Metabotropic glutamate receptors in brain function and pathology

Schoepp, Darryle D.; Conn, P. Jeffrey

doi:10.1016/0165-6147(93)90107-u

Cited by 730 publications

(371 citation statements)

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“…The fact that synaptic transmission at NMDA receptors is modulated by simultaneous activation of mGluR5 (Sorensen and Conn, 2003) could at least provide a clue for the effects of MPEP on the ADE. This functional coupling could result from the postsynaptic association of NMDA receptors with a complex of proteins, which includes different scaffolding proteins (eg PSD-95, Homer, Shank), but other receptors including mGluR5 are also linked to this complex (Kotecha et al, 2003), and activation of mGluR5 can lead to an enhancement of NMDA receptor function through phosphorylation by protein kinase C (Hermans and Challiss, 2001;Schoepp and Conn, 1993). The high affinity of MPEP for mGluR5 receptors, which is more than 1000-fold higher compared to NMDARs, makes it very unlikely that under the used conditions MPEP affects NMDARs directly (Oleary et al, 2000;Gubellini et al, 2001;Spooren et al, 2001;Kozela et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Bäckström

Bachteler

Koch

et al. 2003

Neuropsychopharmacol

235

178

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The glutamatergic system plays an important role in mediating neurobehavioral effects of ethanol. Metabotropic glutamate receptors subtype 5 (mGluR5) are modulators of glutamatergic neurotransmission and are abundant in brain regions known to be involved in ethanol self-administration. Here, we studied the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a highly potent, noncompetitive mGlu5 receptor antagonist, on voluntary ethanol consumption and relapse behavior. For this purpose, we used two models for the measurement of relapse behavior: (i) reinstatement of ethanol-seeking behavior by drug-associated cues and (ii) the alcohol deprivation effect in long-term ethanol-consuming rats. In the first set of experiments, rats were trained to lever press for ethanol in the presence of a distinct set of cues. After extinction, the animals were exposed to the respective cues that initiated reinstatement of responding. A response-contingent ethanol prime further enhanced responding compared to the conditioned cues alone. Under these conditions, MPEP (0, 1, 3, and 10 mg/kg) attenuated ethanol seeking significantly and in a dose-related manner. However, at the highest dose, MPEP also decreased the number of inactive lever responses. In the second set of experiments, rats with 1 year of ethanol experience and repeated deprivation phases were used. A subchronic treatment with MPEP (twice daily; 0, 3, and 10 mg/kg) resulted in a significant and dose-dependent reduction of the alcohol deprivation effect (ADE). Although the same MPEP treatment regimen decreased baseline drinking, this effect was not as pronounced as on the ADE. These results show in two commonly used models of relapse to ethanol that pharmacological targeting of mGlu5 receptors may be a promising approach for the treatment of alcoholism.

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Section: Discussionmentioning

confidence: 99%

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Bäckström

Bachteler

Koch

et al. 2003

Neuropsychopharmacol

235

178

View full text Add to dashboard Cite

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“…mGluRs have been suggested as useful targets for pharmacotherapy in PD (Schoepp and Conn, 1993;Kaatz and Albin, 1995;Nicoletti et al, 1996). A hallmark feature of PD is overactivity of the STN, which may lead to progressive excitotoxic death of the remaining dopamine-containing neurons of the SNc (Saji et al, 1996) and hyperstimulation of the GPi /SNr (GPi ϭ EP in rodents) resulting in a reduction in motor activity (Albin et al, 1989).…”

Section: Discussionmentioning

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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“…According to sequence similarity, transduction mechanisms and pharmacology, mGluRs have been classified into 3 groups: Group I receptors (mGluRs 1 and 5) are coupled to G q/11 proteins and activate phospholipase C, enhancing neuronal excitability; Group II (mGluRs 2 and 3) and III receptors (mGluRs 4, 6, 7 and 8) are coupled to G i/o proteins, lead to inhibition of adenylate cyclase, inhibiting cyclic adenosine monophosphate (cAMP) formation and cAMP-dependent protein kinase A, enhancing neuronal inhibition (Schoepp and Conn, 1993;Pin and Duvoisin, 1995;Conn and Pin, 1997).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

Zhou

Carlton

2008

Neuroscience

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Several lines of evidence indicate that Group II metabotropic glutamate receptor (mGluR) activation can depress sensory transmission. We have reported the expression of Group II mGluRs on unmyelinated axons, many of which were presumed to be nociceptors, in the rat digital nerve (Carlton et al., 2001b). The goals of the present study are to further our understanding of Group II modulation of nociceptor processing in the periphery, documenting behavioral changes using inflammatory models and documenting, for the first time, cutaneous single fiber activity following exposure to a Group II agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) and antagonist LY341495 (LY). The data indicate that peripheral Group II mGluR activation does not depress nociceptive behaviors or nociceptor fiber responses in the non-sensitized state (i.e. following brief nociceptive mechanical or thermal stimulation) but can depress these responses when nociceptors are sensitized by exposure to formalin or inflammatory soup. Group II mGluR agonist-induced inhibition can be blocked by a selective Group II antagonist. Peripheral Group II mGluR-induced inhibition evoked in these studies occurs through activation of local receptors and not through spinal or supraspinal mechanisms. The data indicate that administration of selective Group II agonists may be potent therapeutic agents for prevention of peripheral sensitization and for treatment of inflammatory pain. KeywordsGroup II mGluR; pain; APDC; LY341495; formalin; inflammation; inflammatory soup Glutamate and glutamate receptors play an important role in peripheral pain mechanisms in animals (Carlton, 2001;Carlton et al., 2003) and humans (McNearney et al., 1999;McNearney et al., 2000;Cairns et al., 2001;Alfredson et al., 2001;Alfredson and Lorentzon, 2002;Svensson et al., 2003;Cairns et al., 2003). To date, ionotropic glutamate receptors (iGluRs) including N-methyl-D-aspartate (NMDA) and non-NMDA receptors are implicated in peripheral cutaneous pain mechanisms Bleakman et al., 2006).More recent studies indicate that metabotropic glutamate receptors (mGluRs) can modulate peripheral nociceptor function. In contrast to iGluRs, which are ligand-gated ion channel receptors, mGluRs mediate their function via G-protein coupled receptors which trigger Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2009 June 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript intracellular second-messenger systems (Pin and Duvoisin, 1995). Accordin...

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Metabotropic glutamate receptors in brain function and pathology

Cited by 730 publications

References 49 publications

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

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

Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

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Metabotropic glutamate receptors in brain function and pathology

Cited by 730 publications

References 49 publications

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

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

Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

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