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Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity
- Source :
- Molecular psychiatry. 18(7)
- Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Male
Cannabinoid receptor
medicine.medical_treatment
Extinction, Psychological
chemistry.chemical_compound
Mice
Piperidines
Fatty acid amide hydrolase
Adaptation, Psychological
Conditioning, Psychological
Enzyme Inhibitors
Neuronal Plasticity
Anandamide
Fear
Middle Aged
Amygdala
Endocannabinoid system
Psychiatry and Mental health
medicine.anatomical_structure
Female
Rimonabant
Psychology
psychological phenomena and processes
Personality
Adult
Alkanesulfonates
Microinjections
Polyunsaturated Alkamides
Arachidonic Acids
Polymorphism, Single Nucleotide
Article
Amidohydrolases
Cellular and Molecular Neuroscience
Phenols
medicine
Animals
Humans
Habituation, Psychophysiologic
Molecular Biology
Cannabinoid Receptor Antagonists
Genetic Association Studies
Functional Neuroimaging
medicine.disease
chemistry
nervous system
Extinction (neurology)
Pyrazoles
Cannabinoid
Neuroscience
Basolateral amygdala
Endocannabinoids
Subjects
Details
- ISSN :
- 14765578
- Volume :
- 18
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Molecular psychiatry
- Accession number :
- edsair.doi.dedup.....6c5fea34dbce3c34b63dd11f8d6a84be