and tranylcypromine whereas fluoxetine, sertraline and imipramine effects were not affected. The effects of escitalopram, paroxetine and tranylcypromine paralleled those of ketamine. This study presents novel in vitro evidence indicating that some antidepressant drugs promote dendritic outgrowth and increase synaptic protein levels through mTOR signalling; however, other antidepressant drugs seem to act via a different pathway. mTOR signalling may be a promising target for the development of new antidepressant drugs.

Effects of antidepressant drugs on synaptic protein levels and dendritic outgrowth in hippocampal neuronal cultures.

The alteration of hippocampal plasticity has been proposed to play a critical role in both the pathophysiology and treatment of depression. In this study, the ability of different classes of antidepressant drugs (escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine) to mediate the expression of synaptic proteins and dendritic outgrowth in rat hippocampal neurons was investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. Postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP) levels were evaluated using Western blot analyses. Additionally, dendritic outgrowth was examined to determine whether antidepressant drugs affect the dendritic morphology of hippocampal neurons in B27-deprived cultures. Escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine significantly prevented B27 deprivation-induced decreases in levels of PSD-95, BDNF, and SYP. Moreover, the independent application of fluoxetine, paroxetine, and sertraline significantly increased levels of BDNF under normal conditions. All antidepressant drugs significantly increased the total outgrowth of hippocampal dendrites under B27 deprivation. Specific inhibitors of calcium/calmodulin kinase II (CaMKII), KN-93, protein kinase A (PKA), H-89, or phosphatidylinositol 3-kinase (PI3K), LY294002, significantly decreased the effects of antidepressant drugs on dendritic outgrowth, whereas this effect was observed only with tianeptine for the PI3K inhibitor. Taken together, these results suggest that certain antidepressant drugs can enhance synaptic protein levels and encourage dendritic outgrowth in hippocampal neurons. Furthermore, effects on dendritic outgrowth likely require CaMKII, PKA, or PI3K signaling pathways. The observed effects may be may be due to chronic treatment with antidepressant drugs.

Dexamethasone induces the expression of LRRK2 and α-synuclein, two genes that when mutated cause Parkinson's disease in an autosomal dominant manner.

LRRK2 (leucine-rich repeat kinase 2) has been identified as a gene corresponding to PARK8, an autosomal-dominant gene for familial Parkinson's disease (PD). LRRK2 pathogenic-specific mutants induce neurotoxicity and shorten neurites. To elucidate the mechanism underlying LRRK2 expression, we constructed the LRRK2-promoter-luciferase reporter and used it for promoter analysis. We found that the glucocorticoid receptor (GR) transactivated LRRK2 in a ligand-dependent manner. Using quantitative RT-PCR and Western analysis, we further showed that treatment with dexamethasone, a synthetic GR ligand, induced LRRK2 expression at both the transcriptional and translational levels, in dopaminergic MN9D cells. Dexamethasone treatment also increased expression of α α-synuclein, another PD causative gene, and enhanced transactivation of the α-synuclein promoter-luciferase reporter. In addition, dexamethasone treatment to MN9D cells weakly induced cytotoxicity based on an LDH assay. Because glucocorticoid hormones are secreted in response to stress, our data suggest that stress might be a related factor in the pathogenesis of PD.

Effect of treadmill exercise on the BDNF-mediated pathway in the hippocampus of stressed rats.

A growing body of evidence suggests that exercise enhances hippocampal plasticity and function through BDNF up-regulation, which is potentiated by antidepressant treatment. However, little is known about the molecular mechanisms mediating the effect of exercise. The present study investigated the effect of treadmill exercise on PI3K/Akt signaling, which mediates synaptic plasticity in the hippocampus of stressed rats. Rats were subjected to immobilization stress 2h/day for 7 days. The rats were run on the treadmill at a speed of 15m/min, 30min/day, for 5 days. Western blotting was used to assess changes in the levels of phospho-tyr(490)-Trk receptor, phospho-ser(473)-Akt, phospho-ser(9)-GSK-3ß, phospho-ser(2448)- mTOR, and phosphor-thr(389)-p70S6K, and in BDNF and various synaptic proteins. Immobilization stress significantly decreased BDNF expression and phosphorylation of Trk receptor, Akt, GSK-3ß, mTOR, and p70S6K in the hippocampus of rats; furthermore, synaptophysin, PSD-95, neuroligin 1, and ß-neurexin were decreased. Treadmill exercise significantly attenuated the decreased expression of these proteins. Moreover, exercise significantly increased PI3K/Akt signaling in the absence of immobilization stress. These results suggest that treadmill exercise reverses stress-induced changes in the rat hippocampus via an increase in PI3K/Akt signaling and may induce a functional reconnection of hippocampal synapses that mediate antidepressant actions.

Antioxidant and Proliferative Activities of Bupleuri Radix Extract Against Serum Deprivation in SH-SY5Y Cells.

