cgp-39653 and Schizophrenia

Pharmacological and anatomical evidence suggests that abnormal glutamate neurotransmission may be associated with the pathophysiology of schizophrenia and mood disorders. Medial temporal lobe structural alterations have been implicated in schizophrenia and to a lesser extent in mood disorders. To comprehensively examine the ionotropic glutamate receptors in these illnesses, we used in situ hybridization to determine transcript expression of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate receptor subunits in the medial temporal lobe of subjects with schizophrenia, bipolar disorder (BD), or major depression (MDD). We used receptor autoradiography to assess changes in glutamate receptor binding in the same subjects. Our results indicate that there are region- and disorder-specific abnormalities in the expression of ionotropic glutamate receptor subunits in schizophrenia and mood disorders. We did not find any changes in transcript expression in the hippocampus. In the entorhinal cortex, most changes in glutamate receptor expression were associated with BD, with decreased GluR2, GluR3, and GluR6 mRNA expression. In the perirhinal cortex we detected decreased expression of GluR5 in all three diagnoses, of GluR1, GluR3, NR2B in both BD and MDD, and decreased NR1 and NR2A in BD and MDD, respectively. Receptor binding showed NMDA receptor subsites particularly affected in the hippocampus, where MK801 binding was reduced in schizophrenia and BD, and MDL105,519 and CGP39653 binding were increased in BD and MDD, respectively. In the hippocampus AMPA and kainate binding were not changed. We found no changes in the entorhinal and perirhinal cortices. These data suggest that glutamate receptor expression is altered in the medial temporal lobe in schizophrenia and the mood disorders. We propose that disturbances in glutamate-mediated synaptic transmission in the medial temporal lobe are important factors in the pathophysiology of these severe psychiatric illnesses.

Topics: 2-Amino-5-phosphonovalerate; Adult; Analysis of Variance; Autoradiography; Excitatory Amino Acid Antagonists; Female; Gene Expression Regulation; Humans; In Situ Hybridization; Indoles; Male; Middle Aged; Mood Disorders; Postmortem Changes; Protein Binding; Receptors, Glutamate; Schizophrenia; Temporal Lobe

Post-mortem studies have yet to produce consistent findings on cortical glutamatergic markers in schizophrenia; therefore, it is not possible to fully understand the role of abnormal glutamatergic function in the pathology of the disorder. To better understand the changes in cortical glutamatergic markers in schizophrenia, we measured the binding of radioligands to the ionotropic glutamate receptors (N-methyl D-aspartate, [3H]CGP39653, [3H]MK-801), amino-3-hydroxy-5-methyl-4-isoxazole ([3H]AMPA), kainate ([3H]kainate), and the high-affinity glutamate uptake site ([3H]aspartate) using in situ radioligand binding with autoradiography and levels of mRNA for kainate receptors using in situ hybridization in the dorsolateral prefrontal cortex from 20 subjects with schizophrenia and 20 controls matched for age and sex. Levels of [3H]kainate binding were significantly decreased in cortical laminae I-II (p = 0.01), III-IV (p < 0.05), and V-VI (p < 0.01) from subjects with schizophrenia. By contrast, levels of [3H]MK-801, [3H]AMPA, [3H]aspartate, or [3H]CGP39653 binding did not differ between the diagnostic cohorts. Levels of mRNA for the GluR5 subunit were decreased overall (p < 0.05), with no changes in levels of mRNA for GluR6, GluR7, KA1, or KA2 in tissue from subjects with schizophrenia. These data indicate that the decreased number of kainate receptors in the dorsolateral prefrontal cortex in schizophrenia may result, in part, from reduced expression of the GluR5 receptor subunits.

Topics: 2-Amino-5-phosphonovalerate; Adult; Aged; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Biomarkers; Case-Control Studies; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Humans; In Situ Hybridization; Kainic Acid; Male; Middle Aged; Postmortem Changes; Radioligand Assay; Receptors, Glutamate; Schizophrenia; Tritium

Saturation analyses of [3H]L-689,560, [3H]CGP 39653 and NMDA-specific [3H]ifenprodil binding revealed an equivalent increase (0.7 pmol/mg) in the number of [3H]L-689,560 and [3H]ifenprodil binding sites in superior temporal cortex (BA22) from drug-treated chronic schizophrenic patients and control subjects. No differences were observed between control and schizophrenic subjects for [3H]CGP 39653 binding in BA22, or for any of the radioligands binding to pre-motor cortex (BA6). Since [3H]L-689,560, [3H]CGP 39653 and [3H]ifenprodil label the glycine, glutamate and ifenprodil sites of the NMDA receptor complex, which are associated with NR1, NR1/NR2A and NR1/NR2B subunits respectively, our findings suggest that NR2B-containing receptors are selectively up-regulated in superior temporal cortex in schizophrenia.

Topics: 2-Amino-5-phosphonovalerate; Aminoquinolines; Binding Sites; Cadaver; Excitatory Amino Acid Antagonists; Humans; Isomerism; Piperidines; Receptors, N-Methyl-D-Aspartate; Reference Values; Schizophrenia; Temporal Lobe; Up-Regulation