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

Abstract

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.

The [18F]FDG μPET Readout of a Brain Activation Model to Evaluate the Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator JNJ-42153605

“…18 F]FDG increases correlates with the literature on memantine activation in rodent brain (Dedeurwaerdere et al, 2011). Minor disparities between the findings in literature and the current findings might be explained by differences in animal species and/or route of administration, etc.…”

“…For ketamine, a concentration of 30 mg/kg was chosen, based on literature (Duncan et al, 1998b;Dedeurwaerdere et al, 2011) as higher concentrations (.40mg/kg) are reported to show loss of excitation (Miyamoto et al, 2000). For memantine, a concentration of 20 mg/kg was chosen based on the findings in literature (Dedeurwaerdere et al, 2011).…”

“…For memantine, a concentration of 20 mg/kg was chosen based on the findings in literature (Dedeurwaerdere et al, 2011).…”

“…For example, reversal of ketamine-induced effects was evaluated using both the typical antipsychotic haloperidol and the atypical antipsychotic clozapine (Duncan et al, 1998b) and confirms the model's validity. Besides the NMDAR antagonist ketamine model, administration of another NMDA receptor antagonist, memantine, has also been suggested as an appropriate on-demand model of schizophrenia (Dedeurwaerdere et al, 2011). However, controversy exists on which of these NMDA antagonists is best suited as an animal model.…”

Stimulation of Metabotropic Glutamate (mGlu) 2 Receptor and Blockade of mGlu1 Receptor Improve Social Memory Impairment Elicited by MK-801 in Rats

“…mGlu2/3-receptor agonists have been reported to attenuate NMDA-receptor antagonists-induced increases in glutamate release in the prefrontal cortex (11,23). The attenuation of NMDAreceptor antagonists-evoked hyperactivity in the prefrontal cortex by mGlu2/3-receptor agonists or mGlu2-receptor potentiators was also supported by studies using 2-deoxyglucose uptake (26) and pharmacological magnetic resonance imaging (27 -29). Therefore, the inhibition of the increase in glutamate release through the stimulation of presynaptic mGlu2 receptors might ameliorate the hyperactivity of pyramidal neurons in the prefrontal cortex, and this mechanism might be involved in the action of mGlu2/3-receptor agonists / mGlu2-receptor potentiators on social memory impairment.…”