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1.
Article in English | MEDLINE | ID: mdl-26475745

ABSTRACT

BACKGROUND: Increasingly, data are implicating muscarinic receptors in the aetiology and treatment of mood disorders. This led us to measure levels of different muscarinic receptor-related parameters in the cortex from people with mood disorders and the CNS of rats treated with mood stabilisers and antidepressant drugs. METHODS: We measured [(3)H]AF-DX 384 binding in BA 46 and BA 24 from subjects with bipolar disorders (n = 14), major depressive disorders (n = 19), as well as age- and sex-matched controls (n = 19) and the CNS of rats treated with fluoxetine or imipramine. In addition, we used Western blots to measure levels of CHRM2 protein and oxotremorine-M stimulated [(35)S]GTPγS binding as a measure of CHRM 2 / 4 signaling. RESULTS: Compared with controls, [(3)H]AF-DX 384 binding was lower in BA 24 and BA 46 in bipolar disorders and major depressive disorders, while CHRM2 protein and oxotremorine-M stimulated [(35)S]GTPγS binding was only lower in BA 24. Compared with vehicle, treatment with mood stabilisers, antidepressant drugs for 10 days, or imipramine for 28 days resulted in higher levels of in [(3)H]AF-DX 384 binding select regions of rat CNS. CONCLUSIONS: Our data suggest that levels of CHRM2 are lower in BA 24 from subjects with mood disorders, and it is possible that signalling by that receptor is also less in this cortical region. Our data also suggest increasing levels of CHRM2 may be involved in the mechanisms of action of mood stabilisers and tricyclic antidepressants.


Subject(s)
Antidepressive Agents/pharmacology , Antimanic Agents/pharmacology , Bipolar Disorder/metabolism , Cerebral Cortex/metabolism , Depressive Disorder, Major/metabolism , Receptor, Muscarinic M2/metabolism , Animals , Antidepressive Agents/therapeutic use , Antimanic Agents/therapeutic use , Bipolar Disorder/drug therapy , Cerebral Cortex/drug effects , Depressive Disorder, Major/drug therapy , Disease Models, Animal , Female , Fluoxetine/pharmacology , Humans , Imipramine/pharmacology , Male , Middle Aged , Muscarinic Agonists/pharmacology , Oxotremorine/analogs & derivatives , Oxotremorine/pharmacology , Pirenzepine/analogs & derivatives , Radiopharmaceuticals , Rats, Sprague-Dawley , Tritium
2.
Curr Neuropharmacol ; 13(6): 739-49, 2015.
Article in English | MEDLINE | ID: mdl-26630954

ABSTRACT

The central cholinergic system has been implicated in the pathophysiology of mood disorders. An imbalance in central cholinergic neurotransmitter activity has been proposed to contribute to the manic and depressive episodes typical of these disorders. Neuropharmacological studies into the effects of cholinergic agonists and antagonists on mood state have provided considerable support for this hypothesis. Furthermore, recent clinical studies have shown that the pan-CHRM antagonist, scopolamine, produces rapid-acting antidepressant effects in individuals with either major depressive disorder (MDD) or bipolar disorder (BPD), such as bipolar depression, contrasting the delayed therapeutic response of conventional mood stabilisers and antidepressants. This review presents recent data from neuroimaging, post-mortem and genetic studies supporting the involvement of muscarinic cholinergic receptors (CHRMs), particularly CHRM2, in the pathophysiology of MDD and BPD. Thus, novel drugs that selectively target CHRMs with negligible effects in the peripheral nervous system might produce more rapid and robust clinical improvement in patients with BPD and MDD.


