| 1 | Ann. N. Y. Acad. Sci. 2000 Jun 911: 73-82 |
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| PMID | 10911868 |
| Title | Molecular effects of the psychotropic NMDA receptor antagonist MK-801 in the rat entorhinal cortex: increases in AP-1 DNA binding activity and expression of Fos and Jun family members. |
| Abstract | Noncompetitive NMDA receptor antagonists such as phencyclidine and MK-801 produce psychotropic symptoms that closely resemble schizophrenic psychosis and induce the expression of immediate early genes in limbic cortical areas. We are concentrating on analyzing molecular and physiological effects that these drugs produce in the entorhinal cortex and on the potential connection between these effects and the psychotic symptoms. We show here that MK-801 increases the DNA binding activity of the activator protein-1 (AP-1) complex in the entorhinal cortex. We also observed increased expression of mRNAs for Fos and Jun transcription factor family members c-Fos, FosB, Fra-2, and JUNB, as well as Fos family proteins in the entorhinal cortex after MK-801 administration. This suggests that the activated AP-1 complex consists of these transcription factors. Genes regulated by the AP-1 complex in the entorhinal cortex might be involved in the pathophysiology of psychotic behavior and are potential targets for new antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Eur. J. Pharmacol. 2009 Oct 620: 27-35 |
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| PMID | 19695244 |
| Title | F15063, a potential antipsychotic with dopamine D(2)/D(3) receptor antagonist and 5-HT(1A) receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum. |
| Abstract | Brain region-specific modulation of immediate-early gene (IEG) may constitute a marker of antipsychotic drug-like activity. We investigated the effects of the putative antipsychotic drug N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063), a compound that targets both dopamine D(2) and serotonin 5-HT(1A) receptors, in comparison with haloperidol and clozapine on rat mRNA expression of IEG i.e. the zinc-fingered transcription factors c-fos, fosB, zif268, c-jun and JUNB, two transcription factors of the nuclear receptor family nur77 and nor1, and the effector IEG arc. F15063 (10 mg/kg) and clozapine (10 mg/kg), but not haloperidol (0.63 mg/kg), induced c-fos and fosB mRNA expression in prefrontal cortex, a region associated with control of cognition and negative symptoms of schizophrenia. In striatum, only c-fos, fosB, JUNB and nur77 were induced by clozapine whereas all IEG mRNAs were increased by haloperidol and F15063 (from 2.5 mg/kg) with similar high efficacy despite a total absence of F15063-induced catalepsy. However, at 0.63 mg/kg, F15063 induced a lower degree of striatal IEG mRNA expression than haloperidol and pretreatment with the serotonin 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride (WAY100635) (0.63 mg/kg) increased the level of IEG mRNA induction by F15063. Furthermore, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] at 0.16 mg/kg decreased haloperidol-induced striatal IEG mRNA expression although it exerted no effects on its own. These results are consistent with an activation of serotonin 5-HT(1A) receptors by F15063, thus reducing D(2) blockade-induced striatal IEG mRNA. Furthermore, the substantial F15063-induced expression of IEGs such as c-fos in striatum is not related to cataleptogenic activity and may act more as a marker of efficacious dopamine D(2) receptor blockade. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Psychiatry Res 2009 May 167: 80-7 |
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| PMID | 19342105 |
| Title | Reduction in the protein level of c-Jun and phosphorylation of Ser73-c-Jun in rat frontal cortex after repeated MK-801 treatment. |
| 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. |
| SCZ Keywords | schizophrenia, schizophrenic |