Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain

Shigemoto, Ryuichi; Nomura, Sakashi; Ohishi, Hitoshi; Sugihara, Hidemitsu; Nakanishi, Shigetada; Mizuno, Noboru

doi:10.1016/0304-3940(93)90227-c

Cited by 493 publications

(382 citation statements)

References 18 publications

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“…While dopamine release is necessary for proper mnemonic function, excessive prefrontal dopamine release, such as that induced by NMDA antagonists (Verma and Moghaddam, 1996), can also impair cognitive performance (Arnsten et al, 1994). The expression of mGlu5 receptors is abundant in cortical and limbic regions (Shigemoto et al, 1993;Romano et al, 1995), which are critical sites for the regulation of working memory and learning. Thus, it is tempting to speculate that the activation of dopamine release by MPEP is in part responsible for its behavioral effects.…”

Section: Mglu5-nmda Receptor Interactionmentioning

confidence: 99%

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

Homayoun

Stefani

Adams

et al. 2004

Neuropsychopharmacol

237

182

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Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.

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Section: Mglu5-nmda Receptor Interactionmentioning

confidence: 99%

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

Homayoun

Stefani

Adams

et al. 2004

Neuropsychopharmacol

237

182

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“…After homogenization in 0.32 M sucrose, nuclei were removed by low-speed centrifugation, and a crude membrane fraction was prepared by centrifugation at 35,000 g for 1 h. Western blotting was performed by electrophoresis on a 7.5% sodium dodecyl sulfate polyacrylamide gel according to the procedure described previously (Shigemoto et al, 1993). The mGluRl antibody directed against the carboxy-terminal sequence ofmGluRla was used for analysis of the mGluRl protein, whereas the mGluR5 antibody generated against the carboxy-terminal sequence of mGluR5 (Shigemoto et al, 1993) was used for analysis of the mGluR5 protein. The secondary antibody used was alkaline phosphatase-conjugated anti-rabbit IgG.…”

Section: Northern and Western Blot Analysesmentioning

confidence: 99%

The Metabotropic Glutamate Receptor mGluR5 Induces Calcium Oscillations in Cultured Astrocytes via Protein Kinase C Phosphorylation

Nakahara

Okada²,

Nakanishi

1997

Journal of Neurochemistry

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133

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Abstract:The metabotropic glutamate receptor mGluR5, but not the closely related mGluRl, is expressed in cultured astrocytes, and this expression is up-regulated by specific growth factors. We investigated the capability and underlying mechanisms of mGluR5 to induce oscillatory responses of intracellular calcium concentration ([Ca 2~]) in cultured rat astrocytes. recordings indicated that an mGluR-selective agonist, (1 S,3R)-1 -aminocyclopentane-1,3-dicarboxylate (1 S,3R-ACPD), elicits [Ca2~], oscillations in good agreement with the growth factor-induced up-regulation of mGluR5 in cultured astrocytes. A protein kinase C (PKC) inhibitor, bisindolylmaleimide I, converted a 1S,3R-ACPD-mediated oscillatory response into a nonoscillatory response. In addition, the PKC activator phorbol 12-myristate 13-acetate completely abolished the [Ca2~]increase. These and other pharmacological properties of 1S,3R-ACPD-induced [Ca2~]õscillations correlate well with those of the cloned mGluR5 characterized in heterologous expression systems. Furthermore, the potential involvement of protein phosphatases in [Ca2~]õscilla-tions is suggested. The present study demonstrates that mGluR5 is capable of inducing [Ca2~] 1 oscillations in cultured astrocytes and that phosphorylation/dephosphorylation of mGluR5 is critical in [Ca 2~]oscillations, analogous to the cloned mGluR5 expressed in heterologous cell lines.