Subject(s)
Cholinergic Agents/therapeutic use , Mood Disorders/drug therapy , Mood Disorders/physiopathology , Psychotropic Drugs/therapeutic use , Receptors, Muscarinic/metabolism , Animals , Brain/drug effects , Brain/pathology , Brain/physiopathology , Cholinergic Agents/pharmacology , Humans , Mood Disorders/genetics , Mood Disorders/pathology , Psychotropic Drugs/pharmacology , Receptors, Muscarinic/genetics
3.
Int J Neuropsychopharmacol ; 17(6): 895-906, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24495390

ABSTRACT

We have attempted to replicate studies showing higher levels of serotonin 2A receptors (HTR2A) in the cortex of people with mood disorders and to determine the effects of treating rats with antidepressant drugs on levels of that receptor. In situ [3H]ketanserin binding and autoradiography was used to measure levels of HTR2A in Brodmann's area (BA) 46 and 24 from people with major depressive disorders (MDD, n = 16), bipolar disorders (BD, n = 14) and healthy controls (n = 14) as well as the central nervous system (CNS) of rats (20 per treatment arm) treated for 10 or 28 d with fluoxetine (10 mg/kg/d) or imipramine (20 mg/kg/d). Compared with controls, HTR2A were lower in BA 24, but not BA 46, from people with MDD (p = 0.005); HTR2A were not changed in BD. Levels of HTR2A were lower in BA 24 (p = 0.007), but not BA 46, from people who had died by suicide. Finally, levels of HTR2A were lower in the CNS of rats treated with imipramine, but not fluoxetine, for 28 d, but not 10 d. From our current and previous data we conclude cortical HTR2A are lower in schizophrenia, MDD, people with mood disorders who died by suicide, rats treated with some antipsychotic or some antidepressant drugs. As levels of cortical HTR2A can be affected by the aetiologies of different disorders and mechanisms of action of different drugs, a better understanding of how such changes can occur needs to be elucidated.


Subject(s)
Antidepressive Agents/pharmacology , Cerebral Cortex/drug effects , Depressive Disorder, Major/drug therapy , Imipramine/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Suicide , Adult , Aged , Aged, 80 and over , Animals , Antipsychotic Agents/pharmacology , Bipolar Disorder/drug therapy , Bipolar Disorder/metabolism , Cerebral Cortex/metabolism , Depressive Disorder, Major/metabolism , Female , Fluoxetine/pharmacology , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Gyrus Cinguli/drug effects , Gyrus Cinguli/metabolism , Humans , Male , Middle Aged , Rats, Sprague-Dawley , Young Adult
4.
Article in English | MEDLINE | ID: mdl-23962466

ABSTRACT

[(3)H]4-DAMP is a radioligand that has been used to quantify levels of the muscarinic receptor CHRM3 protein in situ. However, in addition to high affinity binding to CHRM3, [(3)H]4-DAMP binds with low affinity to CHRM1 confounding the potential to discriminate between changes in these two muscarinic receptors. We have developed a [(3)H]4-DAMP binding assay, optimised for measuring CHRM3 protein levels in the cortex, with minimal selectivity towards CHRM1. The selectivity of our assay towards CHRM3 was confirmed using recombinant receptor-expressing, cell lysate preparations. [(3)H]4-DAMP binding levels were similar between wildtype and CHRM1 knockout mice, confirming that the amount of [(3)H]4-DAMP binding to CHRM1 was negligible. We used this assay to measure CHRM3 protein levels in the frontal pole, obtained post-mortem from subjects with bipolar disorder (n = 15), major depressive disorder (n = 15) and matched controls (n = 20) and showed that [(3)H]4-DAMP binding was not altered in either bipolar disorder or major depressive disorder. Western blotting confirmed that CHRM3 protein levels were unchanged in these subjects.


