Panic results in unique molecular and network changes in the amygdala that facilitate fear responses.

Autor: Molosh AI; Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.; Paul and Carol Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA., Dustrude ET; Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA., Lukkes JL; Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA., Fitz SD; Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA., Caliman IF; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Abreu ARR; Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA., Dietrich AD; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Truitt WA; Paul and Carol Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Ver Donck L; Janssen Research & Development, Beerse, Belgium., Ceusters M; Janssen Research & Development, Beerse, Belgium., Kent JM; Janssen Research & Development, LLC, Titusville, NJ, USA., Johnson PL; Paul and Carol Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Shekhar A; Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. ashekhar@iu.edu.; Paul and Carol Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA. ashekhar@iu.edu.; Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, IN, USA. ashekhar@iu.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2020 Feb; Vol. 25 (2), pp. 442-460. Date of Electronic Publication: 2018 Aug 14.
DOI: 10.1038/s41380-018-0119-0
Abstrakt: Recurrent panic attacks (PAs) are a common feature of panic disorder (PD) and post-traumatic stress disorder (PTSD). Several distinct brain regions are involved in the regulation of panic responses, such as perifornical hypothalamus (PeF), periaqueductal gray, amygdala and frontal cortex. We have previously shown that inhibition of GABA synthesis in the PeF produces panic-vulnerable rats. Here, we investigate the mechanisms by which a panic-vulnerable state could lead to persistent fear. We first show that optogenetic activation of glutamatergic terminals from the PeF to the basolateral amygdala (BLA) enhanced the acquisition, delayed the extinction and induced the persistence of fear responses 3 weeks later, confirming a functional PeF-amygdala pathway involved in fear learning. Similar to optogenetic activation of PeF, panic-prone rats also exhibited delayed extinction. Next, we demonstrate that panic-prone rats had altered inhibitory and enhanced excitatory synaptic transmission of the principal neurons, and reduced protein levels of metabotropic glutamate type 2 receptor (mGluR2) in the BLA. Application of an mGluR2-positive allosteric modulator (PAM) reduced glutamate neurotransmission in the BLA slices from panic-prone rats. Treating panic-prone rats with mGluR2 PAM blocked sodium lactate (NaLac)-induced panic responses and normalized fear extinction deficits. Finally, in a subset of patients with comorbid PD, treatment with mGluR2 PAM resulted in complete remission of panic symptoms. These data demonstrate that a panic-prone state leads to specific reduction in mGluR2 function within the amygdala network and facilitates fear, and mGluR2 PAMs could be a targeted treatment for panic symptoms in PD and PTSD patients.
Databáze: MEDLINE
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