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“…Group II (mGluRs 2 and 3) and group III (mGluRs 4 -8) receptors inhibit adenylyl cyclase, although with different pharmacological profiles (for review, see Pin and Duvosin, 1995;Roberts, 1995). Ligand-binding studies have shown the striatum to possess a high density of mGluR binding sites (Albin et al, 1992), and several mGluR mRNAs and proteins are expressed by striatal neurons, including members of all three mGluR groups (Abe et al, 1992;Martin et al, 1992;Shigemoto et al, 1992Shigemoto et al, , 1993Fotuhi et al, 1993;Ohishi et al, 1993a,b;Saugstead et al, 1994;Testa et al, 1994;Joly et al, 1995;Romano et al, 1995).…”

Section: Abstract: Metabotropic Glutamate Receptor; Basal Ganglia; Smentioning

confidence: 99%

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

1997

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Metabotropic glutamate receptors (mGluRs) are a major class of excitatory amino acid receptors. Eight mGluR subtypes, coupled to a variety of effector systems, have been cloned. These receptors have been classified into three groups based on amino acid sequence homology, effector systems, and pharmacological profile. Group I mGluRs increase phosphoinositide turnover, whereas groups II and III mGluRs are negatively coupled to adenylyl cyclase. The striatum possesses a high density of mGluR binding sites, and several mGluR mRNAs and proteins are expressed by striatal neurons. In rats, unilateral striatal injection of the nonsubtype selective mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) results in contralateral rotation with delayed onset, thought to be secondary to an increase in dopamine release. We sought to determine the mGluR subtype(s) involved, the modulation of the rotation by other basal ganglia neurotransmitter systems, and the functional anatomy underlying the rotational behavior. The group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) induced contralateral rotation in a dose-dependent manner, whereas group II and group III agonists were ineffective. Rotation induced by DHPG or 1S,3R-ACPD was attenuated by group I antagonists, but not by group II or group III antagonists. This suggests that the rotation is mediated by group I mGluRs. Rotation induced by DHPG or 1S,3R-ACPD was attenuated by pretreatment with antagonists at muscarinic cholinergic, adenosine A 2 , dopamine D 2 , or dopamine D 1 receptors. Examination of FOS-like immunoreactivity after group I and group II mGluR agonist administration suggests increased activity in the striatopallidal pathway. However, [ 14 C]-2-deoxyglucose uptake studies indicate increased activity in nuclei of the striatopallidal (indirect) pathway, particularly in the subthalamic nucleus, only after group I mGluR activation. Key words: metabotropic glutamate receptor; basal ganglia; subthalamic nucleus; striatum; dopamine; adenosine A2 receptors; muscarinic receptorsExcitatory amino acids (EAAs) are important neurotransmitters in the basal ganglia, and EAAergic agents are being investigated actively as possible pharmacotherapies for basal ganglia disorders. A major class of EAA receptors are the metabotropic glutamate receptors (mGluRs), coupled to second messenger systems via G-proteins. Eight mGluR subtypes have been cloned, several of which possess splice variants. These mGluR subtypes have been categorized into three groups based on their amino acid sequence homology, effector systems, and pharmacological profile. When expressed and activated in transfection systems, group I receptors (mGluRs 1 and 5) stimulate phosphoinositide hydrolysis. Group II (mGluRs 2 and 3) and group III (mGluRs 4 -8) receptors inhibit adenylyl cyclase, although with different pharmacological profiles (for review, see Pin and Duvosin, 1995;Roberts, 1995). Ligand-binding studies have shown the striatum to possess a high density of mGluR binding sites (Albin et al....

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Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain

Cited by 493 publications

References 18 publications

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

The Metabotropic Glutamate Receptor mGluR5 Induces Calcium Oscillations in Cultured Astrocytes via Protein Kinase C Phosphorylation

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

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Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain

Cited by 493 publications

References 18 publications

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

The Metabotropic Glutamate Receptor mGluR5 Induces Calcium Oscillations in Cultured Astrocytes via Protein Kinase C Phosphorylation

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [14C]-2-Deoxyglucose Autoradiographic Study

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Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study