Subject(s)
Cerebral Cortex/drug effects , Mood Disorders/pathology , Muscarinic Antagonists/pharmacokinetics , Piperidines/pharmacokinetics , Receptor, Muscarinic M3/metabolism , Adult , Aged , Animals , Cerebral Cortex/metabolism , Dose-Response Relationship, Drug , Humans , Mice , Mice, Knockout , Middle Aged , Mood Disorders/diagnostic imaging , Pirenzepine/pharmacokinetics , Protein Binding/drug effects , Protein Binding/genetics , Radioligand Assay , Radionuclide Imaging , Receptor, Muscarinic M1 , Receptor, Muscarinic M3/genetics , Receptors, Muscarinic/genetics , Receptors, Muscarinic/metabolism , Tritium/pharmacokinetics
5.
Psychopharmacology (Berl) ; 230(3): 425-37, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23771439

ABSTRACT

RATIONALE: Clozapine affects the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in the brain, which plays an important role in its antipsychotic action. However, previous findings are inconsistent, and related molecular mechanisms require further clarification. OBJECTIVES: Time- and dose-dependent effects of clozapine on the ERK1/2 pathway and its regulatory mechanism were investigated in rat frontal cortex. METHODS AND RESULTS: At 15, 30, 60, and 120 min after intraperitoneal injection of clozapine (5, 10, and 20 mg/kg), changes in ERK1/2, its upstream canonical kinases (Raf1 and mitogen-activated protein kinase kinase 1/2 [MEK1/2]), and its downstream molecule (p90 ribosomal S6 kinase [p90RSK]) were investigated in rat frontal cortex. At 15 min, p-Raf1, p-MEK1/2, p-ERK1/2, and p-p90RSK all increased dose-dependently. At 30 min, p-ERK1/2 and p-p90RSK showed no significant changes, while dose-dependent increases in p-Raf1 and p-MEK1/2 were found. At 60 and 120 min, although p-ERK1/2 and p-p90RSK decreased, increases in p-Raf1 and p-MEK1/2 were maintained. A clozapine-induced reduction in ERK1/2 phosphorylation was evident at both tyrosine and threonine residues, suggesting the involvement of dual specificity phosphatases (DUSPs; mitogen-activated protein kinase phosphatases [MKPs]). mRNA expression of seven Dusps that can dephosphorylate ERK1/2 were examined; Mkp-1 (Dusp1) mRNA increased following clozapine treatment. Moreover, MKP-1 protein and phosphatase activity increased, and binding of MKP-1 to ERK1/2 was also upregulated by clozapine administration. CONCLUSIONS: In rat frontal cortex, clozapine regulates ERK1/2 phosphorylation via MKP-1, which induces uncoupling between Raf1-MEK1/2 and ERK1/2-p90RSK activity. These findings suggest an important role of MKP-1 in the mechanism of action of clozapine.


Subject(s)
Antipsychotic Agents/pharmacology , Clozapine/pharmacology , Dual Specificity Phosphatase 1/metabolism , Animals , Antipsychotic Agents/administration & dosage , Clozapine/administration & dosage , Dose-Response Relationship, Drug , Frontal Lobe/drug effects , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , MAP Kinase Kinase Kinases/metabolism , Male , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Proto-Oncogene Proteins c-raf , Rats , Rats, Sprague-Dawley , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Signal Transduction/drug effects , Time Factors
6.
Int J Neuropsychopharmacol ; 16(1): 37-46, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22338582

ABSTRACT

These studies were undertaken to investigate the selectivity of cortical muscarinic receptor radioligand binding in muscarinic M(1) and M(4) receptor knockout mice and to determine whether a marked decrease in [(3)H]pirenzepine binding in Brodmann's area (BA) 9 from a subset of people with schizophrenia was predictive of decreased muscarinic receptors in other central nervous system (CNS) regions. Our data show that, under the conditions used, [(3)H]pirenzepine binding was highly selective for the muscarinic M(1) receptor whereas both [(3)H]AF-DX 386 and [(3)H]4DAMP had less discriminatory power. In addition, the data suggest that a marked decrease in [(3)H]pirenzepine binding in BA 9 from a subset of people with schizophrenia is predictive of decreases in muscarinic receptors in other CNS regions. However, there were some region-specific decreases in muscarinic receptors in tissue from people with schizophrenia who were outside this subset. These data add to a growing body of evidence suggesting there are widespread decreases in muscarinic receptors in the CNS of some subjects with schizophrenia, as demonstrated by neuroimaging. Our data have implications for understanding the potential clinical utility of drugs directed at the orthosteric and allosteric sites of muscarinic receptors to treat schizophrenia.


