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 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
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
Berlin ,
Subject
Pharmacology. Therapy
Human medicine
Source (journal)
Psychopharmacology. - Berlin
Volume/pages
214(2011) :2 , p. 505-514
ISSN
0033-3158
ISI
000287759500012
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
E-info
https://repository.uantwerpen.be/docman/iruaauth/7a3c44/15ead645dff.pdf
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