New perspectives for the development of selective metabotropic glutamate receptor ligands

Pin, Jean‐Philippe; Colle, Cyril De; Bessis, Anne-Sophie; Acher, Francine

doi:10.1016/s0014-2999(99)00258-7

Cited by 140 publications

(109 citation statements)

References 94 publications

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“…The present results show that the group I mGlu receptor agonist DHPG (Pin et al 1999) raised extracellular DA in the mPFC of the conscious rat by stimulating mGlu1 and mGlu5 receptors in the VTA. The effect of DHPG on extracellular DA was characterized in several aspects.…”

Section: Discussionsupporting

confidence: 50%

Stimulation of group I mGlu receptors in the ventrotegmental area enhances extracellular dopamine in the rat medial prefrontal cortex

Renoldi

Calcagno

Borsini

et al. 2006

Journal of Neurochemistry

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Group I mGlu receptors have been implicated in the control of brain dopamine release. However, the receptor subtype involved and the precise site of action have not been determined. In this study we show that (R,S)3,5-dihydroxyphenylglycine (DHPG; 6 and 60 nmol ICV), a selective group I mGlu receptor agonist, raised extracellular dopamine respectively by 176% and 243% of basal values in the medial prefrontal cortex as assessed by in vivo microdialysis in conscious rats. (R,S)2-chloro-5-hydroxyphenylglycine (60 nmol ICV), a selective mGlu5 receptor agonist, raised extracellular dopamine by 396% of basal values. Intra-VTA DHPG (0.6-6 nmol) mimicked ICV injection whereas intracortical infusion (1-1000 lmol/L) had no effect. DHPG-induced rise of extracellular dopamine was reversed by tetrodotoxin and by the selective mGlu1 and mGlu5 receptor antagonists 7(hydroxyimino)cyclopropa [b]chromen-1a-carboxylate (CPCCOEt) and 2-methyl-6-(phenylethynyl)pyridine (MPEP) either ICV or into the ventrotegmental area (VTA), suggesting that neuronal release and both mGlu1 and mGlu5 receptors were involved. These results support the existence of functional mGlu1 and mGlu5 receptors in the VTA regulating the release of dopamine in the medial prefrontal cortex. Keywords: 2-methyl-6-(phenylethynyl)pyridine, 7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate, (R,S)3,5-dihydroxyphenylglycine, dopamine, medial prefrontal cortex, mGlu1 and mGlu5 receptors, ventrotegmental area.

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Section: Discussionsupporting

confidence: 50%

Stimulation of group I mGlu receptors in the ventrotegmental area enhances extracellular dopamine in the rat medial prefrontal cortex

Renoldi

Calcagno

Borsini

et al. 2006

Journal of Neurochemistry

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“…Indeed, Fig. 4B shows that eCB-LTD is completely abolished by the broad-spectrum mGlu antagonist LY341495 and more importantly by the specific mGlu5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) (36). In accord with a role of mGlu5, it was found that direct stimulation with the specific group 1 mGluR agonist (S)-DHPG (100 M, 10 min) also causes LTD.…”

