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
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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
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