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Cited by 229Cannabis and Cannabinoid ResearchMemory and Neural MechanismsStress Responses and Cortisol

Amygdala FAAH and anandamide: mediating protection and recovery from stress

Open access
Gunduz-Cinar, Ozge, Hill, Matthew N., McEwen, Bruce S., Holmes, Andrew·2013·Trends in Pharmacological Sciences
DOI 10.1016/j.tips.2013.08.008PMC PMC4169112
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Abstract

A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region – the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA–CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that stress rapidly mobilizes fatty acid amide hydrolase (FAAH) in the basolateral amygdala (BLA), depleting anandamide (AEA) and increasing anxiety, while FAAH inhibition or deletion protects against stress effects and facilitates fear extinction. It proposes restoring deficient BLA AEA via FAAH inhibitors as a therapeutic strategy for stress-related anxiety disorders.

Key findings

  • Stress rapidly induces FAAH activity and reduces BLA AEA, increasing BLA excitability and anxiety-like behavior; FAAH inhibition with URB597 reduces HPA-axis and anxiety responses to stress, with effects localized to the BLA rather than central or medial amygdala.
  • Chronic stress produces sustained FAAH enhancement, prolonged BLA AEA reductions, and increased BLA dendritic arborization/spinogenesis; these morphological changes are absent in FAAH-lacking mutant mice, and genetic loss or repeated pre-stress FAAH inhibition (JNJ5003) prevents stress-induced AEA reductions and increases in HPA activity and anxiety-like behavior.
  • FAAH inhibition facilitates long-term fear extinction and rescues deficient extinction in rodent models: systemic AM3506 augmented extinction-induced BLA AEA and reduced fear on extinction retrieval, and intra-BLA SR141716A blocked the pro-extinction effect, indicating BLA AEA–CB1R signaling is necessary and sufficient.
  • Clinical reports cited show decreased peripheral AEA and increased brain CB1R binding in anxiety disorders such as PTSD, and preliminary clinical trials with selective FAAH inhibitors including PF04457845 and URB597 are underway or planned.

Methods

  • Narrative review of preclinical and clinical literature on FAAH, AEA, stress, fear, and anxiety; no original experimental design, sample, or primary data are reported.
  • Synthesizes rodent pharmacological and genetic studies, including FAAH inhibitors (URB597, AM3506, JNJ5003), CB1R manipulations, stress models, fear extinction paradigms, and BLA-specific infusions.
  • Main analysis is qualitative integration of findings across studies; no systematic review protocol, meta-analysis, or statistical pooling is described.

Limitations

  • The paper states that mechanisms underlying the pro-extinction effects of BLA FAAH inhibition remain to be elucidated, the precise contribution of CB1R signaling pathways to anxiety is essentially unknown, and the role of BLA 2-AG/MAGL signaling in stress responsivity and recovery is much less certain.
  • The paper notes that sex differences in the ECB system and anxiety may complicate these relationships, and that the prediction of fewer side effects from FAAH inhibitors awaits thorough clinical investigation.
  • Evident from the text: this is a narrative review without primary data or quantitative synthesis, so conclusions depend on the cited preclinical and preliminary clinical literature rather than new experimental results.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.tips.2013.08.008

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 122 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior.

    “Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior.”
    • Also stated in: § FAAH modulation of anxiety and stress · plain
      “genetic loss or repeated, pre-stress pharmacological inhibition (JNJ5003) of FAAH prevents stress-induced reductions in AEA and increases in HPA activity and anxiety-like behavior [68,73,74]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [68] Hill MN Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure Mol. Psychiatry 2013 http://dx.doi.org/10.1038/mp.2012.90 PMC4148304 22776900 source

      Not checked in the free run.

    • cites [73] Rossi S Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition Mol. Pharmacol 2010 78 260 268 20424126 source

      Not checked in the free run.

    • cites [74] Hill MN Endogenous cannabinoid signaling is essential for stress adaptation Proc. Natl. Acad. Sci. U.S.A 2010 107 9406 9411 20439721 PMC2889099 source

      Not checked in the free run.

  • Premisecitation

    AEA is actively degraded by the serine hydrolase enzyme FAAH.

    “the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH).”
    • Also stated in: § FAAH regulation of ECB signaling · plain
      “This enzyme was later identified as the serine hydrolase enzyme, FAAH [42–44]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Ueda N Partial purification and characterization of the porcine brain enzyme hydrolyzing and synthesizing anandamide J. Biol. Chem 1995 270 23823 23827 7559559 source

      Not checked in the free run.

    • cites [43] Desarnaud F Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization J. Biol. Chem 1995 270 6030 6035 7890734 source

      Not checked in the free run.

    • cites [44] Cravatt BF Chemical characterization of a family of brain lipids that induce sleep Science 1995 268 1506 1509 7770779 source

      Not checked in the free run.

