Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Review ArticleMINIREVIEWS

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Gerard J. Marek, Berthold Behl, Anton Y. Bespalov, Gerhard Gross, Younglim Lee and Hans Schoemaker
Molecular Pharmacology March 2010, 77 (3) 317-326; DOI: https://doi.org/10.1124/mol.109.059865
Gerard J. Marek
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Berthold Behl
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anton Y. Bespalov
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gerhard Gross
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Younglim Lee
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hans Schoemaker
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

This article has a correction. Please see:

  • Correction to “Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?” - May 01, 2010

Abstract

Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytrypatmine2A receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-d-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.059865

  • ABBREVIATIONS:

    5-HT2A
    5-hydroxytryptamine2A
    NMDA
    N-methyl-d-aspartate
    mGlu2/3
    metabotropic glutamate 2/3
    ADX47273
    [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]
    GluN2A
    N-methyl-d-aspartate NR2A subunits
    GlyT1
    glycine transporter subtype 1
    GRM3
    mGlu3 receptor gene
    LY354740
    (1S,2S,5R,6S)-2-aminobicylo[3.1.0]hexane-2,6-dicarboxylic acid
    LY404039
    (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid
    LY544344
    (1S,2S,5R,6S)-2[(2′S)-(2′-amino)-propionyl]aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid
    LY2140023
    methionine prodrug of (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid
    mGlu
    metabotropic glutamate
    MK-801
    dizocilpine
    MRI
    magnetic resonance imaging
    NAM
    negative allosteric modulator
    PAM
    positive allosteric modulator
    PANSS
    positive and negative symptom score
    PCP
    phencyclidine
    PFC
    prefrontal cortex
    SSR504734
    (2-chloro-N-[(S)-phenyl[(2S)]-piperidin-2-yl]methyl)-3-trifluoromethyl benzamide
    ORG 25935
    cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)aminomethylcarboxylic acid hydrochloride.

  • Received July 28, 2009.
  • Accepted November 23, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 77 (3)
Molecular Pharmacology
Vol. 77, Issue 3
1 Mar 2010
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Review ArticleMINIREVIEWS

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Gerard J. Marek, Berthold Behl, Anton Y. Bespalov, Gerhard Gross, Younglim Lee and Hans Schoemaker
Molecular Pharmacology March 1, 2010, 77 (3) 317-326; DOI: https://doi.org/10.1124/mol.109.059865

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Review ArticleMINIREVIEWS

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Gerard J. Marek, Berthold Behl, Anton Y. Bespalov, Gerhard Gross, Younglim Lee and Hans Schoemaker
Molecular Pharmacology March 1, 2010, 77 (3) 317-326; DOI: https://doi.org/10.1124/mol.109.059865
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • mGlu2/3 Receptor Agonists
    • mGlu2 Receptor Potentiators (e.g., PAMs)
    • Glycine Transporter 1 Inhibitors
    • mGlu5 Receptor Potentiators
    • Conclusions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Mechanotransduction in Cancer
  • Intracellular mGlu5
  • NADPH Oxidases and Influenza Virus Infections
Show more MINIREVIEWS

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2022 by the American Society for Pharmacology and Experimental Therapeutics