Section: Resultsmentioning

confidence: 77%

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

Robbe

Köpf

Rémaury

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

518

502

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Do endocannabinoids (eCBs) participate in long-term synaptic plasticity in the brain? Using pharmacological approaches and genetically altered mice, we show that stimulation of prelimbic cortex afferents at naturally occurring frequencies causes a longterm depression of nucleus accumbens glutamatergic synapses mediated by eCB release and presynaptic CB1 receptors. Translation of glutamate synaptic transmission into eCB retrograde signaling involved metabotropic glutamate receptors and postsynaptic intracellular Ca 2؉ stores. These findings unveil the role of the eCB system in activity-dependent long-term synaptic plasticity and identify a mechanism by which marijuana can alter synaptic functions in the endogenous brain reward system. E xogenous cannabinoids, such as the active component of Cannabis sativa L, (Ϫ)-transdelta9-tetrahydrocannabinol, as well as endocannabinoids (eCBs; anandamide and 2-arachidonoyl-glycerol) share the same target in the central nervous system: a Gi͞Go-coupled receptor named CB1 (1, 2). Activation of CB1 receptors inhibits both inhibitory and excitatory synaptic transmission in the hippocampus (3, 4), substantia nigra pars compacta (5), the cerebellum (6), the prefrontal cortex (7), and the nucleus accumbens (NAc) (8, 9). Both eCBs and CB1 have been involved in a short-lasting form of synaptic regulation: the ''depolarization-induced suppression'' of both inhibitory (10-15) and excitatory transmission (16). However, the involvement of eCB in long-lasting activity-dependent synaptic plasticity remained to be documented. The mesocorticolimbic dopaminergic system, and particularly the NAc, is essential to the reinforcing properties of addictive drugs (17, 18). Cannabinoids activate mesolimbic dopamine neurons (19) and increase NAc dopamine levels (20), similarly to other drugs of abuse. Our finding that CB1 are localized at the excitatory afferents to the NAc where exogenous cannabimimetics inhibit glutamatergic synaptic transmission (9) raised two questions: how does synaptic activity lead to the production of eCBs in the NAc, and what are the physiological correlates of eCB release on synaptic transmission? Methods Slice Preparation and Electrophysiology. Whole-cell patch-clamp and extracellular field recordings were made from medium spiny neurons in parasagittal slices of mouse NAc. These methods have been described in detail previously (9). In brief, mice (male C57BL6, 4-6 weeks) were anesthetized with isoflurane and decapitated. The brain was sliced (300-400 m) in the parasagittal plane by using a vibratome and maintained in physiological saline at 4°C. Slices containing the NAc were stored at least 1 h at room temperature before being placed in the recording chamber and superfused (2 ml͞min) with artificial cerebrospinal fluid that contained (in mM): 126 NaCl, 2.5 KCl, 1.2 MgCl 2 , 2.4 CaCl 2, 18 NaHCO 3 , 1.2 NaH 2 PO 4 , and 11 glucose, and was equilibrated with 95% O 2 ͞5% CO 2 . All experiments were done at room temperature. The superfusion medium contained picrotoxin (100 M) to...

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“…Alternately, Zn 2ϩ binding to the ATD lip of K260H could also be speculated to interfere with the intramolecular communication between the ATD and the seven-transmembrane moiety (7TM) of the family C receptor. We and others have suggested a mechanism underlying the signal transduction through the receptor, where the signal is transferred to the G-protein coupling area by an intramolecular interaction between the ATD and the 7TM of the receptor (1,9,53). Hence, the antagonistic effect of Zn 2ϩ binding could be thought to arise from a disruption of a structural motif in the ATD lobe necessary for the signal transfer process.…”

Section: H]-quis Binding To Wt and Mutant Mglurlb Receptorsmentioning

confidence: 99%

Construction of a High Affinity Zinc Binding Site in the Metabotropic Glutamate Receptor mGluR1

Jensen

Sheppard

Jensen

et al. 2001

Journal of Biological Chemistry

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The metabotropic glutamate receptors (mGluRs) belong to family C of the G-protein-coupled receptor (GPCR) superfamily. The receptors are characterized by having unusually long amino-terminal domains (ATDs), to which agonist binding has been shown to take place. Previously, we have constructed a molecular model of the ATD of mGluR1 based on a weak amino acid sequence similarity with a bacterial periplasmic binding protein. The ATD consists of two globular lobes, which are speculated to contract from an "open" to a "closed" conformation following agonist binding. In the present study, we have created a Zn 2؉ binding site in mGluR1b by mutating the residue Lys 260 to a histidine. Zinc acts as a noncompetitive antagonist of agonist-induced IP accumulation on the K260H mutant with an IC 50 value of 2 M. Alanine mutations of three potential "zinc coligands" in proximity to the introduced histidine in K260H knock out the ability of Zn 2؉ to antagonize the agonist-induced response. Zn 2؉ binding to K260H does not appear to affect the dimerization of the receptor. Instead, we propose that binding of zinc has introduced a structural constraint in the ATD lobe, preventing the formation of a "closed" conformation, and thus stabilizing a more or less inactive "open" form of the ATD. This study presents the first metal ion site constructed in a family C GPCR. Furthermore, it is the first time a metal ion site has been created in a region outside of the seven transmembrane regions of a GPCR and the loops connecting these. The findings offer valuable insight into the mechanism of ATD closure and family C receptor activation. Furthermore, the findings demonstrate that ATD regions other than those participating in agonist binding could be potential targets for new generations of ligands for this family of receptors.

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New perspectives for the development of selective metabotropic glutamate receptor ligands

Cited by 140 publications

References 94 publications

Stimulation of group I mGlu receptors in the ventrotegmental area enhances extracellular dopamine in the rat medial prefrontal cortex

Stimulation of group I mGlu receptors in the ventrotegmental area enhances extracellular dopamine in the rat medial prefrontal cortex

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

Construction of a High Affinity Zinc Binding Site in the Metabotropic Glutamate Receptor mGluR1

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