Subject(s)
Cerebral Cortex/metabolism , Radiopharmaceuticals/metabolism , Receptor, Muscarinic M1/metabolism , Receptor, Muscarinic M4/metabolism , Schizophrenia/metabolism , Adult , Aged , Animals , Cerebral Cortex/pathology , Cohort Studies , Female , Humans , Male , Mice , Mice, Knockout , Middle Aged , Muscarinic Antagonists/metabolism , Pirenzepine/metabolism , Protein Binding/physiology , Radioligand Assay , Schizophrenia/pathology , Young Adult
7.
Front Biosci (Landmark Ed) ; 16(3): 962-79, 2011 01 01.
Article in English | MEDLINE | ID: mdl-21196212

ABSTRACT

APOE is a major component of several lipoproteins. In addition to its role as a lipid transport protein APOE also serves a dual role as a glial derived, synaptic signalling molecule and thought to play an important role in synaptic plasticity and cognition. Polymorphisms within the APOE gene have been associated with the incidence of Alzheimer's disease. In light of the similarities in the cognitive deficits experienced in both Alzheimer's disease and schizophrenia as well as the comorbidity of depression in Alzheimer's disease, aberrant APOE signalling has been implicated in the pathologies of schizophrenia and mood disorders. The schizophrenia candidate gene, reelin, also shares common receptors with APOE, further supporting a role for APOE in the pathology of these disorders. This review will summarise the current understanding of the involvement of APOE and its receptors in the symptomatology and pathology of schizophrenia and mood disorders and the implications of this involvement for drug treatment.


Subject(s)
Apolipoproteins E/genetics , Apolipoproteins E/physiology , Mood Disorders/genetics , Schizophrenia/genetics , Alzheimer Disease/genetics , Bipolar Disorder/genetics , Bipolar Disorder/physiopathology , Cell Adhesion Molecules, Neuronal/physiology , Central Nervous System/metabolism , Cognition/physiology , Depressive Disorder, Major/physiopathology , Extracellular Matrix Proteins/physiology , Humans , Lipid Metabolism , Mood Disorders/physiopathology , Myelin Sheath/pathology , Nerve Tissue Proteins/physiology , Neuroglia/physiology , Neuronal Plasticity/drug effects , Receptors, LDL/physiology , Reelin Protein , Schizophrenia/physiopathology , Serine Endopeptidases/physiology , Signal Transduction/physiology , Synapses/physiology
8.
Psychiatry Res ; 167(1-2): 80-7, 2009 May 15.
Article in English | MEDLINE | ID: mdl-19342105

ABSTRACT

Repeated administration of NMDA antagonists can induce behavioral alterations that mimic symptoms of psychosis, as seen in schizophrenia. JNK, one of the MAPKs, and c-Jun, its downstream target molecule, play important roles in regulating apoptosis in neural cells, and have been suggested as being associated with the pathophysiology of psychosis and the mechanism of action of some antipsychotics. We investigated changes in the JNK-c-Jun pathway and other Jun family proteins in the rat frontal cortex after single and repeated administration of MK-801 to examine acute and chronic responses. Neither the protein level nor the phosphorylation of JNK changed after single or repeated doses of MK-801. However, after repeated treatments, but not a single treatment, with MK-801, a down-regulation occurred in the protein level and of Ser73 phosphorylation of c-Jun in the rat frontal cortex. Other members of the Jun family, JunB and JunD, were unchanged. Repeated exposure to MK-801 down-regulated the phosphorylation and protein level of c-Jun in the rat frontal cortex, which may be related to the long-term effects of chronic treatment with MK-801.


