Cited by 103Neuroscience and Neuropharmacology ResearchRegulation of Appetite and ObesityNeurotransmitter Receptor Influence on Behavior

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Increased measures of anxiety and weight gain in mice lacking the group III metabotropic glutamate receptor mGluR8

Duvoisin, Robert M., Zhang, Connie, Pfankuch, Timothy F., O'Connor, Heather, Gayet‐Primo, Jacqueline, Quraishi, Salma, Raber, Jacob·2005·European Journal of Neuroscience

DOI 10.1111/j.1460-9568.2005.04210.x

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Abstract

To study the role of the metabotropic glutamate receptor 8 (mGluR8), mice lacking this receptor were generated by homologous recombination. Homozygous mGluR8-deficient mice are about 8% heavier than their wild-type age-matched controls after reaching 4 weeks of age. This weight difference is not caused by an altered food intake and is not exacerbated by feeding the animals a high-fat diet. Moreover, mGluR8-/- mice are mildly insulin resistant, possibly as a result of being overweight. Behavioral testing revealed a reduced locomotor activity of mGluR8-/- mice compared with wild-type mice during the first 3 days in a novel enclosed environment. However after 3 days, the locomotor activities of wild-type and mGluR8-/- mice were similar, suggesting a reduced exploratory behavior of mGluR8-/- mice in a novel enclosed environment. By contrast, there were no genotype differences in locomotor activity in the open field, plus maze, or in total time spent exploring objects during object recognition tests, indicating that there is a dissociation between effects of mGluR8 deficiency in exploratory activity in a novel safe enclosed environment vs. a more anxiogenic novel open environment. The absence of mGluR8 also leads to increased measures of anxiety in the open field and elevated plus maze. Whether the diverse phenotypic differences observed in mGluR8-/- mice result from the misregulation of a unique neural pathway, possibly in the thalamus or hypothalamus, or whether they are the consequence of multiple developmental and functional alterations in synaptic transmission, remains to be determined.

