Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata

Marino, Michael J.; Awad-Granko, H.; Ciombor, Kelly J.; Conn, P. Jeffrey

doi:10.1016/s0028-3908(02)00097-7

Cited by 36 publications

(28 citation statements)

References 70 publications

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“…which can be blocked by the mGluR5-selective antagonist MPEP (Awad et al, 2000), whereas mGluR1 plays a predominant role in regulating activity of neurons in the SNr (Marino et al, 2001). However, both of these neuronal populations express both mGluR1 and mGluR5, and previous studies suggest that each of these receptor subtypes can contribute to depolarization of either neuronal population under certain pathological conditions such as dopamine depletion (Marino et al, 2002). Thus, although it is possible that selective mGluR5 potentiators will selectively potentiate responses that are normally mediated by the respective mGluR subtype, it is also possible that these compounds could recruit mGluR5 activity in neurons in which this receptor is present but does not normally contribute to neuronal depolarization.…”

Section: Vu-29 Is Selective For Mglur5mentioning

confidence: 96%

Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

Chen¹,

Nong²,

Goudet³

et al. 2007

Mol Pharmacol

107

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Exciting advances have been made in the discovery of selective positive allosteric modulators of the metabotropic glutamate receptor (mGluR) mGluR5. These compounds may provide a novel approach that could be useful in the treatment of certain central nervous system disorders. However, because of their low potencies, previously described mGluR5 potentiators are not useful for functional studies in native preparations. In addition, binding sites at which these compounds act have not been identified. It has been suggested that two allosteric potentiators, 3,3Ј-difluorobenzaldazine and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), act by binding to the same allosteric site as the negative allosteric modulators of mGluR5 such as 2-methyl-6-(phenylethynyl)pyridine (MPEP). However, another mGluR5 potentiator, N- {4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide, does not bind to this site, bringing this hypothesis into question. We have synthesized a series of CDPPB analogs and report that these compounds bind to the MPEP site with affinities that are closely related to their potencies as mGluR5 potentiators. Furthermore, allosteric potentiation is antagonized by a neutral ligand at the MPEP site and reduced by a mutation of mGluR5 that eliminates MPEP binding. Together, these data suggest that interaction with the MPEP site is important for allosteric potentiation of mGluR5 by CDPPB and related compounds. In addition, whole-cell patch-clamp studies in midbrain slices reveal that a highly potent analog of CDPPB, 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), selectively potentiates mGluR5 but not mGluR1-mediated responses in midbrain neurons, whereas a previously identified allosteric potentiator of mGluR1 has the opposite effect.Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. In addition to eliciting fast excitatory synaptic responses, glutamate has important neuromodulatory effects by the activation of G protein-coupled receptors (GPCRs) termed metabotropic glutamate receptors (mGluRs). The mGluRs play important roles in a broad range of central nervous system functions and have potential as novel targets for the development of new therapeutic agents for a number of neurological and psychiatric disorders, including Parkinson's disease (Marino

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Section: Vu-29 Is Selective For Mglur5mentioning

confidence: 96%

Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

Chen¹,

Nong²,

Goudet³

et al. 2007

Mol Pharmacol

107

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“…However, no selective antagonist of mGlu1 receptors has so far been rigorously tested in animal models of Parkinson's disease. In parkinsonian animals, both mGlu1 and mGlu5 receptors significantly increase the excitation of subthalamic and SNr neurons (Marino et al, 2002). Although these findings imply that the two receptor subtypes might have 566 redundant roles in the basal ganglia of these animals, it remains to be established whether blockade of mGlu1 receptor alone is sufficient to produce anti-parkinsonian activity.…”

Section: B Extrapyramidal Motor Dysfunctionsmentioning

confidence: 99%

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Ferraguti

Crepaldi

Nicoletti³

2008

Pharmacol Rev

192

205

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Almost 25 years after the first report that glutamate can activate receptors coupled to heterotrimeric G-proteins, tremendous progress has been made in the field of metabotropic glutamate receptors. Now, eight members of this family of glutamate receptors, encoded by eight different genes that share distinctive structural features have been identified. The first cloned receptor, the metabotropic glutamate ( mGlu) receptor mGlu1 has probably been the most extensively studied mGlu receptor, and in many respects it represents a prototypical subtype for this family of receptors. Its biochemical, anatomical, physiological, and pharmacological characteristics have been intensely investigated. Together with subtype 5, mGlu1 receptors constitute a subgroup of receptors that couple to phospholipase C and mobilize Ca(2+) from intracellular stores. Several alternatively spliced variants of mGlu1 receptors, which differ primarily in the length of their C-terminal domain and anatomical localization, have been reported. Use of a number of genetic approaches and the recent development of selective antagonists have provided a means for clarifying the role played by this receptor in a number of neuronal systems. In this article we discuss recent advancements in the pharmacology and concepts about the intracellular transduction and pathophysiological role of mGlu1 receptors and review earlier data in view of these novel findings. The impact that this new and better understanding of the specific role of these receptors may have on novel treatment strategies for a variety of neurological and psychiatric disorders is considered

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“…We have demonstrated that a separation may exist in modulation of expression of the glutamatergic postsynaptic density (PSD) gene Homer1a by different antipsychotics Polese et al 2002), after acute as well as prolonged treatments ). These observations lead us to hypothesize that glutamatergic receptors, and their intracellular effectors, may be involved in mechanism of action of antipsychotics (Marino et al 2002;Schwieler et al 2008) and that antipsychotics may differentially modulate postsynaptic glutamatergic molecules and signaling pathways. Therefore, the aim of this study is to investigate whether acute and prolonged antipsychotic treatments, acting mainly on dopamine D 2 receptors, induces changes in gene expression of molecules involved in postsynaptic glutamatergic signaling and synaptic plasticity (Konradi and Heckers 2003).…”

Section: Introductionmentioning

confidence: 99%

Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole

Iasevoli¹,

Tomasetti²,

Marmo³

et al. 2010

Psychopharmacology

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These results suggest that haloperidol and sertindole may significantly modulate glutamatergic transcripts of the postsynaptic density. Sertindole induces constitutive genes in the cortex predominantly, which may correlate with its propensity to improve cognitive functions. Haloperidol preferentially modulates gene expression in the striatum, consistent with its action at nigrostriatal projections and its propensity to give motor side effects.

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Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata

Cited by 36 publications

References 70 publications

Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole

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