Regulation of Ionotropic Glutamate Receptors by Their Auxiliary Subunits (original) (raw)
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Neuropsychopharmacology, 2000
The effect of chronic administration of the putative atypical antipsychotic E-5842, a preferential sigma 1 receptor ligand, on ionotropic glutamate receptor subunit levels of mRNA and protein, was studied. The repeated administration of E-5842 differentially regulated levels of the NMDA-2A and of GluR2 subunits in a regionally specific way. Levels of immunoreactivity for the NMDA-2A subunit were upregulated in the medial prefrontal cortex, the frontoparietal cortex, the cingulate cortex, and in the dorsal striatum, while they were down-regulated in the nucleus accumbens. Levels of the GluR2 subunit of the AMPA receptor were up-regulated in the medial prefrontal cortex and the nucleus accumbens and down-regulation was observed in the dorso-lateral striatum. Regulation of the levels of mRNA for the different subunits was also observed in some cases. The results show that E-5842, through a mechanism still unknown, is able to modify levels of several glutamate receptor subunits and these changes could be related to its antipsychotic activity in preclinical tests.
Antipsychotic drug effects on glutamatergic activity
Brain Research, 1997
Previous work from this laboratory indicated that some antipsychotic drugs possess unique action at N-methyl-D-aspartate NMDA Ž. receptors. A functional neurochemical assay showed that, at concentrations similar to those found in the cerebrospinal fluid CSF of schizophrenics, antipsychotic drugs augment NMDA activity while, at higher concentrations, NMDA activity is suppressed. Using similar analysis, the present paper reports that this pattern of response is also shown by the antipsychotic drugs thioridazine and chlorpromazine. In contrast, promazine, which is structurally similar to chlorpromazine but lacking both D-effects and antipsychotic potency, had no 2 influence on NMDA receptors. In addition, sulpiride and metoclopramide, drugs with high affinity for D-dopamine receptors but with 2 weak or no antipsychotic efficacy, also lack effects at the NMDA receptor. Thus, the drugs with clinical efficacy that were tested in the present and previous studies all share unique influence on NMDA receptors. Further work with other antipsychotic agents will be necessary to determine if influence on NMDA receptors contributes to antipsychotic effectiveness. q 1997 Elsevier Science B.V.
Neuroscience Letters, 2000
Sigma 1 (s 1 ) receptor mRNA expression was studied in the prefrontal cortex, striatum, hippocampus and cerebellum of rat brain by northern blot and in situ hybridization. The effects of a chronic treatment with antipsychotic drugs (haloperidol and clozapine), and with E-5842, a s 1 receptor ligand and putative atypical antipsychotic on s 1 receptor expression were examined. A signi®cant increase in the levels of s 1 receptor mRNA in the prefrontal cortex and striatum after E-5842 administration was observed, while no apparent changes were seen with either haloperidol or clozapine. Our results suggest a long-term adaptation of the s 1 receptor at the level of mRNA expression in speci®c areas of the brain as a response to a sustained treatment with E-5842. q
Glutamate and Schizophrenia: Pathophysiology and Therapeutics
Current Medicinal Chemistry-Central Nervous …, 2002
Since the 1950's, the major thrust of antipsychotic drugs development has been centered around the monoamine dopamine since all antipsychotic drugs potently block dopamine receptors. However, in the last fifteen years increasing attention has been focused on serotonin (5-HT), and 5-HT 2A receptors in particular as the atypical antipsychotic drugs (e.g., clozapine, olanzepine, risperidone) potently block this receptor. These atypical antipsychotic drugs, in addition to having a decreased incidence of motor side effects, also improve particular symptoms (negative symptoms and cognitive dysfunction) upon which typical antipsychotic drugs exert little effect. However, even these atypical antipsychotic drugs have limited efficacy for many patients. Current neuroimaging studies have implicated corticalstriatal-thalamic circuits and interactions of these circuits with areas such as the hippocampus, pontine nuclei and the cerebellum. Within the thalamocortical pathways, clear abnormalities appear to be present within the glutamate system. In addition, the psychotomimetic effects of drugs which induce psychosis may be dependent upon interactions between the monoamines and glutamate. Therefore, current strategies are directed toward the discovery of novel antipsychotic drugs that act directly on the glutamate system. The largest unresolved answer facing the field is whether the critical problem in schizophrenia is a "hypoglutamatergic" or a "hyperglutamatergic" state. One of the dangers facing the strategy of enhancing glutamatergic transmission is that overactivation of ionotropic NMDA and AMPA receptors can lead to neurotoxicity. Thus directions being pursued involve more subtly modulating regulatory sites on these ionotropic receptors or directing agents to the modulatory G-protein coupled metabotropic glutamate (mGlu) receptors.