Subject(s)
Dizocilpine Maleate/pharmacology , Extracellular Signal-Regulated MAP Kinases/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Frontal Lobe/metabolism , Proto-Oncogene Proteins c-jun/drug effects , Proto-Oncogene Proteins c-jun/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Antipsychotic Agents/pharmacology , Apoptosis/drug effects , Behavior, Animal/drug effects , Down-Regulation/drug effects , Frontal Lobe/drug effects , Male , Neurons/drug effects , Neurons/metabolism , Phosphorylation/drug effects , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Schizophrenia/chemically induced , Schizophrenia/metabolism , Signal Transduction/drug effects
9.
Exp Mol Med ; 40(4): 435-44, 2008 Aug 31.
Article in English | MEDLINE | ID: mdl-18779656

ABSTRACT

Repeated electroconvulsive seizure (ECS), a model for electroconvulsive therapy (ECT), exerts neuroprotective and proliferative effects in the brain. This trophic action of ECS requires inhibition of apoptotic activity, in addition to activation of survival signals. c-Myc plays an important role in apoptosis of neurons, in cooperation with the Bcl-2 family proteins, and its activity and stability are regulated by phosphorylation and ubiquitination. We examined c-Myc and related proteins responsible for apoptosis after repeated ECS. In the rat frontal cortex, repeated ECS for 10 days reduced the total amount of c-Myc, while increasing phosphorylation of c-Myc at Thr58, which reportedly induces degradation of c-Myc. As expected, ubiquitination of both phosphorylated and total c-Myc increased after 10 days ECS, suggesting that ECS may reduce c-Myc protein level via ubiquitination-proteasomal degradation. Bcl-2 family proteins, caspase, and poly(ADP-ribose) polymerase (PARP) were investigated to determine the consequence of down-regulating c-Myc. Protein levels of Bcl-2, Bcl-X(L), Bax, and Bad showed no change, and cleavage of caspase-3 and PARP were not induced. However, phosphorylation of Bad at Ser-155 and binding of Bad to 14-3-3 increased without binding to Bcl-X(L) after repeated ECS, implying that repeated ECS sequesters apoptotic Bad and frees pro-survival Bcl-XL. Taken together, c-Myc down-regulation via ubiquitination-proteasomal degradation and Bad inactivation by binding to 14-3-3 may be anti-apoptotic mechanisms elicited by repeated ECS in the rat frontal cortex. This finding further supports the trophic effect of ECS blocking apoptosis as a possible therapeutic effect of ECT.


Subject(s)
Electroconvulsive Therapy/adverse effects , Frontal Lobe/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Seizures/metabolism , bcl-Associated Death Protein/metabolism , 14-3-3 Proteins/metabolism , Animals , Down-Regulation , Male , Models, Biological , Neurons/metabolism , Periodicity , Phosphorylation , Protein Binding , Protein Processing, Post-Translational , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Sprague-Dawley , Seizures/etiology , Tumor Cells, Cultured , Ubiquitination , bcl-Associated Death Protein/antagonists & inhibitors
10.
Prog Neuropsychopharmacol Biol Psychiatry ; 32(7): 1637-42, 2008 Oct 01.
Article in English | MEDLINE | ID: mdl-18590792

ABSTRACT

Intracerebroventricular (ICV) injection of ouabain, a specific Na-K ATPase inhibitor, induced behavioral changes in rats, a putative animal model for bipolar disorder. The binding of ouabain to Na-K ATPase is known to affect signaling molecules in vitro such as extracellular signal-regulated kinase1/2 (ERK1/2). Although ERK has been suggested to be related to the behavioral alterations induced by various psychotomimetics, the effect of ouabain on ERK in the brain related to behavioral changes has not been examined. After ICV injection of ouabain in rats, we investigated changes in the phosphorylation of mitogen-activated protein kinase kinase1/2 (MEK1/2), ERK1/2, and p90 ribosomal s6 kinase (p90RSK) in rat striatum, frontal cortex, and hippocampus along with changes in locomotor activity. Ouabain induced the following biphasic dose-dependent changes in locomotor activity: no change with 10(-6) M, a statistically significant decrease with 10(-5) M, no change with 10(-4) M, and a statistically significant increase with 0.5x10(-3) and 10(-3) M. The phosphorylation level of MEK1/2, ERK1/2, and p90RSK in rat striatum showed dose-dependent changes similar to those observed in locomotor activity with relatively high correlation. The phosphorylation of these molecules in rat frontal cortex and hippocampus also changed in a similar dose-dependent pattern. Taken together, ouabain induced biphasic dose-dependent changes in locomotor activity and the phosphorylation of the ERK1/2 pathway. These findings suggest a possible relationship between ouabain-induced behavioral changes and ERK activity in the brain and suggest an important role of ERK in regulating locomotor activity and mood state.