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Supraspinal metabotropic glutamate receptor subtype 8: a switch to turn off pain
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“…in the inner zone in the open field test and a significant reduction in the entries into the open arms in the elevated plus maze test (Linden et al. 2002; Duvoisin et al. 2005, 2010a; Robbins et al. 2007). mGluR8 -/-mice showed also increased acoustic startle response (Duvoisin et al. 2010a).”
Background
Behavioural profile of selective ligands for mGlu7 and mGlu8 glutamate receptors in agonistic encounters between mice.
Navarro, J. F., Castro, V. D., & Martín‐López, M. (2009) · PubMed · Cited by 16
An Exome-wide Association Study for Type 2 Diabetes–Attributed End-Stage Kidney Disease in African Americans
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“Metabotropic glutamate receptor 8, the protein product encoded by GRM8, is associated with weight gain in mouse models.(47,48) Previous studies suggest that obesity is a major risk factor for kidney disease in patients with diabetes.”
Background
Role of metabotropic glutamate receptors in CNS disorders
O’Connor, R. M., & Cryan, J. F. (2010) · Cambridge University Press eBooks · doi:10.1017/cbo9780511760334.017 · Cited by 15
Related functions of mGlu4 and mGlu8
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“…of anxiety in the open field and elevated zero maze, sensorimotor function on the rotorod, and fear conditioning, as mGlu4 and/or mGlu8 were shown to affect performance in these tests (Davis et al., 2012; Duvoisin et al., 2010a; Duvoisin et al., 2011; Duvoisin et al., 2010b; Duvoisin et al., 2005).”
BackgroundMethod
Association between alopecia areata, anxiety, and depression: Insights from a bidirectional two-sample Mendelian randomization study
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The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review
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Loss-of-Function Models of the Metabotropic Glutamate Receptor Genes Grm8a and Grm8b Display Distinct Behavioral Phenotypes in Zebrafish Larvae (Danio rerio)
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Structural Basis for ( S )-3,4-Dicarboxyphenylglycine (DCPG) As a Potent and Subtype Selective Agonist of the mGlu 8 Receptor
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Selective activation of mGluR8 receptors modulates retinal ganglion cell light responses
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“C57Bl/6 mice (Charles River, Wilmington, MA) and congenic mGluR8−/− mice (Duvoisin et al., 2005) were fed and housed under a 12 hour light/dark cycle.”
Method
Inhibition mediated by group III metabotropic glutamate receptors regulates habenula activity and defensive behaviors
Ostenrath, A. M., Faturos, N., Çobanoğlu, Y. I. Ç., Serneels, B., Jeong, I., Dayanc, E. D., Enz, A., Hinrichsen, F., Mutlu, A. K., Bardenhewer, R., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62115-z · Cited by 8
Role of melatonin in autism spectrum disorders in a male murine transgenic model: Study in the prefrontal cortex
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Roles of metabotropic glutamate receptor 8 in neuropsychiatric and neurological disorders
Mao, L., Mathur, N., Shah, K., & Wang, J. Q. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.10.003 · Cited by 9
A candidate syntenic genetic locus is associated with voluntary exercise levels in mice and humans
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“water maze [51].”
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Human CLOCK enhances neocortical function
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“Although Grm8 was downregulated in the deep-layer excitatory neurons of HU mice (Supplementary Table 7 and 9), previous work on Grm8 / GRM8 KO mice and human neurons did not detect apparent deficits in cognitive behaviors, axonal growth and spine formation 103–105 .”
Transcriptional regulation of NRF1 on metabotropic glutamate receptors in a neonatal hypoxic‑ischemic encephalopathy rat model
Wang, D., Xu, M., Huang, L., Wang, X., & Zhu, L. (2022) · Pediatric Research · doi:10.1038/s41390-022-02353-9 · Cited by 4
“mGlu8 transcript expression declines progressively during postnatal development(47) and has been linked to anxiety and pain.(48,49) Given the extensive significance of mGluRs in motor and cognitive activities outlined above, upregulating NRF1 could enhance cognitive skills in neonatal HIE rats by stimulating the trans…”
Background
Metabotropic Glutamate Receptor Ligands as Novel Therapeutic Agents
Brady, A. E., & Conn, P. J. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-055-3_14 · Cited by 4
Metabotropic Glutamate Receptors in Amygdala Functions
Ferraguti, F. (2017) · Springer eBooks · doi:10.1007/978-3-319-56170-7_13 · Cited by 5
Efectos de la administración de (RS)-3,4-DCPG, un antagonista mixto de los receptores AMPA y agonista de los receptores mGlu8, en la conducta agresiva de los ratones
Navarro, J. F., Castro, V. D., & Martín‐López, M. (2009) · Revista de Psiquiatría y Salud Mental · doi:10.1016/s1888-9891(09)72404-8 · Cited by 3
Metabotropic Receptors for Glutamate and GABA
Stewart, G. D., Kniazeff, J., Przeau, L., Rondard, P., Pin, J., & Goudet, C. (2012) · InTech eBooks · doi:10.5772/32481 · Cited by 4
“Both mGlu7 and mGlu8 KO animals display increase anxiety (Cryan et al., 2003; Duvoisin et al., 2005).”
Background
Metabotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Acher, F., Battaglia, G., Bräuner‐Osborne, H., Conn, P. J., Duvoisin, R. M., Ferraguti, F., Flor, P. J., Goudet, C., Gregory, K. J., Hampson, D. R., et al. (2019) · IUPHAR/BPS Guide to Pharmacology CITE · doi:10.2218/gtopdb/f40/2019.4 · Cited by 3
