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 (mGlu2/3) antagonists have been recognized for antidepressant-like actions in preclinical models, but have not been evaluated for prophylactic effects. We assessed the role of mGlu2/3 in modulating stress resilience using subtype-specific knockout mice lacking mGlu2 (Grm2−/−) or mGlu3 (Grm3−/−), and pharmacological manipulations of mGlu2/3 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 stress-induced anhedonia. Pharmacological blockade of mGlu2/3 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 mGlu2/3 enhanced stress resilience and deletion of mGlu2, but not mGlu3, conferred a stress-resilient phenotype, indicating that prophylactic treatments reducing mGlu2 activity may protect against stress-induced changes underlying the development or recurrence of stress-induced disorders, including depression.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.
Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman AT. Prevalence and predictors of recurrence of major depressive disorder in the adult population. Acta Psychiatr Scand. 2010;122:184–91.
Burcusa SL, Iacono WG. Risk for recurrence in depression. Clin Psychol Rev. 2007;27:959–85.
Kessler RC. The effects of stressful life events on depression. Annu Rev Psychol. 1997;48:191–214.
Wohleb ES, Gerhard D, Thomas A, Duman RS. Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine. Curr Neuropharmacol. 2017;15:11–20.
Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci. 2015;38:279–94.
Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74.
Amat J, Paul E, Watkins LR, Maier SF. Activation of the ventral medial prefrontal cortex during an uncontrollable stressor reproduces both the immediate and long-term protective effects of behavioral control. Neuroscience. 2008;154:1178–86.
Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997;37:205–37.
Kiritoshi T, Neugebauer V. Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex. Neuropharmacology. 2015;95:388–94.
Hascup ER, Hascup KN, Stephens M, Pomerleau F, Huettl P, Gratton A, et al. Rapid microelectrode measurements and the origin and regulation of extracellular glutamate in rat prefrontal cortex. J Neurochem. 2010;115:1608–20.
Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, et al. Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci. 1997;17:7503–22.
Schoepp DD. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther. 2001;299:12–20.
Joffe ME, Conn PJ. Antidepressant potential of metabotropic glutamate receptor mGlu2 and mGlu3 negative allosteric modulators. Neuropsychopharmacology. 2018;44:214–36.
Ohishi H, Shigemoto R, Nakanishi S, Mizuno N. Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol. 1993;335:252–66.
Chaki S, Yoshikawa R, Hirota S, Shimazaki T, Maeda M, Kawashima N, et al. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology. 2004;46:457–67.
Dwyer JM, Lepack AE, Duman RS. mTOR activation is required for the antidepressant effects of mGluR(2)/(3) blockade. Int J Neuropsychopharmacol. 2012;15:429–34.
Koike H, Fukumoto K, Iijima M, Chaki S. Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression. Behav Brain Res. 2013;238:48–52.
Dwyer JM, Lepack AE, Duman RS. mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure. J Mol Psychiatry. 2013;1:15.
Ago Y, Yano K, Araki R, Hiramatsu N, Kita Y, Kawasaki T, et al. Metabotropic glutamate 2/3 receptor antagonists improve behavioral and prefrontal dopaminergic alterations in the chronic corticosterone-induced depression model in mice. Neuropharmacology. 2013;65:29–38.
Campo B, Kalinichev M, Lambeng N, El Yacoubi M, Royer-Urios I, Schneider M, et al. Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression. J Neurogenet. 2011;25:152–66.
Dong C, Zhang JC, Yao W, Ren Q, Ma M, Yang C, et al. Rapid and sustained antidepressant action of the mGlu2/3 receptor antagonist MGS0039 in the social defeat stress model: comparison with ketamine. Int J Neuropsychopharmacol. 2017;20:228–36.
Koike H, Iijima M, Chaki S. Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists. Neuropharmacology. 2011;61:1419–23.
Koike H, Chaki S. Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behav Brain Res. 2014;271:111–5.
Fukumoto K, Iijima M, Chaki S. The antidepressant effects of an mGlu2/3 receptor antagonist and ketamine require AMPA receptor stimulation in the mPFC and Subsequent activation of the 5-HT neurons in the DRN. Neuropsychopharmacology. 2016;41:1046–56.
Witkin JM, Marek GJ, Johnson BG, Schoepp DD. Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol Disord Drug Targets. 2007;6:87–100.
Chaki S. mGlu2/3 receptor antagonists as novel antidepressants. Trends Pharmacol Sci. 2017;38:569–80.
Witkin JM, Mitchell SN, Wafford KA, Carter G, Gilmour G, Li J, et al. Comparative effects of LY3020371, a potent and selective metabotropic glutamate (mGlu) 2/3 receptor antagonist, and ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist in rodents: evidence supporting the use of mGlu2/3 antagonists, for the treatment of depression. J Pharmacol Exp Ther. 2017;361:68–86.