Subject(s)
Brain/enzymology , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Motor Activity/drug effects , Ouabain/pharmacology , Signal Transduction/drug effects , Animals , Behavior, Animal/drug effects , Brain/drug effects , Dose-Response Relationship, Drug , Gene Expression Regulation, Enzymologic/drug effects , Injections, Intraventricular/methods , Male , Phosphorylation/drug effects , Rats , Rats, Sprague-Dawley
11.
Int J Neuropsychopharmacol ; 11(4): 509-17, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18272021

ABSTRACT

Haloperidol, a classical antipsychotic drug, affects the extracellular signal-regulated kinase (ERK) pathway in the brain. However, findings are inconsistent and the mechanism by which haloperidol regulates ERK is poorly understood. Therefore, we examined the ERK pathway and the related protein phosphatase 2A (PP2A) in detail after haloperidol administration. Haloperidol (0.5 and 1 mg/kg) induced biphasic changes in the phosphorylation level of mitogen-activated protein kinase kinase (MEK), ERK, and p90 ribosomal S6 kinase (p90RSK) without changing Raf-1 phosphorylation. Fifteen minutes after haloperidol administration, MEK-ERK-p90RSK phosphorylation increased, whilst PP2A activity decreased. At 60 min, the reverse was observed and the binding of PP2A to MEK and ERK increased. Higher dosages of haloperidol (2 and 4 mg/kg), affected neither MEK-ERK-p90RSK phosphorylation nor PP2A activity. Accordingly, PP2A regulates acute dose- and time-dependent changes in MEK-ERK-p90RSK phosphorylation after haloperidol treatment. These findings suggest the involvement of a dephosphorylating mechanism in the acute action of haloperidol.


Subject(s)
Antipsychotic Agents/pharmacology , Extracellular Signal-Regulated MAP Kinases/physiology , Haloperidol/pharmacology , Mitogen-Activated Protein Kinases/physiology , Prefrontal Cortex/physiology , Protein Phosphatase 2/physiology , Ribosomal Protein S6 Kinases, 90-kDa/physiology , Signal Transduction/drug effects , Animals , Blotting, Western , Dose-Response Relationship, Drug , Extracellular Signal-Regulated MAP Kinases/genetics , Immunoprecipitation , Male , Mitogen-Activated Protein Kinases/genetics , Phosphoprotein Phosphatases/metabolism , Phosphorylation/drug effects , Prefrontal Cortex/drug effects , Prefrontal Cortex/enzymology , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins c-raf/physiology , Rats , Rats, Sprague-Dawley , Ribosomal Protein S6 Kinases, 90-kDa/genetics , raf Kinases/physiology
12.
Neurosci Lett ; 434(1): 23-8, 2008 Mar 21.
Article in English | MEDLINE | ID: mdl-18262357

