Jun Zhou1, Yi Luo1, Jie-Ting Zhang1, Ming-Xing Li1, Can-Ming Wang1, Xin-Lei Guan1, Peng-Fei Wu1,2, Zhuang-Li Hu1,2, You Jin1, Lan Ni1, Fang Wang1,2,3,4, Jian-Guo Chen1,2,3,4. 1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2. Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China. 3. Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China. 4. The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
Abstract
BACKGROUND AND PURPOSE: Posttraumatic stress disorder (PTSD) is a mental disorder with enhanced retention of fear memory and has profound impact on quality of life for millions of people worldwide. The β-adrenoceptor antagonist propranolol has been used in preclinical and clinical studies for the treatment of PTSD, but the mechanisms underlying its potential efficacy on fear memory retention remain to be elucidated. EXPERIMENTAL APPROACH: We investigated the action of propranolol on the retention of conditioned fear memory, the surface expression of glutamate receptor GluA1 subunits of AMPA receptors and synaptic adaptation in the lateral amygdala (LA) of rats. KEY RESULTS: Propranolol attenuated reactivation-induced strengthening of fear retention while reducing enhanced surface expression of GluA1 subunits and restoring the impaired long-term depression in LA. These effects of propranolol were mediated by antagonizing reactivation-induced enhancement of adrenergic signalling, which activates PKA and calcium/calmodulin-dependent protein kinase II and then regulates the trafficking of AMPA receptors via phosphorylation of GluA1 subunits at the C-terminus. Both i.p. injection and intra-amygdala infusion of propranolol attenuated reactivation-induced enhancement of fear retention. CONCLUSIONS AND IMPLICATIONS: Reactivation strengthens fear retention by increasing the level of noradrenaline and promotes the surface expression of GluA1 subunits and the excitatory synaptic transmission in LA. These findings uncover one mechanism underlying the efficiency of propranolol on retention of fear memories and suggest that β-adrenoceptor antagonists, which act centrally, may be more suitable for the treatment of PTSD.
BACKGROUND AND PURPOSE:Posttraumatic stress disorder (PTSD) is a mental disorder with enhanced retention of fear memory and has profound impact on quality of life for millions of people worldwide. The β-adrenoceptor antagonist propranolol has been used in preclinical and clinical studies for the treatment of PTSD, but the mechanisms underlying its potential efficacy on fear memory retention remain to be elucidated. EXPERIMENTAL APPROACH: We investigated the action of propranolol on the retention of conditioned fear memory, the surface expression of glutamate receptor GluA1 subunits of AMPA receptors and synaptic adaptation in the lateral amygdala (LA) of rats. KEY RESULTS:Propranolol attenuated reactivation-induced strengthening of fear retention while reducing enhanced surface expression of GluA1 subunits and restoring the impaired long-term depression in LA. These effects of propranolol were mediated by antagonizing reactivation-induced enhancement of adrenergic signalling, which activates PKA and calcium/calmodulin-dependent protein kinase II and then regulates the trafficking of AMPA receptors via phosphorylation of GluA1 subunits at the C-terminus. Both i.p. injection and intra-amygdala infusion of propranolol attenuated reactivation-induced enhancement of fear retention. CONCLUSIONS AND IMPLICATIONS: Reactivation strengthens fear retention by increasing the level of noradrenaline and promotes the surface expression of GluA1 subunits and the excitatory synaptic transmission in LA. These findings uncover one mechanism underlying the efficiency of propranolol on retention of fear memories and suggest that β-adrenoceptor antagonists, which act centrally, may be more suitable for the treatment of PTSD.
Authors: Robert H Pietrzak; Renée el-Gabalawy; Jack Tsai; Jitender Sareen; Alexander Neumeister; Steven M Southwick Journal: J Affect Disord Date: 2014-03-27 Impact factor: 4.839
Authors: David A Morilak; Gabe Barrera; David J Echevarria; April S Garcia; Angelica Hernandez; Shuaike Ma; Corina O Petre Journal: Prog Neuropsychopharmacol Biol Psychiatry Date: 2005-10-13 Impact factor: 5.067
Authors: John D Johnson; Valerie Cortez; Sarah L Kennedy; Teresa E Foley; Hugo Hanson; Monika Fleshner Journal: Brain Behav Immun Date: 2008-05-12 Impact factor: 7.217
Authors: Marco Atzori; Roberto Cuevas-Olguin; Eric Esquivel-Rendon; Francisco Garcia-Oscos; Roberto C Salgado-Delgado; Nadia Saderi; Marcela Miranda-Morales; Mario Treviño; Juan C Pineda; Humberto Salgado Journal: Front Synaptic Neurosci Date: 2016-08-26