Publication
Title
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
Author
Abstract
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.
Language
English
Source (journal)
Psychopharmacology. - Berlin
Publication
Berlin : 2011
ISSN
0033-3158
Volume/pages
214:2(2011), p. 505-514
ISI
000287759500012
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 16.02.2011
Last edited 21.06.2017
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