Inhibition mediated by group III mGluRs regulates habenula activity and defensive behaviorsPreprint
Ostenrath, A. M., Faturos, N., Çobanoğlu, Y. I. Ç., Serneels, B., Jeong, I., Enz, A., Hinrichsen, F., Mutlu, A. K., Bardenhewer, R., Jetti, S. K., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.11.612421 · Cited by 3
Thalamocortical mGlu8 Modulates Dorsal Thalamus Excitatory Transmission and Sensorimotor Activity
Nabit, B. P., Taylor, A., & Winder, D. G. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.0119-24.2024 · Cited by 3
“…& Conn, 2021)). c r In classical, non-conditioned measures of anxiety, constitutive grm8 KO mice showed altered locomotor activity in open field (Duvoisin et al., 2005a; Lüffe et al., 2022) (both decreased(Duvoisin et al., 2005a) and increased(Gerlai et al., 2002)), increased anxiety…”
BackgroundResultInfluential
Psychotic symptoms associated increased CpG methylation of metabotropic glutamate receptor 8 gene in Chinese Han males with schizophrenia and methamphetamine induced psychotic disorder: a longitudinal study
Dong, H., Luo, T., Yang, C., Liu, M., Shen, Y., & Hao, W. (2024) · Schizophrenia · doi:10.1038/s41537-024-00506-9 · Cited by 2
“The absence of mGluR8 leads to reduced locomotor activity in a novel enclosed environment, delayed response to electric shock, transient delay in response to scene fear and increased measures of anxiety in the open ﬁ eld and elevated plus maze 50,51 .”
Background
Selective agonism of mGlu8 receptors by (S)-3,4-dicarboxyphenylglycine does not affect sleep stages in the rat
Cavas, M., Scesa, G., Martín‐López, M., & Navarro, J. F. (2016) · Pharmacological Reports · doi:10.1016/j.pharep.2016.09.019 · Cited by 2
“Moreover, group III mGlu receptors agonists show an anxiolytic profile that have largely been attributed to mGlu8 receptor activation [47-49] and a number of studies demonstrate mGlu8 involment in amygdala-dependent fear learning [43,44,50].”
Background
Chapter 4.6 Genetic factors underlying anxiety-behavior: A meta-analysis of rodent studies involving targeted mutations of neurotransmission genes
Belzung, C., Leman, S., & Griebel, G. (2008) · Handbook of behavioral neuroscience · doi:10.1016/s1569-7339(07)00015-x · Cited by 2
Molecular pharmacology of mGlu7/8 heterodimers reveals unique properties of orthosteric agonists and positive allosteric modulators
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Metabotropic Glutamate Receptors in Anxiety Disorder
Xu, J., & Zhu, Y. (2023) · IntechOpen eBooks · doi:10.5772/intechopen.1002630 · Cited by 2
Metabotropic glutamate receptor-8 relieves neonatal maternal separation-induced visceral hypersensitivity in rats by regulating expression of TNF-α
Wang, X., Shao, L., Hua, H., & Chen, Y. (2023) · Annals of Translational Medicine · doi:10.21037/atm-22-6452 · Cited by 1
“Other studies have demonstrated that MGluR8 knockout mice show increased anxiety until age of 6 months (38,39).”
Single-nuclei transcriptomics of dog hippocampus reveals the distinct cellular mechanism of domesticationPreprint
Zhou, Q.-J., Liu, X., Zhang, L., Wang, R., Yin, T., Li, X., Li, G., He, Y., Ding, Z., Ma, P., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.29.478120 · Cited by 1
On the Neurobiology of Physical Activity in Mice and Human : In search of Eating Disorders Determinants
Kostrzewa, E. (2014) · Utrecht University Repository (Utrecht University)
Anxiety and mood disorders
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Effects of the administration of (RS)-3,4-DCPG, a mixed AMPA receptor antagonist/mGluR8 receptor agonist, on aggressive behaviour in mice
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Modulation endogène des récepteurs métabotropiques du glutamate : bases moléculaires et implications fonctionnelles de la sensibilité au chlore extracellulaire
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Authors: Duvoisin, R. M., Zhang, C., Pfankuch, T. F., O'Connor, H., Gayet‐Primo, J., Quraishi, S., & Raber, J.
Affiliations: Oregon Health & Science University (US)
Cornell University (US)
Oregon National Primate Research Center (US)
ORCID: Duvoisin, Robert M.
Raber, Jacob
Venue: European Journal of Neuroscience
Publisher: Wiley
Published: 2005-07
Volume: 22
Issue: 2
Pages: 425-436
ISSN: 0953-816X (ISSN-L)
1460-9568
DOI: 10.1111/j.1460-9568.2005.04210.x
OpenAlex: W1894780092
Cited by: 102
References: 57
Citations by year: 2026: 2 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 1 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 6 · 2014: 7 · 2013: 5 · 2012: 8
FWCI: 2.04
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 20 d)
Locations: European Journal of Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: Ellison Medical Foundation
National Institutes of Health
National Institute on Aging (R01AG020904, AG20904)
National Eye Institute (R01EY009534, EY09534)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: anxiety, weight gain, obesity, insulin resistance, locomotor activity, exploratory behavior, novel environment, object recognition, thalamus, hypothalamus, synaptic transmission
MeSH terms: Age Factors, Animals, Anxiety, Avoidance Learning, Behavior, Animal, Blood Glucose, Body Composition, Drug Tolerance, Eating, Exploratory Behavior, Genotype, Insulin, Molecular Biology, Motor Activity, Psychomotor Performance, Reaction Time, Research Design, Time Factors, Blotting, Western, Weight Gain, Absorptiometry, Photon, Receptors, Metabotropic Glutamate, Mice, Knockout, Maze Learning, Recognition, Psychology, Mice

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Increased measures of anxiety and weight gain in mice lacking the group III metabotropic glutamate receptor mGluR8

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