  • Premisecitation

    ECBs are not stored in readily releasable pools but are rapidly synthesized on-demand upon depolarization-induced calcium increase.

    “Unlike most neurotransmitters, however, ECBs are not stored in readily releasable pools, but instead are rapidly synthesized `on-demand' upon depolarization-induced calcium increase.”
    • Also stated in: § Concluding remarks · plain
      “The `on-demand' nature of ECB release makes it a particularly attractive target for drug development because FAAH inhibitors would selectively augment CB1R signaling in neural circuits where AEA was recruited [52].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Blankman JL Cravatt BF Chemical probes of endocannabinoid metabolism Pharmacol. Rev 2013 65 849 871 23512546 PMC3639726 source

      Not checked in the free run.

  • Interpretationreasoning

    Selective alleviation of anxiety symptoms could be produced by increasing levels of endogenously activated ECBs and avoiding widespread behavioral effects caused by exogenously applied, ubiquitously activating CB1R agonists.

    “That is, selective alleviation of symptoms could be produced by increasing levels of endogenously activated ECBs and avoiding widespread behavioral effects caused by exogenously applied, ubiquitously activating cannabinoid receptor type 1 (CB1R) agonists.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The anxiety-reducing properties of THC extend to preclinical rodent assays and models.

    “Finally, the anxiety-reducing properties of THC extend to preclinical rodent assays and models [9], demonstrating that the anxiolytic properties of cannabinoids are well conserved across species.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Moreira FA Wotjak CT Cannabinoids and anxiety Curr. Top. Behav. Neurosci 2010 2 429 450 21309120 source

      Not checked in the free run.

  • May combine two claims. 26
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Premisecitation

    Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in the BLA.

    “Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region – the basolateral amygdala (BLA).”
    • Also stated in: § FAAH modulation of anxiety and stress · plain
      “Collectively, these findings support a model in which stress rapidly mobilizes FAAH, depletes the signaling pool of AEA, and increases BLA excitability to drive anxiety [67]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Hill MN Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output J. Neurosci 2010 30 14980 14986 21068301 PMC3073528 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    2-AG is synthesized postsynaptically by diacylglycerol lipase, whereas AEA is predominantly synthesized by NAPE-PLD, also at postsynaptic sites in regions including the BLA, but also presynaptically at others such as the hippocampus.

    “The ECB 2-arachidonoylglycerol (2-AG) is synthesized, postsynaptically, by diacylglycerol lipase, whereas the ECB anandamide (AEA) is predominantly synthesized by N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), also at postsynaptic sites in regions including the BLA, but also presynaptically at others (e.g., hippocampus) [17,18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Nyilas R Enzymatic machinery for endocannabinoid biosynthesis associated with calcium stores in glutamatergic axon terminals J. Neurosci 2008 28 1058 1063 18234884 PMC6671412 source

      Not checked in the free run.

    • cites [18] Egertova M Localization of N-acyl phosphatidyl-ethanolamine phospholipase D (NAPE-PLD) expression in mouse brain: a new perspective on N-acylethanolamines as neural signaling molecules J. Comp. Neurol 2008 506 604 615 18067139 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Targeting components of the ECB system could represent a novel therapeutic approach to developing effective anxiolytic medications devoid of the unwanted effects of cannabis.

    “It also led to the notion that targeting components of the ECB system could represent a novel therapeutic approach to developing effective anxiolytic medications devoid of the unwanted effects of cannabis (e.g., cognitive impairment, abuse liability) [4,12] (Box 1).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Van Dam NT Characteristics of clinically anxious versus non-anxious regular, heavy marijuana users Addict. Behav 2012 37 1217 1223 22727786 source

      Not checked in the free run.

    • cites [12] Buckner JD Problematic alcohol and cannabis use among young adults: the roles of depression and discomfort and distress tolerance Addict. Behav 2007 32 1957 1963 17258398 PMC1986746 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA-CB1 receptor signaling and synaptic plasticity in the BLA.

    “Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA–CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [50] Gunduz-Cinar O Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity Mol. Psychiatry 2013 18 813 823 22688188 PMC3549323 source

      Not checked in the free run.

    • cites [51] Azad SC Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling J. Neurosci 2004 24 9953 9961 15525780 PMC6730232 source

      Not checked in the free run.

    • cites [86] Marsicano G The endogenous cannabinoid system controls extinction of aversive memories Nature 2002 418 530 534 12152079 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CB1R negatively regulates N- and P/Q-type voltage-gated calcium channels and positively regulates inwardly rectifying K+ channels, as well as calcineurin, to change the phosphorylation state of effector molecules.

