Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
4339496 | Neuroscience | 2010 | 10 Pages |
Abstract
The main purpose of this study was to explore the sites and mechanisms of action of metabotropic glutamate receptor 1 (mGluR1) blockade for antipsychotic-like activity using a Fos mapping approach, with the intent of better understanding the similarities and differences between the pharmacological actions of mGluR1 antagonists and atypical antipsychotic drugs such as clozapine. Previously, we showed that an allosteric mGluR1 antagonist (negative allosteric modulator), 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one (CFMTI), induces Fos expression in the nucleus accumbens and the medial prefrontal cortex (mPFC), but not in the dorsolateral striatum, similar to the action of clozapine. In the present study, the Fos expression profile of CFMTI was more extensively evaluated in various areas of the brain. CFMTI induced Fos expression mainly in glutamatergic neurons in the mPFC, in a manner similar to clozapine. A significant increase in Fos expression was also observed in the locous coeruleus, central amygdaloid nucleus, the bed nucleus of the stria terminalis and the primary somatosensory cortex, but not in the ventral tegmental area, dorsal raphe or lateral septum. Fos expression in orexin neurons in the lateral hypothalamic/perifornical area (LH/PFA) is known to be positively correlated with the weight gain liability of atypical antipsychotics. CFMTI did not increase Fos expression in orexin neurons in the LH/PFA, in contrast to clozapine, which does have weight gain liability. These results suggest that CFMTI has unique and shared actions on Fos expression in various regions of the brain compared with clozapine.
Keywords
BCIPN-methyl-d-aspartateMPFCc-fosmGluR1DLPFCVTAmetabotropic glutamate receptor 1BNSTVGLUT1DAB5-bromo-4-chloro-3-indolyl phosphateLPFCshell of the nucleus accumbensVMH3, 3′-DiaminobenzidineTPBSPSSCExtrapyramidal side effectNMDANBTEPSDMHDBHPCPSSCPBSBSACeAG protein coupled receptordorsolateral striatumbovine serum albuminEDTAEthylenediaminetetraacetic acidstandard saline citrateImmunohistochemistryIHCnitro blue tetrazoliumvesicular glutamate transporter 1Dorsal raphé phosphate-buffered saline containing 0.3% Triton X-100Phencyclidineprefrontal cortexprimary somatosensory cortexmedial prefrontal cortexlateral prefrontal cortexdorsolateral prefrontal cortexArcPhosphate-buffered salinenegative allosteric modulatorventral tegmental areabed nucleus of the stria terminalislateral septal nucleuscentral amygdaloid nucleusdorsomedial hypothalamic nucleusVentromedial hypothalamic nucleusarcuate hypothalamic nucleusclozapineMetabotropic glutamate receptor
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Authors
G. Suzuki, A. Satow, H. Ohta,