Journal of Pharmacology and Experimental Therapeutics, 2008
Ϫ)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]hexane-4,6dicarboxylic acid (LY404039) is a potent and selective group II metabotropic glutamate [(mGlu)2 and mGlu3] receptor agonist for which its prodrug LY2140023 [(1R,4S,5S,6S)-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid,4-[(2S)-2-amino-4-(methylthio)-1oxobutyl]amino-, 2,2-dioxide monohydrate] has recently been shown to have efficacy in the treatment of the positive and negative symptoms of schizophrenia. In this article, we use mGlu receptor-deficient mice to investigate the relative contribution of mGlu2 and mGlu3 receptors in mediating the antipsychotic profile of LY404039 in the phencyclidine (PCP) and d-amphetamine (AMP) models of psychosis. To further explore the mechanism of action of LY404039, we compared the drugs' ability to block PCP-induced hyperlocomotion to that of atypical antipsychotics in wild-type and mice lacking mGlu2/3 receptors. In wild-type animals, LY404039 (3-30 mg/kg i.p.) significantly reversed AMP (5 1 Current affiliation: Merck and Company Inc., North Wales, Pennsylvania. Article, publication date, and citation information can be found at
American Journal of Psychiatry, 2009
Objective-Preclinical and clinical data implicate the group II metabotropic glutamate receptors (mGluR2 and mGluR3) in the pathophysiology of schizophrenia. Moreover, a recent phase II clinical trial has demonstrated the antipsychotic efficacy of a mGluR2/3 agonist. The current study was designed to distinguish the expression of mGluR2 and mGluR3 receptor protein in schizophrenia and to quantify glutamate carboxypeptidase II (GCPII) in order to explore a role for the metabotropic receptors in schizophrenia therapeutics. GCPII is an enzyme that metabolizes Nacetylaspartylglutamate (NAAG), the only known specific endogenous agonist of mGluR3 in the mammalian brain.
Journal of Psychiatry and Neuroscience, 2018
Background: The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic altera tions in the NAcc of a large schizophrenia cohort. Methods: We performed immunoblots on postmortem NAcc samples from 30 individ uals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the Nmethyldaspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms). In addition, we measured the group 1 mGluR endogenous regulators, neurochondrin and Homer1b/c, which have recently been implicated in the pathophysiology of schizophrenia. Results: Protein levels of glutamatergic re ceptors and endogenous regulators were not significantly different between the controls and individuals who had schizophrenia. Further more, mGluR5, but not mGluR1, showed a positive association with NMDA receptor subunits, suggesting differential interactions be tween these receptors in this brain region. Limitations: Investigation of these proteins in antipsychoticnaive individuals, in addition to the subregions of the NAcc and subcellular fractions, will strengthen future studies. Conclusion: The present study does not provide evi dence for glutamatergic abnormalities within the NAcc of individuals with schizophrenia. Taken together with the results of previous studies, these findings suggest NMDA receptors and group 1 mGluRs are altered in a brain region-dependent manner in individuals with schizophrenia. The differential associations between mGluR1, mGluR5 and NMDA receptors observed in this study warrant further re search into the interactions of these proteins and the implications for the therapeutic and adverse effect profile of glutamatergicbased novel therapeutics.
Modulation of glutamate receptors in response to the novel antipsychotic olanzapine in rats
Biological Psychiatry, 2001
Background: A disturbance in glutamate neurotransmission has been hypothesized in schizophrenia. Hence, the beneficial effects of pharmacological treatment may be related to adaptive changes taking place in this neurotransmitter system. Methods: In this study, we investigated the modulation of ionotropic and metabotropic glutamate receptors in the rat brain following acute or chronic exposure to the novel antipsychotic olanzapine. Results: In accordance with the clear distinction between classical and atypical drugs, olanzapine did not alter glutamate receptor expression in striatum. Chronic, not acute, exposure to olanzapine was capable of up-regulating hippocampal mRNA levels for GluR-B and GluR-C, two ␣-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-forming subunits. This effect could be relevant for the improvement of schizophrenic alterations, which are thought to depend on dysfunction of the glutamatergic transmission within the hippocampal formation. We also found that the expression of group II glutamate metabotropic receptors was up-regulated in the frontal cortex after chronic exposure to clozapine, and to a lesser extent olanzapine, but not with haloperidol. Conclusions: The adaptive mechanisms taking place in glutamatergic transmission might prove useful in ameliorating some of the dysfunction observed in the brain of schizophrenic patients.