An allosteric modulator of metabotropic glutamate receptors (mGluR₂), (+)-TFMPIP, inhibits restraint stress-induced phasic glutamate release in rat prefrontal cortex

Abstract

The potential anxiolytic effects of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor subgroup 2 (mGluR₂) were investigated using a self-referencing recording technique with enzyme-based microelectrode arrays (MEAs) that reliably measures tonic and phasic changes in extracellular glutamate levels in awake rats. Studies involved glutamate measures in the rat prefrontal cortex during subcutaneous injections of the following: vehicle, a mGluR₂/₃ agonist, LY354740 (10 mg/kg), or a mGluR₂ PAM, 1-Methyl-2-((cis-(R,R)-3-methyl-4-(4-trifluoromethoxy-2-fluoro)phenyl)piperidin-1-yl)methyl)-1H-imidazo[4,5-b]pyridine ((+)-TFMPIP; 1.0 or 17.8 mg/kg). Studies assessed changes in tonic glutamate levels and the glutamatergic responses to a 5-min restraint stress. Subcutaneous injection of (+)-TFMPIP at a dose of 1.0 mg/kg (day 3: -7.1 ± 15.1 net AUC; day 5: -24.8 ± 24.9 net AUC) and 17.8 mg/kg (day 3: -46.5 ± 33.0 net AUC; day 5: 34.6 ± 36.8 net AUC) significantly attenuated the stress-evoked glutamate release compared to vehicle controls (day 3: 134.7 ± 50.6 net AUC; day 5: 286.6 ± 104.5 net AUC), whereas the mGluR₂/₃ agonist LY354740 had no effect. None of the compounds significantly affected resting glutamate levels, which we have recently shown to be extensively derived from neurons. Taken together, these data support that systemic administration of (+)-TFMPIP produces phasic rather than tonic release of glutamate that may play a major role in the effects of stress on glutamate neuronal systems in the prefrontal cortex.