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Title
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Memantine-induced brain activation as a model for the rapid screening of potential novel antipsychotic compounds : exemplified by activity of an mGlu2/3 receptor agonist
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Author
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Abstract
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| Rationale Schizophrenia is a severe, disabling chronic disorder affecting approximately 1% of the population. Improvements and development of more robust and hopefully predictive screening assays for this disease should enhance the identification and development of novel treatments. The present study describes a rapid and robust method for the testing of potential novel antipsychotics by utilising a simplified [14C]2-deoxyglucose (2-DG) autoradiography method following memantine-induced brain activation. Methods Male C57BL/6JCRL mice were given vehicle, ketamine or memantine (10, 20 and 30 mg/kg, subcutaneously (s.c.)) and sacrificed 45 min post-[14 C]2-DG administration. In subsequent reversal studies, the memantine challenge was further validated with haloperidol (0.32 mg/kg, s.c.) and clozapine (2.5 and 10 mg/kg, s.c.) in parallel with the ketamine model (Duncan et al. 1998a). Lastly, the effects of an mGlu2/3 receptor agonist, LY404039 (10 mg/kg, s.c.), on both ketamine and memantine-induced brain activation was determined. Results Both N-methyl-d-aspartate (NMDA) antagonists dose-dependently induced significant region-specific increases in 2-DG uptake. Interestingly, memantine elicited a considerably greater brain activation signature with a larger dynamic window than ketamine. The atypical antipsychotic clozapine significantly reversed memantine-induced 2-DG uptake whilst the typical antipsychotic haloperidol was inactive. Pre-treatment with LY404039 fully reversed both the ketamine- and memantine-induced increase in 2-DG uptake without effects on basal 2-DG uptake. Conclusion This novel pre-clinical imaging methodology displays potential for the screening of compounds targeting the NMDA receptor hypofunction hypothesis of schizophrenia and should assist in developing compounds from the bench to clinic. |
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Language
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English
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Source (journal)
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Psychopharmacology. - Berlin
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Publication
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Berlin
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2011
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ISSN
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0033-3158
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DOI
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10.1007/S00213-010-2052-Z
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Volume/pages
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214
:2
(2011)
, p. 505-514
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ISI
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000287759500012
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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