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.
BACKGROUND
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 [(14)C]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.


CONCLUSIONS
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.
Department of Neuroscience, Janssen Research and Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium. stefanie.dedeurwaerdere@hotmail.com
Stefanie
S
Dedeurwaerdere
Cindy
C
Wintmolders
Roel
R
Straetemans
Darrel
D
Pemberton
Xavier
X
Langlois
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography; D001692:Biological Transport; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D007649:Ketamine; D008297:Male; D008559:Memantine; D051379:Mice; D008810:Mice, Inbred C57BL; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002250:Carbon Radioisotopes; D003499:Cyclic S-Oxides; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D007649:Ketamine; D003847:Deoxyglucose; D008559:Memantine