Group II metabotropic glutamate receptor blockade promotes stress resilience in mice

Abstract

Stress is a leading risk factor for the onset and recurrence of major depression. Enhancing stress resilience may be a therapeutic strategy to prevent the development of depression in at-risk populations or its recurrence in depressed patients. Group II metabotropic glutamate receptor (mGlu 2/3) antagonists have been recognized for antidepressant-like actions in preclinical models, but have not been evaluated for prophylactic effects. We assessed the role of mGlu 2/3 in modulating stress resilience using subtypespecific knockout mice lacking mGlu 2 (Grm2 −/−) or mGlu 3 (Grm3 −/−), and pharmacological manipulations of mGlu 2/3 activity during or prior to the induction and reinstatement of stress-induced behavioral deficits. Grm2 −/− , but not Grm3 −/− , mice exhibited reduced forced-swimming test immobility time and were resilient to developing inescapable shock (IES)-induced escape deficits. Grm2 −/− mice were also resilient to developing corticosterone (CORT)-induced escape deficits and chronic social defeat stressinduced anhedonia. Pharmacological blockade of mGlu 2/3 with the antagonist LY341495 during stress prevented the development of IES-and CORT-induced escape deficits, while activation with the agonist LY379268 increased susceptibility to escape deficits. Prophylactic treatment with the LY341495, both systemically and via microinjection into the medial prefrontal cortex (mPFC), up to 7 days before IES, prevented both the induction of escape deficits and their reinstatement by brief re-exposure to IES up to 20 days after treatment. Overall, blockade of mGlu 2/3 enhanced stress resilience and deletion of mGlu 2 , but not mGlu 3 , conferred a stressresilient phenotype, indicating that prophylactic treatments reducing mGlu 2 activity may protect against stress-induced changes underlying the development or recurrence of stress-induced disorders, including depression.

Modulation by chronic stress and ketamine of ionotropic AMPA/NMDA and metabotropic glutamate receptors in the rat hippocampus

“…mGlu2 is a presynaptic metabotropic glutamate receptor, whose activation negatively modulates glutamate release (Chaki et al, 2013); recent evidence has associated changes in mGlu2 levels with stress vulnerability (Nasca et al, 2015;Highland et al, 2019).…”

“…Glutamate metabotropic receptors (mGlu) have also been involved in the regulation of the stress response (Peterlik et al, 2016). In particular, although conflicting results were obtained from different groups using different animal models of stress, mGlu2 levels were reported to be linked with stress vulnerability (Nasca et al, 2015;Highland et al, 2019), and antidepressant treatments were found to modulate mGlu2 expression (Morley-Fletcher et al, 2011;Bigio et al, 2016;Nasca et al, 2017;Zanos et al, 2019). Both positive and negative allosteric mGlu2 modulators are under development as putative new antidepressant drugs (O'Brien et al, 2018).…”

Glutamic Acid Decarboxylase Concentration Changes in Response to Stress and Altered Availability of Glutamic Acid in Rabbit (Oryctolagus cuniculus) Brain Limbic Structures

“…For several decades, ketamine, a non-specific antagonist of NMDARs with analgesic and anaesthetic use in high doses, has been used in the clinic, especially in veterinary medicine. The properties of metabotropic receptors also suggest their beneficial regulatory potential for the stress response, but they are not currently being fully utilised [ 47 , 48 , 49 , 50 ]. In the present study, an mGluR antagonist was used to determine the role of mGluRs during exposure to a single stress factor.…”

Harnessing the Neurobiology of Resilience to Protect the Mental Well-Being of Healthcare Workers During the COVID-19 Pandemic

“…Stress has both subjective and objective effects on sleep quantity, quality, and structure, which appear to be mediated by changes in metabotropic glutamate receptor functioning in limbic brain regions ( Highland et al, 2019 ; Sweeten et al, 2021 ). In addition, sleep deprivation leads to reduced hippocampal neurogenesis and plasticity, potentially impairing resilience to stress ( Saletin et al, 2016 ).…”