OBJECTIVE: Bupleuri Radix (BR) is a major component of several Oriental herbal medicines used to treat stress and mental illness. There are evidences that antidepressant drugs modulate oxidative damage implicated in the pathophysiology of neuropsychiatric disorder, including depression. The aim of the present study was to investigate antioxidant and proliferative effects of BR against oxidative stress induced by serum deprivation in SH-SY5Y cells. METHODS: We examined the antioxidant effects of BR on a number of measures, including cell viability, formation of reactive oxygen species (ROS), superoxide dismutase (SOD) activity and levels of both Bcl-2 and Bax. We also investigated the effects of BR on cell proliferation using the bromodeoxyuridine (BrdU) assay, and used Western blot analysis to measure changes in expression of the cell cycle phase regulators. RESULTS: 1) Serum deprivation significantly induced the loss of cell viability, the formation of ROS, the reduction of SOD activity, down-regulation of Bcl-2 expression and up-regulation of Bax expression. However, BR extract reversed these effects in dose-dependent manner. 2) Serum deprivation significantly reduced cell proliferation. Western blot analysis revealed that serum deprivation significantly decreased cyclinD1 and phosphorylated retinoblastoma (pRb) expression, and increased p27 expression. On the other hand, BR dose dependently reversed these effects. CONCLUSION: This study suggests that aqueous extract of BR may exert potent antioxidant effects and also play an important role in regulating cell cycle progression during neurogenesis. These effects of BR may be a potentially important mechanism of antidepressant underlying the observed antioxidant and proliferative effects.

Effects of antipsychotic drugs on the expression of synaptic proteins and dendritic outgrowth in hippocampal neuronal cultures.

Recent evidence has suggested that atypical antipsychotic drugs regulate synaptic plasticity. We investigated whether some atypical antipsychotic drugs (olanzapine, aripiprazole, quetiapine, and ziprasidone) altered the expression of synapse-associated proteins in rat hippocampal neuronal cultures under toxic conditions induced by B27 deprivation. A typical antipsychotic, haloperidol, was used for comparison. We measured changes in the expression of various synaptic proteins including postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP). Then we examined whether these drugs affected the dendritic morphology of hippocampal neurons. We found that olanzapine, aripiprazole, and quetiapine, but not haloperidol, significantly hindered the B27 deprivation-induced decrease in the levels of these synaptic proteins. Ziprasidone did not affect PSD-95 or BDNF levels, but significantly increased the levels of SYP under B27 deprivation conditions. Moreover, olanzapine and aripiprazole individually significantly increased the levels of PSD-95 and BDNF, respectively, even under normal conditions, whereas haloperidol decreased the levels of PSD-95. These drugs increased the total outgrowth of hippocampal dendrites via PI3K signaling, whereas haloperidol had no effect in this regard. Together, these results suggest that the up-regulation of synaptic proteins and dendritic outgrowth may represent key effects of some atypical antipsychotic drugs but that haloperidol may be associated with distinct actions.

Effects of antipsychotic drugs on BDNF, GSK-3ß, and ß-catenin expression in rats subjected to immobilization stress.

Brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3ß (GSK-3ß), and ß-catenin have been reported to be altered in patients with schizophrenia and have been targeted by antipsychotic drugs. Atypical antipsychotics, but not typical antipsychotics, exert neuroprotective effects by regulating these proteins. In this study, we analyzed the effects of the atypical antipsychotic drugs olanzapine and aripiprazole and a typical antipsychotic drug, haloperidol, on the expression of BDNF, phosphorylated GSK-3ß, and ß-catenin in the hippocampus of rats subjected to immobilization stress. Rats were subjected to immobilization stress 6h/day for 3 weeks. The effects of olanzapine (2 mg/kg), aripiprazole (1.5 mg/kg), and haloperidol (1.0 mg/kg) were determined on BDNF, serine9-phosphorylated GSK-3ß, and ß-catenin expression by Western blotting. Immobilization stress significantly decreased the expression of BDNF, phosphorylated GSK-3ß, and ß-catenin in the hippocampus. Chronic administration of olanzapine and aripiprazole significantly attenuated the decreased expression of these proteins in the hippocampus of rats caused by immobilization stress, and significantly increased the levels of these proteins even without the immobilization stress. However, chronic haloperidol had no such effect. These results suggest that olanzapine and aripiprazole may exert beneficial effects by upregulating BDNF, phosphorylated GSK-3ß, and ß-catenin in patients with schizophrenia.

Protective effects of atypical antipsychotic drugs against MPP(+)-induced oxidative stress in PC12 cells.

