Efficacy of negative allosteric modulators of mGlu(2) and mGlu(3) in a rodent model of Major depressive disorder

Introduction Current first‐line medications for Major depressive disorder (MDD) exhibit an undesirable delay in onset and poor efficacy in the general population, and there remains a great unmet need for novel fast‐acting antidepressant medications that retain efficacy in treatment‐resistant populations. The rapid reversal of depressive‐like symptoms by ketamine and related antidepressants is thought to be mediated by acutely enhancing glutamate signaling within the prefrontal cortex (PFC). Likewise, non‐selective antagonists that inhibit metabotropic glutamate receptor subtypes 2 (mGlu 2 ) and 3 (mGlu 3 ), exemplified by LY341495, modulate PFC glutamate transmission and have shown efficacy in preclinical models of MDD. Previous research has relied heavily on molecules that display similar potency for inhibiting mGlu 2 and mGlu 3 , thus the specific contributions of each individual mGlu subtype remain unclear. Recently, our lab has developed highly selective and centrally penetrant negative allosteric modulators (NAMs) for both mGlu 2 and mGlu 3 . These exciting new tools have allowed us to test the hypothesis that selectively inhibiting mGlu 2 or mGlu 3 will confer rapid antidepressant efficacy in rodent models of depressive‐like behavior. Methods We modeled MDD symptomology in adult C57Bl/6J mice through chronic (4‐week) treatment with the stress hormone corticosterone (CORT). Anxiogenic, anhedonic, and depressive outcomes were assessed using a battery of behavioral assays. To interrogate the effects of CORT treatment on PFC function, we evaluated basal membrane and synaptic properties of layer 5 pyramidal neurons and we assessed mGlu function through a variety of pharmacological approaches. Results Chronic CORT treatment induced anhedonic‐ and depressive‐like behaviors in adult mice while no effects on anxiety‐like behavior were observed. Acute treatment with either the mGlu 2 NAM VU6001966 or the mGlu 3 NAM VU0650786 reversed CORT‐induced anhedonia as assessed with the sucrose preference test. In contrast, VU6001966 and VU0650786 exhibited differential effects on despair‐like behavior in the tail suspension and forced swim tests. In slices prepared from the PFC, we found that acute application of LY341495 or VU6001966 enhanced glutamate transmission, while VU0650786 was without effect. Conclusions We have validated that chronic CORT treatment induces several behavioral and synaptic changes consistent with a depressive‐like phenotype. Together, our data suggest that NAMs of both mGlu 2 or mGlu 3 reverse stress‐induced anhedonia and should continue to be explored as potential treatments for MDD. However, the mechanisms of action of these two drug classes is distinct and warrants further study. We are continuing to explore these mechanistic differences as well as the specific neurocircuits affected by CORT exposure and mGlu 2 and mGlu 3 NAM treatment. Support or Funding Information This work was supported by National Institutes of Health (NIH) grants R01MH062646 and R37NS031373 (P.J.C.). M.E.J. was supported by NIH grant T32MH093366 and a postdoctoral fellowship through the Pharmaceutical Research and Manufacturers of America Foundation. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .