@article {Marekmol.109.059865, author = {Gerard J. Marek and Berthold Behl and Anton Y Bespalov and Gerhard Gross and Younglim Lee and Johannes Schoemaker}, title = {Glutamatergic (N-methyl-D-aspartate receptor) hypofrontality in schizophrenia: Too little juice or a miswired brain}, elocation-id = {mol.109.059865}, year = {2009}, doi = {10.1124/mol.109.059865}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications which effectively treat positive symptoms of schizophrenia (e.g,, delusions and hallucinations) and have been approved by regulatory agencies since the 1950{\textquoteright}s. Blockade of 5-hydroxytrypatmine2A (5-HT2A) 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 receptor channel has inspired a search for glutamatergic therapeutic mechanisms since ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerabate the symptoms of schizophrenic patients. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors in 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 glutamate2/3 (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 activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we will also discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter (GlyT1) 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.The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2009/11/23/mol.109.059865}, eprint = {https://molpharm.aspetjournals.org/content/early/2009/11/23/mol.109.059865.full.pdf}, journal = {Molecular Pharmacology} }