title: Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior.
abstract: The neural factors underlying individual differences in susceptibility to chronic stress remain poorly understood. Preclinical studies demonstrate that mouse strains vary greatly in anxiety-related responses to chronic stress in a manner paralleled by differential stress-induced changes in glutamatergic signaling in the basolateral amygdala (BLA). Previous work has also shown that alterations in the amygdala gene expression of the GluN1 NMDA and the GluK1 kainate receptors are associated with stress-induced alterations in anxiety-like behavior in the C57BL/6J mouse strain. Using in vivo behavioral pharmacological and ex vivo physiological approaches, the aim of the current study was to further elucidate changes in glutamate neurotransmission in the BLA caused by stress and to test the functional roles of GluN1 and GluK1 in mediating stress-related changes in behavior. Results showed that stress-induced alterations in anxiety-like behavior (light/dark exploration test) were absent following bilateral infusion of the GluK1 agonist ATPA into the BLA. Intra-BLA infusion of the competitive NMDA antagonist AP5 produced a generalized behavioral disinhibition/locomotor hyperactivity, irrespective of stress. Slice electrophysiological recordings showed that ATPA augmented BLA GABAergic neurotransmission and that stress increased the amplitude of network-dependent spontaneous excitatory postsynaptic currents and amplitude of GABAergic miniature inhibitory postsynaptic currents in BLA. These findings could indicate stress-induced BLA glutamatergic neuronal network hyperexcitability and a compensatory increase in GABAergic neurotransmission, suggesting that GluK1 agonism augmented GABAergic inhibition to prevent behavioral sequelae of stress. Current data could have implications for developing novel therapeutic approaches, including GluK1 agonists, for stress-related anxiety disorders.
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Masneuf
authors.affiliation: Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Lowery-Gionta
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Colacicco
authors.affiliation: Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pleil
authors.affiliation: Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Chia
authors.initials: C
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Crowley
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Flynn
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
authors.affiliation: Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA. Electronic address: thomas_kash@med.unc.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kash
mesh_terms: D017109:Akathisia, Drug-Induced / Q000503:physiopathology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology*; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000819:agonists / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000188:drug therapy / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D009419:Nerve Tissue Proteins; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; C121673:Gprin1 protein, mouse
keywords: Basolateral amygdala; C57BL/6J; GluK1; GluN1; Glutamate; Stress