    “In addition, CB1R negatively regulates N- and P/Q-type voltage-gated calcium channels [26] and positively regulates inwardly rectifying K+ channels [26,27], as well as protein serine/threonine phosphatase 2B (calcineurin, PP2B) to change the phosphorylation state of various effector molecules [28,29].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [26] Mato S Role of the cyclic-AMP/PKA cascade and of P/Q-type Ca2+ channels in endocannabinoid-mediated long-term depression in the nucleus accumbens Neuropharmacology 2008 54 87 94 17606273 source

      Not checked in the free run.

    • cites [27] Twitchell W Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons J. Neurophysiol 1997 78 43 50 9242259 source

      Not checked in the free run.

    • cites [28] Cannich A CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice Learn. Mem 2004 11 625 632 15466318 PMC523082 source

      Not checked in the free run.

    • cites [29] Heifets BD Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin Proc. Natl. Acad. Sci. U.S.A 2008 105 10250 10255 18632563 PMC2481322 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Following synthesis, ECBs are retrogradely transported into the extracellular space to bind ECB receptors present on presynaptic terminals.

    “Following their synthesis, ECBs are retrogradely transported into the extracellular space to bind ECB receptors present on presynaptic terminals [19–21].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Katona I Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission J. Neurosci 2001 21 9506 9518 11717385 PMC6763903 source

      Not checked in the free run.

    • cites [20] Gulyas AI Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala Eur. J. Neurosci 2004 20 441 458 15233753 source

      Not checked in the free run.

    • cites [21] McDonald AJ Mascagni F Localization of the CB1 type cannabinoid receptor in the rat basolateral amygdala: high concentrations in a subpopulation of cholecystokinin-containing interneurons Neuroscience 2001 107 641 652 11720787 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CB2R is mainly found in the periphery but also in some microglia and neuronal populations in the CNS.

    “whereas CB2R is mainly found in the periphery but also in some microglia and neuronal populations in the central nervous system (CNS) [15,16]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Gong JP Cannabinoid CB2 receptors: immunohistochemical localization in rat brain Brain Res 2006 1071 10 23 16472786 source

      Not checked in the free run.

    • cites [16] Xi ZX Brain cannabinoid CB2 receptors modulate cocaine's actions in mice Nat. Neurosci 2011 14 1160 1166 21785434 PMC3164946 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CB1R is the most densely expressed ECB receptor in the brain and is present at high levels in corticolimbic regions mediating anxiety, including the mPFC, hippocampus, and BLA.

    “CB1R is the most densely expressed in the brain and is present at high levels in corticolimbic regions mediating anxiety, including the medial prefrontal cortex (mPFC) and hippocampus, as well as the BLA [11,14]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Di Marzo V De Petrocellis L Why do cannabinoid receptors have more than one endogenous ligand? Philos. Trans. R. Soc. Lond. B: Biol. Sci 2012 367 3216 3228 23108541 PMC3481524 source

      Not checked in the free run.

    • cites [14] Mackie K Distribution of cannabinoid receptors in the central and peripheral nervous system Handb. Exp. Pharmacol 2005 168 299 325 16596779 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Stimulation of CB1R recruits various signaling pathways, including Gi/o coupling that reduces adenylyl cyclase and downregulates cAMP/PKA signaling, Gβγ-induced PLC-β-mediated calcium influx, and activation of MAP kinases.

    “Stimulation of CB1R recruits various signaling pathways [22]. These pathways include CB1R coupling to Gi/o proteins that reduces adenylyl cyclase activity and downregulates cyclic AMP/protein kinase A signaling [23], by Gβγ-induced phospholipase C-β-mediated increases in intracellular calcium influx, and by activation of mitogen-activated protein kinases [24,25].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [22] Ramikie TS Patel S Endocannabinoid signaling in the amygdala: anatomy, synaptic signaling, behavior, and adaptations to stress Neuroscience 2012 204 38 52 21884761 PMC3236282 source

      Not checked in the free run.

    • cites [23] Azad SC Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala Learn. Mem 2008 15 143 152 18323569 PMC2275656 source

      Not checked in the free run.

    • cites [24] Rhee MH Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes J. Neurochem 1998 71 1525 1534 9751186 source

      Not checked in the free run.

    • cites [25] Guo J Ikeda SR Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons Mol. Pharmacol 2004 65 665 674 14978245 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many neural and behavioral effects of exogenously administered cannabinoids can be traced to activation of the ECB system.

    “Many of the neural and behavioral effects of exogenously administered cannabinoids can be traced directly to activation of the `endocannabinoid' (ECB) system [10]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Mechoulam R Parker LA The endocannabinoid system and the brain Annu. Rev. Psychol 2013 64 21 47 22804774 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AEA actions are not restricted to CB1R; ECBs also act at CB2R, GPR55, TRPV1, and other G protein subtypes such as Gs and/or Gq11.

