Journal ArticleDOI
Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice.
Leah M. Mayo,Anna Asratian,Johan Lindé,Lovisa Holm,Daniel Nätt,Gaëlle Augier,Niclas Stensson,Haley A. Vecchiarelli,Georgia Balsevich,Robert J. Aukema,Bijar Ghafouri,Primavera A. Spagnolo,Francis S. Lee,Matthew N. Hill,Markus Heilig +14 more
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TLDR
It is suggested that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.Abstract:
Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C->A substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.read more
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Elevated Anandamide, Enhanced Recall of Fear Extinction, and Attenuated Stress Responses Following Inhibition of Fatty Acid Amide Hydrolase: A Randomized, Controlled Experimental Medicine Trial
Leah M. Mayo,Anna Asratian,Johan Lindé,Maria Morena,Maria Morena,Roosa Haataja,Valter Hammar,Gaëlle Augier,Matthew N. Hill,Matthew N. Hill,Markus Heilig +10 more
TL;DR: The beneficial effects of FAAH inhibition on fear extinction, as well as stress- and affect-related behaviors, provide a strong rationale for developing this drug class as a treatment for posttraumatic stress disorder.
Journal ArticleDOI
Cannabinoid Regulation of Fear and Anxiety: an Update
TL;DR: Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.
Journal ArticleDOI
Neurobiology of cannabinoid receptor signaling .
TL;DR: Understanding the neurobiology of cannabinoid receptor signaling in depth will aid optimal design of therapeutic interventions, minimizing unwanted side effects.
Journal ArticleDOI
Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety
Maria Morena,Robert J. Aukema,Kira D. Leitl,Kira D. Leitl,Asim J. Rashid,Haley A. Vecchiarelli,Haley A. Vecchiarelli,Haley A. Vecchiarelli,Sheena A. Josselyn,Matthew N. Hill,Matthew N. Hill +10 more
TL;DR: The data indicate that viral-mediated augmentation of anandamide hydrolysis within the basolateral amygdala reduces behavioral indices of stress, anxiety, and conditioned fear expression and provides new insights on the mechanisms by which amygdalar endocannabinoid signaling regulates emotional behavior.
Journal ArticleDOI
Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala
Farhana Yasmin,Farhana Yasmin,Roberto Colangeli,Maria Morena,Sarah B. Filipski,Mario van der Stelt,Quentin J. Pittman,Cecilia J. Hillard,G. Campbell Teskey,Bruce S. McEwen,Matthew N. Hill,Matthew N. Hill,Sumantra Chattarji,Sumantra Chattarji +13 more
TL;DR: Oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala, offering insights into potential therapeutic strategies for targeting endocannabinoid signaling to prevent the gradual development of affective symptoms and underlying amygdalar dysfunction triggered by traumatic stress.
References
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Journal ArticleDOI
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