title: Synergistic regulation of glutamatergic transmission by serotonin and norepinephrine reuptake inhibitors in prefrontal cortical neurons.
abstract: The monoamine system in the prefrontal cortex has been implicated in various mental disorders and has been the major target of anxiolytics and antidepressants. Clinical studies show that serotonin and norepinephrine reuptake inhibitors (SNRIs) produce better therapeutic effects than single selective reuptake inhibitors, but the underlying mechanisms are largely unknown. Here, we found that low dose SNRIs, by acting on 5-HT(1A) and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. The synergistic effect of SNRIs on AMPARs was blocked by inhibition of activator of G protein signaling 3, a G protein modulator that prevents reassociation of G(i) protein α subunit and prolongs the βγ-mediated signaling pathway. Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT(1A) and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons.
authors: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214 and.
authors: Eunice Y
authors: EY
authors: Yuen
authors: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214 and.
authors: Luye
authors: L
authors: Qin
authors: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214 and Veterans Affairs Western New York Healthcare System, Buffalo, New York 14215.
authors: Jing
authors: J
authors: Wei
authors: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214 and.
authors: Wenhua
authors: W
authors: Liu
authors: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214 and.
authors: Aiyi
authors: A
authors: Liu
authors: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214 and Veterans Affairs Western New York Healthcare System, Buffalo, New York 14215 zhenyan@buffalo.edu.
authors: Zhen
authors: Z
authors: Yan
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003891:Desipramine / Q000494:pharmacology*; D004357:Drug Synergism; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000166:cytology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D001640:Bicuculline; D002352:Carrier Proteins; D003891:Desipramine; D034281:Dynamins; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D018091:Receptors, AMPA; D018341:Receptors, Adrenergic, alpha-2; D017367:Selective Serotonin Reuptake Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; D020696:rab5 GTP-Binding Proteins; C498913:Gpsm1 protein, rat
keywords: AGS3; Cortex; Electrophysiology; G Protein-coupled Receptor (GPCR); Ionotropic Glutamate Receptor; Norepinephrine; Serotonin; p38 MAPK