ABSTRACT

In experimental animals, including rats, MK-801 produces characteristic behavioural changes that model schizophrenia. It has been hypothesized that these changes accompany long-term synaptic changes, which require protein neosynthesis. We observed the effect of MK-801 on the "mammalian target of rapamycin" (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) pathway that regulates protein synthesis in the rat frontal cortex. A single injection of MK-801 (0.5, 1, or 2mg/kg) induced an acute increase in the phosphorylation of Akt (Ser-473) eIF4E-binding protein (4E-BP1) (Thr-37/46) and p70S6K (Thr-389). In contrast, after repeated treatment with MK-801 (1mg/kg for 5 or 10 days), the phosphorylation of Akt (Ser-473), mTOR (Ser-2481), 4E-BP1 (Thr-37/46), p70S6K (Thr-389), and S6 (Ser-240/244) increased. Thus, proteins in the mTOR/p70S6K pathway are modulated in chronic MK-801 animal models. These findings may suggest that repeated MK-801 treatment activates the signal transduction pathways involved in the initiation of protein synthesis in the rat frontal cortex.


Subject(s)
Dizocilpine Maleate/pharmacology , Prefrontal Cortex/drug effects , Protein Biosynthesis/drug effects , Protein Kinases/drug effects , Ribosomal Protein S6 Kinases, 70-kDa/drug effects , Animals , Eukaryotic Initiation Factor-4E/biosynthesis , Eukaryotic Initiation Factor-4E/drug effects , Eukaryotic Initiation Factor-4E/genetics , Excitatory Amino Acid Antagonists/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Glutamic Acid/metabolism , Hallucinogens/pharmacology , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Phosphorylation/drug effects , Prefrontal Cortex/metabolism , Protein Biosynthesis/genetics , Protein Kinases/biosynthesis , Protein Kinases/genetics , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/biosynthesis , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Signal Transduction/drug effects , Signal Transduction/physiology , TOR Serine-Threonine Kinases , Transcriptional Activation/drug effects , Transcriptional Activation/physiology , Up-Regulation/drug effects , Up-Regulation/physiology
13.
Exp Mol Med ; 39(3): 353-60, 2007 Jun 30.
Article in English | MEDLINE | ID: mdl-17603289

ABSTRACT

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Antipsychotic Agents/pharmacology , Clozapine/pharmacology , Frontal Lobe/drug effects , Glycogen Synthase Kinase 3/metabolism , Haloperidol/pharmacology , Phosphoproteins/physiology , Proto-Oncogene Proteins c-akt/physiology , Adaptor Proteins, Signal Transducing/metabolism , Animals , Dishevelled Proteins , Dopamine Antagonists/pharmacology , Frontal Lobe/enzymology , Male , Phosphoproteins/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Serotonin Antagonists/pharmacology , Signal Transduction
14.
Int J Neuropsychopharmacol ; 10(3): 359-68, 2007 Jun.
Article in English | MEDLINE | ID: mdl-16780607

ABSTRACT

Repeated administrations of NMDA receptor antagonists induce behavioural changes which resemble the symptoms of schizophrenia in animals. ERK and GSK-3beta associated signalling pathways have been implicated in the pathogenesis of psychosis and in the action mechanisms of various psychotropic agents. Here, we observed the phosphorylations of ERK and GSK-3beta and related molecules in the rat frontal cortex after repeated intraperitoneal injections of MK-801, over periods of 1, 5, and 10 d. Repeated treatment with 0.5, 1, and 2 mg/kg MK-801 increased the phosphorylation levels of the MEK-ERK-p90RSK and Akt-GSK-3beta pathways and concomitantly and significantly increased CREB phosphorylation in the rat frontal cortex. However, single MK-801 treatment did not induce these significant changes. In addition, the immunoreactivities of HSP72, Bax, and PARP were not altered, which suggests that neuronal damage may not occur in the rat frontal cortex in response to chronic MK-801 treatment. These findings suggest that chronic exposure to MK-801 may induce pro-survival and anti-apoptotic activity without significant neuronal damage in the rat frontal cortex. Moreover, this adaptive change might be associated with the psychotomimetic action of MK-801.


