Bidirectional variation in glutamate efflux in the medial prefrontal cortex induced by selective positive and negative allosteric mGluR5 modulators
| Autor: | Trevor W. Robbins, Sarah N. Isherwood, Anton Pekcec, Jeffrey W. Dalley |
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| Přispěvatelé: | Pekcec, Anton [0000-0001-9045-4740], Apollo - University of Cambridge Repository |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Pyridines Receptor Metabotropic Glutamate 5 Allosteric regulation impulsivity Glutamic Acid glutamate Pharmacology Biochemistry NMDA receptors Receptors N-Methyl-D-Aspartate 03 medical and health sciences Cellular and Molecular Neuroscience Glutamatergic 0302 clinical medicine Allosteric Regulation Piperidines mental disorders medicine Animals Rats Wistar Prefrontal cortex mGluR5 prefrontal cortex Oxadiazoles Metabotropic glutamate receptor 5 Chemistry Glutamate receptor Imidazoles Signal Transduction & Synaptic Transmission Glutamic acid Rats Dizocilpine 030104 developmental biology nervous system NMDA receptor Original Article ORIGINAL ARTICLES Dizocilpine Maleate Excitatory Amino Acid Antagonists 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Neurochemistry |
| Popis: | Dysregulation of prefrontal cortical glutamatergic signalling via NMDA receptor hypofunction has been implicated in cognitive dysfunction and impaired inhibitory control in such neuropsychiatric disorders as schizophrenia, attention‐deficit hyperactivity disorder and drug addiction. Although NMDA receptors functionally interact with metabotropic glutamate receptor 5 (mGluR5), the consequence of this interaction for glutamate release in the prefrontal cortex (PFC) remains unknown. We therefore investigated the effects of positive and negative allosteric mGluR5 modulation on changes in extracellular glutamate efflux in the medial PFC (mPFC) induced by systemic administration of the non‐competitive NMDA receptor antagonist dizocilpine (or MK801) in rats. Extracellular glutamate efflux was measured following systemic administration of the positive allosteric mGluR5 modulator [S‐(4‐Fluoro‐phenyl)‐{3‐[3‐(4‐fluoro‐phenyl)‐[1,2,4]‐oxadiazol‐5‐yl]‐piperidin‐1‐yl}‐methanone] (ADX47273; 100 mg/kg, p.o.) and negative allosteric mGluR5 modulator [2‐chloro‐4‐{[1‐(4‐fluorophenyl)‐2,5‐dimethyl‐1H‐imidazol‐4‐yl]ethynyl}pyridine] (RO4917523; 0.3 mg/kg, p.o.), using a wireless glutamate biosensor in awake, freely moving rats. The effect of MK801 (0.03–0.06 mg/kg, s.c.) on mPFC glutamate efflux was also investigated in addition to the effects of MK801 (0.03 mg/kg, s.c.) following ADX47273 (100 mg/kg, p.o.) pre‐treatment. ADX47273 produced a sustained increase in glutamate efflux and increased the effect of NMDA receptor antagonism on glutamate efflux in the mPFC. In contrast, negative allosteric mGluR5 modulation with RO4917523 decreased glutamate efflux in the mPFC. These findings indicate that positive and negative allosteric mGluR5 modulators produce long lasting and opposing actions on extracellular glutamate efflux in the mPFC. Positive and negative allosteric modulators of mGluR5 may therefore be viable therapeutic agents to correct abnormalities in glutamatergic signalling present in a range of neuropsychiatric disorders. |
| Databáze: | OpenAIRE |
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