Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics.

BACKGROUND Metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5) are novel therapeutic targets for major depression (MD), bipolar disorder (BD) and schizophrenia. We aimed to determine whether mGluR2/3 and mGluR5 binding in the anterior cingulate cortex (ACC), a brain region essential for the regulation of mood, cognition and emotion, were differentially altered in these pathologies. METHODS Using postmortem human brains derived from 2 cohorts, [(3)H]LY341495 binding to mGluR2/3 and [(3)H]MPEP binding to mGluR5 were measured by receptor autoradiography in the ACC. The first cohort comprised samples from individuals who had MD with psychosis (MDP), MD without psychosis (MDNP) and matched controls (n = 11-12 per group). The second cohort comprised samples from individuals who had MDNP, BD, schizophrenia and matched controls (n = 15 per group). RESULTS No differences in mGluR2/3 or mGluR5 binding were observed in the MDP, MDNP, BD or schizophrenia groups compared with the control group (all p > 0.05). Importantly, there were also no differences in binding densities between the psychiatric disorders (p > 0.05). We did, however, observe age-related effects, with consistent negative associations between mGluR2/3 and age in the control group (r < -0.575, p < 0.025) and the psychotic disorder groups (MDP and schizophrenia: r = -0.765 to -0.515, p < 0.05), but not in the mood disorder groups (MDNP, BD). LIMITATIONS Replication in larger independent cohorts and medication-naive individuals would strengthen these findings. CONCLUSION Our findings suggest that mGluRs are unaltered in the ACC; however, the presence of altered receptor function cannot be discounted and requires further investigation. Taken together with previous studies, which report differential changes in mGluR2, 3 and 5 across these disorders, we suggest mGluRs may be affected in a brain region-specific manner.

[1]  L. Munsie,et al.  Pharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia , 2010, The Pharmacogenomics Journal.

[2]  Xu-Feng Huang,et al.  Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment , 2013, Schizophrenia Research.

[3]  K. Davis,et al.  Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia , 2005, Synapse.

[4]  C. Zarate,et al.  Novel glutamatergic agents for major depressive disorder and bipolar disorder , 2012, Pharmacology Biochemistry and Behavior.

[5]  M. Papp,et al.  Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in the rat hippocampus in an animal model of depression. , 2001, Polish journal of pharmacology.

[6]  L. Minuzzi,et al.  Reduced metabotropic glutamate receptor 5 in the Flinders Sensitive Line of rats, an animal model of depression: An autoradiographic study , 2012, Brain Research Bulletin.

[7]  P. McKenna,et al.  Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. , 1998, Brain research. Molecular brain research.

[8]  D. Jeste,et al.  Treating older adults with schizophrenia: challenges and opportunities. , 2013, Schizophrenia bulletin.

[9]  M. Webster,et al.  Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients , 2012, Translational Psychiatry.

[10]  R. Spanagel,et al.  Rescue of Infralimbic mGluR2 Deficit Restores Control Over Drug-Seeking Behavior in Alcohol Dependence , 2013, The Journal of Neuroscience.

[11]  M. Olive.  Metabotropic glutamate receptor ligands as potential therapeutics for addiction. , 2009, Current drug abuse reviews.

[12]  M. Webster,et al.  Neuropathology markers and pathways associated with molecular targets for antipsychotic drugs in postmortem brain tissues: Exploration of drug targets through the Stanley Neuropathology Integrative Database , 2012, European Neuropsychopharmacology.

[13]  P. Thuras,et al.  mRNA and protein expression for novel GABAA receptors θ and ρ2 are altered in schizophrenia and mood disorders; relevance to FMRP-mGluR5 signaling pathway , 2013, Translational Psychiatry.

[14]  Ravi S. Menon,et al.  Glutamate and glutamine in the anterior cingulate and thalamus of medicated patients with chronic schizophrenia and healthy comparison subjects measured with 4.0-T proton MRS. , 2003, The American journal of psychiatry.

[15]  Bernadette Lipinski,et al.  Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study , 2000, Biological Psychiatry.

[16]  V. Haroutunian,et al.  Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia , 2006, Molecular Psychiatry.

[17]  D. Volk,et al.  Alterations in metabotropic glutamate receptor 1α and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. , 2010, The American journal of psychiatry.

[18]  A. Caricasole,et al.  Imipramine treatment up-regulates the expression and function of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus , 2002, Neuropharmacology.

[19]  L. Grégoire,et al.  mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys , 2008, Neurobiology of Aging.