Gleason SD, Li X, Smith IA, Ephlin JD, Wang XS, Heinz BA, et al. mGlu2/3 agonist-induced hyperthermia: an in vivo assay for detection of mGlu2/3 receptor antagonism and its relation to antidepressant-like efficacy in mice. CNS Neurol Disord Drug Targets. 2013;12:554–66.
Ornstein PL, Bleisch TJ, Arnold MB, Kennedy JH, Wright RA, Johnson BG, et al. 2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability. J Med Chem. 1998;41:358–78.
Linden AM, Shannon H, Baez M, Yu JL, Koester A, Schoepp DD. Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice. Psychopharmacology (Berl). 2005;179:284–91.
Wright RA, Johnson BG, Zhang C, Salhoff C, Kingston AE, Calligaro DO, et al. CNS distribution of metabotropic glutamate 2 and 3 receptors: transgenic mice and [(3)H]LY459477 autoradiography. Neuropharmacology. 2013;66:89–98.
Hajszan T, Dow A, Warner-Schmidt JL, Szigeti-Buck K, Sallam NL, Parducz A, et al. Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry. 2009;65:392–400.
Carter BS, Hamilton DE, Thompson RC. Acute and chronic glucocorticoid treatments regulate astrocyte-enriched mRNAs in multiple brain regions in vivo. Front Neurosci. 2013;7:139.
Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.
Golden SA, Covington HE III, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.
Lehmann ML, Herkenham M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. J Neurosci. 2011;31:6159–73.
Ashokan A, Hegde A, Mitra R. Short-term environmental enrichment is sufficient to counter stress-induced anxiety and associated structural and molecular plasticity in basolateral amygdala. Psychoneuroendocrinology. 2016;69:189–96.
Greenwood BN, Fleshner M. Exercise, learned helplessness, and the stress-resistant brain. Neuromolecular Med. 2008;10:81–98.
Brachman RA, McGowan JC, Perusini JN, Lim SC, Pham TH, Faye C, et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry. 2016;79:776–86.
McGowan JC, LaGamma CT, Lim SC, Tsitsiklis M, Neria Y, Brachman RA, et al. Prophylactic ketamine attenuates learned fear. Neuropsychopharmacology. 2017;42:1577–89.
Amat J, Dolzani SD, Tilden S, Christianson JP, Kubala KH, Bartholomay K, et al. Previous ketamine produces an enduring blockade of neurochemical and behavioral effects of uncontrollable stress. J Neurosci. 2016;36:153–61.
Mastrodonato A, Martinez R, Pavlova IP, LaGamma CT, Brachman RA, Robison AJ, et al. Ventral CA3 activation mediates prophylactic ketamine efficacy against stress-induced depressive-like behavior. Biol Psychiatry. 2018;84:846–56.
Zanos P, Thompson SM, Duman RS, Zarate CA Jr., Gould TD. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32:197–227.
Witkin JM, Monn JA, Schoepp DD, Li X, Overshiner C, Mitchell SN, et al. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J Pharmacol Exp Ther. 2016;358:71–82.
Palucha-Poniewiera A, Wieronska JM, Branski P, Stachowicz K, Chaki S, Pilc A. On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039. Psychopharmacology (Berl). 2010;212:523–35. PMCID: 2981731
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–5.
Maier SF, Seligman ME. Learned helplessness at fifty: insights from neuroscience. Psychol Rev. 2016;123:349–67.
Maier SF, Watkins LR. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev. 2005;29:829–41.
Amat J, Aleksejev RM, Paul E, Watkins LR, Maier SF. Behavioral control over shock blocks behavioral and neurochemical effects of later social defeat. Neuroscience. 2010;165:1031–8.
Linden AM, Bergeron M, Schoepp DD. Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo. Neuropharmacology. 2005;49:120–34.
Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F, et al. L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci USA. 2013;110:4804–9.
Nasca C, Bigio B, Zelli D, Nicoletti F, McEwen BS. Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility. Mol Psychiatry. 2015;20:755–63.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Highland, J.N., Zanos, P., Georgiou, P. et al. Group II metabotropic glutamate receptor blockade promotes stress resilience in mice. Neuropsychopharmacol. 44, 1788–1796 (2019). https://doi.org/10.1038/s41386-019-0380-1
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41386-019-0380-1
This article is cited by
-
Curcumin Ameliorates Depressive-like Behaviors by Modulating mGluR2/PGC-1α-Mediated Glutamatergic Homeostasis and Mitochondrial Function
Molecular Neurobiology (2026)
-
Are mGluR2/3 Inhibitors Potential Compounds for Novel Antidepressants?
Cellular and Molecular Neurobiology (2023)
-
mGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development
European Archives of Psychiatry and Clinical Neuroscience (2023)
-
The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders
Nature Reviews Neuroscience (2022)
-
Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor
Nature Neuroscience (2022)
