Memantine-induced brain activation as a model for the rapid screening of potential novel antipsychotic compounds: Exemplified by an mGlu2/3 receptor agonist

Schizophrenia is a severe, disabling chronic disorder affecting approximately 1% of the population. Unfortunately, patients afflicted by this difficult to treat psychiatric illness remain stigmatized and are likely to suffer permanent cognitive and social deficits. 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) uptake autoradiography technique following memantine-induced brain activation.
Male C57BL/6JCRL mice were treated with either vehicle, ketamine (30 mg/kg, s.c.) or memantine (20 mg/kg, s.c.). Both NMDA antagonists induced significant increases in 2-DG uptake in specific brain region such as lateral orbital cortex, olfactory tubercle, piriform cortex, cingulate cortex, retrosplenial cortex, lacunosum molecular layer of the hippocampus and the lateral posterior thalamic nucleus. Interestingly, memantine elicited a more robust brain activation signature with a larger dynamic window than ketamine. For further characterisation of the assay, we also tested the effect of diet (fasting versus non-fasting) and different vehicles. In addition, dedicated software, developed particularly for this assay, was evaluated for automated quantification of the brain sections.
In subsequent reversal studies, we found that in accordance to the ketamine challenge model (Duncan et al. 1998), the “atypical” anti-psychotic clozapine (2.5 and 10 mg/kg, s.c.) significantly reversed memantine-induced 2-DG uptake whilst the “typical” anti-psychotic haloperidol (0.32 mg/kg, s.c.) was inactive thus further validating our choice of memantine for the challenge agent. An additional study then determined the effects of a mGlu2/3 receptor agonist on both ketamine and memantine-induced brain activation. Pre-treatment with LY404039 (10 mg/kg, s.c.) fully reversed both the ketamine and memantine-induced increase in 2-DG uptake without effects on basal 2-DG uptake.
Finally, a small animal PET study was performed with [18F]-FDG in mice and rats investigating the effect of memantine (20 mg/kg) administration in vivo. This study confirmed the memantine-induced brain activation previously demonstrated by autoradiography.
In conclusion, this novel pre-clinical method shows potential for the screening of compounds targeting the NMDA receptor hypofunction hypothesis of schizophrenia and may assist in translating these findings from the bench to clinic.