[20]  T. Woo,et al.  Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. , 2004, Archives of general psychiatry.

[21]  A. Rothschild.  Challenges in the treatment of major depressive disorder with psychotic features. , 2013, Schizophrenia bulletin.

[22]  D F Swaab,et al.  Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients. , 2012, Journal of affective disorders.

[23]  F. Nicoletti,et al.  Metabotropic glutamate receptors: From the workbench to the bedside , 2011, Neuropharmacology.

[24]  Natalie Matosin,et al.  Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia , 2013, Neuroscience & Biobehavioral Reviews.

[25]  K. Newell.  Metabotropic glutamate receptor 5 in schizophrenia: emerging evidence for the development of antipsychotic drugs. , 2013, Future medicinal chemistry.

[26]  Gregor Hasler,et al.  Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study. , 2011, The American journal of psychiatry.

[27]  Marzena Wylezinska,et al.  Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. , 2008, The international journal of neuropsychopharmacology.

[28]  M. Śmiałowska,et al.  Effect of chronic imipramine or electroconvulsive shock on the expression of mGluR1a and mGluR5a immunoreactivity in rat brain hippocampus , 2002, Neuropharmacology.

[29]  P. Ward,et al.  Selective Alterations in Ionotropic Glutamate Receptors in the Anterior Cingulate Cortex in Schizophrenia , 2002, Neuropsychopharmacology.

[30]  E. Frank,et al.  Density of metabotropic glutamate receptors 2 and 3 (mGluR2/3) in the dorsolateral prefrontal cortex does not differ with schizophrenia diagnosis but decreases with age , 2011, Schizophrenia Research.

[31]  J. Tiihonen,et al.  mGluR1/5 receptor densities in the brains of alcoholic subjects: A whole-hemisphere autoradiography study , 2013, Psychiatry Research: Neuroimaging.

[32]  M. Riva,et al.  Modulation of glutamate receptors in response to the novel antipsychotic olanzapine in rats , 2001, Biological Psychiatry.

[33]  P. Malherbe,et al.  Distribution and abundance of metabotropic glutamate receptor subtype 2 in rat brain revealed by [3H]LY354740 binding in vitro and quantitative radioautography: Correlation with the sites of synthesis, expression, and agonist stimulation of [35S]GTPγs binding , 2005 .

[34]  K. Davis,et al.  Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus , 2000, Biological Psychiatry.

[35]  Natalie Matosin,et al.  Rethinking metabotropic glutamate receptor 5 pathological findings in psychiatric disorders: implications for the future of novel therapeutics , 2014, BMC Psychiatry.

[36]  C Taylor,et al.  Substance misuse and psychiatric comorbidity: an overview of the OPCS National Psychiatric Morbidity Survey. , 1998, Addictive behaviors.

[37]  Robert C. Thompson,et al.  Altered expression of glutamate signaling, growth factor and glia genes in the locus coeruleus of patients with major depression , 2010, Molecular Psychiatry.

[38]  M. Olive.  Metabotropic glutamate receptors: Molecular mechanisms, role in neurological disorders and pharmacological effects , 2014 .

[39]  P. Conn,et al.  Metabotropic glutamate receptors as therapeutic targets for schizophrenia , 2012, Neuropharmacology.

[40]  G. Hasler,et al.  Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[41]  K. Hashimoto,et al.  Increased Levels of Glutamate in Brains from Patients with Mood Disorders , 2007, Biological Psychiatry.

[42]  E. Torrey,et al.  Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression , 2007, Journal of Neural Transmission.

[43]  P. Gasquoine.  Localization of function in anterior cingulate cortex: From psychosurgery to functional neuroimaging , 2013, Neuroscience & Biobehavioral Reviews.

[44]  A. Douaihy,et al.  Treatment of substance abusing patients with comorbid psychiatric disorders. , 2012, Addictive behaviors.

[45]  J. Kleinman,et al.  Comparative analysis of group II metabotropic glutamate receptor immunoreactivity in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects , 2002, Molecular Psychiatry.

[46]  M. Webster,et al.  The Stanley Neuropathology Consortium Integrative Database: a Novel, Web-Based Tool for Exploring Neuropathological Markers in Psychiatric Disorders and the Biological Processes Associated with Abnormalities of Those Markers , 2010, Neuropsychopharmacology.

[47]  R. Yolken,et al.  The Stanley Foundation brain collection and Neuropathology Consortium , 2000, Schizophrenia Research.

[48]  Oliver Mf.  Metabotropic glutamate receptor ligands as potential therapeutics for addiction. , 2009 .