Recent studies have suggested that some atypical antipsychotic drugs may have protective properties against oxidative stress. To confirm these findings, we investigated the protective effects of atypical antipsychotic drugs such as olanzapine, aripiprazole, and ziprasidone on oxidative stress induced by the N-methyl-4-phenylpyridinium (MPP(+)) ion in PC12 cells. Haloperidol, a typical antipsychotic drug, was used for comparison. We determined the antioxidant effects of atypical antipsychotic drugs using a number of measures, including cell viability, the formation of reactive oxygen species (ROS), superoxide dismutase (SOD) activity and Bax levels. MPP(+) treatment induced significant loss of cell viability, the formation of ROS, reduction of SOD activity, and up-regulation of Bax expression. However, olanzapine, aripiprazole and ziprasidone reversed these effects caused by MPP(+) treatment, but ziprasidone did not influence cell viability. In contrast, haloperidol did not affect all these effects. Moreover, haloperidol strongly increased the expression of Bax under MPP(+)-free conditions. Olanzapine, aripiprazole, and ziprasidone, but not haloperidol, may exert antioxidant effects through modulating ROS levels, SOD activity, and Bax expression to provide protective effects against MPP(+)-induced oxidative stress in PC12 cells. These results suggest that some atypical antipsychotic drugs have a useful therapeutic effect by reducing oxidative stress in schizophrenic patients.

Differential effects of ziprasidone and haloperidol on immobilization-stress-induced CRF mRNA expression in the hypothalamic paraventricular nucleus of rats.

OBJECTIVES: Corticotropin-releasing factor (CRF) plays a prominent role in mediating the effect of stressors on the hypothalamic-pituitary-adrenal axis. In this study, we examined the effects of chronic administration of second-generation antipsychotic drug ziprasidone on CRF mRNA expression in the hypothalamic paraventricular nucleus (PVN) of rats with or without immobilization stress. METHODS: The rats were subjected to immobilization stress 2 h/day for 3 weeks. The effect of ziprasidone (2.5 mg/kg, 21 days) on CRF mRNA expression was determined using in situ hybridization of tissue sections from the rat hypothalamic PVN. Haloperidol (1.0 mg/kg, 21 days) was used for comparison. RESULTS: Haloperidol increased the expression of CRF mRNA in the PVN under basal conditions, whereas ziprasidone had no effect. Chronic immobilization stress increased CRF expression. The chronic administration of ziprasidone prevented the increase in CRF mRNA expression caused by immobilization stress. CONCLUSIONS: These results suggest that ziprasidone may have a regulatory effect on the stress-induced CRF mRNA expression and a role in the treatment of depressive mood symptom.

Genetic association of BDNF val66met and GSK-3beta-50T/C polymorphisms with tardive dyskinesia.

AIMS: Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD), and a growing body of evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in both the antipsychotic effects and the pathogenesis of TD. BDNF and glycogen synthase kinase (GSK)-3beta are important in neuronal survival, and thus abnormal regulation of BDNF and GSK-3beta may contribute to TD pathophysiology. This study investigated the relationship between two polymorphisms, val66met in the BDNF coding region and -50T/C in the GSK-3beta promoter, and susceptibility to TD among a matched sample of patients having schizophrenia with TD (n = 83), patients with schizophrenia without TD (n = 78), and normal control subjects (n = 93). METHODS: All subjects were Korean. The BDNF val66met and GSK-3beta-50T/C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses. RESULTS: Polymerase chain reaction analysis revealed no significant difference in the occurrence of the polymorphisms among the TD, non-TD, and control subjects, but a significant interaction was observed among the groups possessing BDNF val allele in compound genotypes (P = 0.001). We found that the schizophrenic subjects with the C/C GSK-3beta genotype, who carry the val allele of the BDNF gene, are expected to have a decreased risk of developing neuroleptic-induced tardive dyskinesia (P < 0.001). CONCLUSIONS: Our results demonstrate that the GSK-3beta C/C genotype with the BDNF val allele is associated with patients having schizophrenia without TD. This study also suggests that the BDNF and GSK-3beta gene polymorphisms work in combination, but not individually, in predisposing patients with schizophrenia to TD.

Differential effects of ziprasidone and haloperidol on immobilization stress-induced mRNA BDNF expression in the hippocampus and neocortex of rats.

Recent in vivo and in vitro experiments have demonstrated that second-generation antipsychotic drugs (SGAs) might have neuroprotective effects. Ziprasidone is a SGA that is efficacious in the treatment of schizophrenia. In this study, we sought to analyze the effects of ziprasidone on the expression of the neuroprotective protein brain-derived neurotrophic factor (BDNF) in the rat hippocampus and neocortex, with or without immobilization stress. The effect of ziprasidone (2.5mg/kg) on the expression of BDNF mRNA was determined by in situ hybridization in tissue sections from the rat hippocampus and neocortex. Haloperidol (1.0mg/kg) was used for comparison. Haloperidol strongly decreased the expression of BDNF mRNA in both the hippocampal and cortical regions, with or without immobilization stress (p<0.01). In contrast, the administration of ziprasidone significantly attenuated the immobilization stress-induced decrease in BDNF mRNA expression in the rat hippocampus and neocortex (p<0.01). Ziprasidone exhibited differential effects on BDNF mRNA expression in the rat hippocampus and neocortex. These results suggest that ziprasidone might have a neuroprotective effect by recovering stress-induced decreases in BDNF mRNA expression.