Subject(s)
Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Extracellular Signal-Regulated MAP Kinases/physiology , Glycogen Synthase Kinase 3/physiology , Prefrontal Cortex/drug effects , Signal Transduction/drug effects , Animals , Blotting, Western , Cyclic AMP Response Element-Binding Protein/physiology , Glycogen Synthase Kinase 3 beta , HSP72 Heat-Shock Proteins/metabolism , Immunohistochemistry , Male , Poly(ADP-ribose) Polymerases/metabolism , Rats , Rats, Sprague-Dawley , Up-Regulation/drug effects , bcl-2-Associated X Protein/biosynthesis
15.
Psychiatry Res ; 145(1): 75-8, 2006 Nov 29.
Article in English | MEDLINE | ID: mdl-17027991

ABSTRACT

The effects of chronic electroconvulsive shock (ECS), given daily for 1, 5 and 10 days, on the activation of extracellular signal-regulated kinase (ERK) were studied in the rat frontal cortex. The phosphorylation of MEK1/2 and ERK1/2 increased through 5 days of ECS. Thereafter, a plateau was achieved. The expression of brain-derived neurotrophic factor was continuously increased for 10 days. Our data show that the effect of ECS on ERK1/2 signaling is increased with chronic treatment.


Subject(s)
Electroshock , Frontal Lobe/pathology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Animals , Brain-Derived Neurotrophic Factor/metabolism , Enzyme Activation/physiology , Immunoblotting , MAP Kinase Kinase 1 , MAP Kinase Kinase Kinase 2/metabolism , Male , Phosphorylation , Rats , Rats, Sprague-Dawley , Signal Transduction/physiology
16.
Neurosci Lett ; 390(3): 171-5, 2005 Dec 30.
Article in English | MEDLINE | ID: mdl-16143450

ABSTRACT

We have attempted to determine the effects of electroconvulsive shock (ECS) on protein phosphatase 2A (PP2A) in the frontal cortices of rats. PP2A exhibited a 30% increase in activity immediately after ECS treatment. Immunoblot analysis revealed that phosphorylation signals, including protein kinase B (Akt/PKB), glycogen synthase kinase-3beta (GSK-3beta), and cyclic adenosine monophosphate response element binding protein (CREB) were reduced immediately after ECS treatment. When an additional ECS was administered after the activation of these kinases, the immediate reactivation of PP2A overrode the kinase activity. ECS induces transient PP2A activation prior to kinase activation, and this pattern of activity may induce the biphasic phosphorylation of substrate proteins.


Subject(s)
Electroshock/methods , Frontal Lobe/radiation effects , Gene Expression Regulation/radiation effects , Phosphoprotein Phosphatases/metabolism , Analysis of Variance , Animals , Blotting, Western/methods , Dose-Response Relationship, Radiation , Enzyme Activation/radiation effects , Frontal Lobe/metabolism , Male , Phosphorylation/radiation effects , Protein Kinases/metabolism , Protein Phosphatase 2 , Rats , Rats, Sprague-Dawley , Serine/metabolism , Threonine/metabolism , Time Factors
17.
FEBS Lett ; 515(1-3): 141-5, 2002 Mar 27.
Article in English | MEDLINE | ID: mdl-11943210

ABSTRACT

Hyperthermia such as that occurring during fever may improve cell survival during infection, although its mechanism of action is largely unknown. Here we show that acute exposure to mild, but not severe, heat shock induces the synthesis of cyclin D1 that plays a critical role(s) in G1 progression of the cell cycle. This induction seemed to be regulated through multiple Ras signal pathways involving extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, and Rac1/NADPH oxidase, all of which have well been documented to be responsible for growth factor-induced cyclin D1 expression. In a physiological sense, mild heat shock may regulate cell proliferation through inducing cyclin D1 along with growth factors.


Subject(s)
Cyclin D1/biosynthesis , Heat-Shock Response/physiology , Signal Transduction/physiology , ras Proteins/metabolism , Animals , Cell Cycle/physiology , Cell Division/physiology , Cell Line , Enzyme Inhibitors/pharmacology , Fever/metabolism , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Mice , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/metabolism , NADPH Oxidases/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Rats , Signal Transduction/drug effects , rac1 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/metabolism
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