Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity

被引：0
作者：
O Gunduz-Cinar
K P MacPherson
R Cinar
J Gamble-George
K Sugden
B Williams
G Godlewski
T S Ramikie
A X Gorka
S O Alapafuja
S P Nikas
A Makriyannis
R Poulton
S Patel
A R Hariri
A Caspi
T E Moffitt
G Kunos
A Holmes
机构：
[1] Laboratory of Behavioral and Genomic Neuroscience,Department of Psychiatry and Molecular Physiology and Biophysics
[2] Section on Behavioral and Genomic Neuroscience,Department of Psychology and Neuroscience
[3] National Institute on Alcoholism and Alcohol Abuse,Department of Psychiatry and Behavioral Sciences
[4] NIH,undefined
[5] Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences,undefined
[6] Laboratory of Physiologic Studies,undefined
[7] National Institute on Alcohol Abuse and Alcoholism,undefined
[8] NIH,undefined
[9] Vanderbilt University Medical Center,undefined
[10] Duke University,undefined
[11] Duke University,undefined
[12] Institute for Genome Sciences and Policy,undefined
[13] Duke University,undefined
[14] Social,undefined
[15] Genetic,undefined
[16] and Developmental Psychiatry Research Centre,undefined
[17] Institute of Psychiatry,undefined
[18] King's College London,undefined
[19] Center for Drug Discovery,undefined
[20] Northeastern University,undefined
[21] Dunedin School of Medicine,undefined
[22] University of Otago,undefined
来源：
Molecular Psychiatry | 2013年 / 18卷
关键词：
amygdala; anxiety; cannabinoid; fear; gene; stress;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
Endocannabinoids are released ‘on-demand’ on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.
引用
收藏
页码：813 / 823
页数：10
相关论文
共 262 条
[11]  
Azad SC(2010)Inhibitors of monoacylglycerol lipase, fatty-acid amide hydrolase and endocannabinoid transport differentially suppress capsaicin-induced behavioral sensitization through peripheral endocannabinoid mechanisms Pharmacol Res 62 249-258
[12]  
Bisogno T(2010)Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system Nat Neurosci 13 1113-1119
[13]  
Rammes G(2008)Neural mechanisms of extinction learning and retrieval Neuropsychopharmacology 33 56-72
[14]  
Cascio MG(2010)Neuronal circuits of fear extinction Eur J Neurosci 31 599-612
[15]  
Kamprath K(2007)Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task Neuropsychopharmacology 32 1032-1041
[16]  
Marsicano G(2004)Endocannabinoid transport tightly controls 2-arachidonoyl glycerol actions in the hippocampus: effects of low temperature and the transport inhibitor AM404 Eur J Neurosci 19 2991-2996
[17]  
Tang J(2011)Cannabinoid transmission in the basolateral amygdala modulates fear memory formation via functional inputs to the prelimbic cortex J Neurosci 31 5300-5312
[18]  
Monory K(2005)Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear Neuropsychopharmacology 30 516-524
[19]  
Bisogno T(2010)Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects Chem Biol 17 1256-1266
[20]  
Di Marzo V(2012)Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice Br J Pharmacol 165 1556-1571
12345678910