Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: interaction with serotonergic systems
| Autor: | Margaret J. Bradbury, Greg Holtz, Sara Rao, Mark A. Varney, Darlene R. Giracello, Jeffery J. Anderson, Deborah F. Chapman, H. Schaffhauser |
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| Rok vydání: | 2003 |
| Předmět: |
Agonist
Male medicine.medical_specialty Hypothalamo-Hypophyseal System Serotonin medicine.drug_class Pyridines Receptor Metabotropic Glutamate 5 Pituitary-Adrenal System Pharmacology Serotonergic Receptors Metabotropic Glutamate Anxiolytic Buspirone Rats Sprague-Dawley Cellular and Molecular Neuroscience Desensitization (telecommunications) Internal medicine mental disorders medicine Animals Dose-Response Relationship Drug Metabotropic glutamate receptor 5 Chemistry Antagonist Rats Serotonin Receptor Agonists Endocrinology Receptors Serotonin 5-HT1A receptor Excitatory Amino Acid Antagonists Receptors Serotonin 5-HT1 medicine.drug |
| Zdroj: | Neuropharmacology. 44(5) |
| ISSN: | 0028-3908 |
| Popis: | The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) produces anxiolytic or antidepressant effects in several rodent models through incompletely described mechanisms. Anxiolytics and antidepressants share several neuroendocrine features, including acute activation of the hypothalamic-pituitary-adrenal (HPA)-axis, desensitization of neuroendocrine responses with repeated dosing, and desensitization of the HPA axis to 5-HT1A agonist stimulation. We characterized these neuroendocrine parameters in rats treated systemically with MPEP and compared them to those induced by the anxiolytic buspirone. Acutely, MPEP dose-dependently (0.1-10 mg/kg i.p.) increased plasma corticosterone concentrations. These responses were blocked by 50% with the 5-HT1A antagonist WAY100635. The corticosterone responses to both 3 mg/kg MPEP and buspirone were decreased by 80% after 5 days of twice-daily injections. Repeated injection with MPEP decreased HPA-axis sensitivity to buspirone challenge by 75%. This desensitization was not associated with changes in mGluR5 or 5-HT1A receptor binding properties, expression of G-protein subunits coupled to these receptors, or in 5-HT-stimulated binding of [(3)H]-GTPgammaS to membranes. We conclude that MPEP acutely disinhibits the HPA axis, in part through uncharacterized changes in serotonergic signaling. Desensitization of 5-HT1A responses after repeated MPEP administration may indicate that, like other anxiolytics and antidepressants, plasticity in 5-HT signal transduction pathways has occurred. |
| Databáze: | OpenAIRE |
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