    “Enriching the picture further, the actions of AEA are not restricted to CB1R, given that ECBs also act, sometimes in a non-retrograde manner, at CB2R [30], GPR55 [31], and TRPV1 (transient receptor potential vanilloid type 1) channels [32–34], as well as other G protein subtypes such as Gs and/or Gq11 [35,36].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [30] Mechoulam R Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors Biochem. Pharmacol 1995 50 83 90 7605349 source

      Not checked in the free run.

    • cites [31] Ryberg E The orphan receptor GPR55 is a novel cannabinoid receptor Br. J. Pharmacol 2007 152 1092 1101 17876302 PMC2095107 source

      Not checked in the free run.

    • cites [32] Zygmunt PM Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide Nature 1999 400 452 457 10440374 source

      Not checked in the free run.

    • cites [33] Smart D The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1) Br. J. Pharmacol 2000 129 227 230 10694225 PMC1571834 source

      Not checked in the free run.

    • cites [34] Melck D Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors Biochem. Biophys. Res. Commun 1999 262 275 284 10448105 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Within amygdala subnuclei, FAAH is highly expressed on pyramidal neurons in the BLA, and to a significantly lesser extent in the central nucleus (CeA).

    “Within amygdala subnuclei, FAAH is highly expressed on pyramidal neurons in the BLA, and to a significantly lesser extent in the central nucleus (CeA) [19,20,46,47].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [19] Katona I Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission J. Neurosci 2001 21 9506 9518 11717385 PMC6763903 source

      Not checked in the free run.

    • cites [20] Gulyas AI Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala Eur. J. Neurosci 2004 20 441 458 15233753 source

      Not checked in the free run.

    • cites [46] Tsou K Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry Neurosci. Lett 1998 254 137 140 10214976 source

      Not checked in the free run.

    • cites [47] Kamprath K Short-term adaptation of conditioned fear responses through endocannabinoid signaling in the central amygdala Neuropsychopharmacology 2011 36 652 663 20980994 PMC3055679 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of CB1R in the BLA causes a decrease in both glutamatergic and GABAergic transmission, with typically a net reduction in neuronal excitability on application of CB1R agonists, probably due to presynaptic inhibition of glutamate release.

    “Although activation of CB1R in the BLA causes a decrease in both glutamatergic and GABAergic transmission, there is typically a net reduction in neuronal excitability on application of CB1R agonists, probably due to CB1R-mediated presynaptic inhibition of glutamate release [48,49].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Azad SC Activation of the cannabinoid receptor type 1 decreases glutamatergic and GABAergic synaptic transmission in the lateral amygdala of the mouse Learn. Mem 2003 10 116 128 12663750 PMC196665 source

      Not checked in the free run.

    • cites [49] Domenici MR Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission J. Neurosci 2006 26 5794 5799 16723537 PMC6675276 source

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Manipulations that alter FAAH activity, such as stress or administration of compounds targeting FAAH, would be predicted to functionally impact BLA functions, including anxiety.

    “By extension, manipulations that lead to alterations in FAAH activity, such as stress or administration of compounds targeting FAAH [52], would be predicted to functionally impact BLA functions, including anxiety.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Blankman JL Cravatt BF Chemical probes of endocannabinoid metabolism Pharmacol. Rev 2013 65 849 871 23512546 PMC3639726 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tonic ECB signaling in the BLA and elsewhere is mediated by AEA, whereas phasic ECB responses to robust neuronal activation are sub-served by 2-AG.

    “There is growing evidence that tonic ECB signaling in the BLA and elsewhere is mediated by AEA, whereas phasic ECB responses to robust neuronal activation are sub-served by 2-AG [53–56].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [53] Gorzalka BB Regulation of endocannabinoid signaling by stress: implications for stress-related affective disorders Neurosci. Biobehav. Rev 2008 32 1152 1160 18433869 source

      Not checked in the free run.

    • cites [54] Kim J Alger BE Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses Nat. Neurosci 2010 13 592 600 20348918 PMC2860695 source

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    • cites [55] Ahn K Enzymatic pathways that regulate endocannabinoid signaling in the nervous system Chem. Rev 2008 108 1687 1707 18429637 PMC3150828 source

      Not checked in the free run.

    • cites [56] Jourdan T Endocannabinoid-activated Nlrp3 inflammasome in infiltrating macrophages mediates β-cell loss in type 2 diabetes Nat. Med 2013 19 1132 1140 23955712 PMC4050982 source

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  • May combine two claims.

    Premisecitation

    CB1R signaling generated by increased AEA can produce long-term depression of inhibitory transmission in the BLA, a change in synaptic plasticity which can serve to promote excitability.

    “By contrast, CB1R signaling generated by increased AEA can also produce long-term depression of inhibitory transmission in the BLA, a change in synaptic plasticity which can serve to promote excitability [50,51].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Gunduz-Cinar O Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity Mol. Psychiatry 2013 18 813 823 22688188 PMC3549323 source

      Not checked in the free run.

    • cites [51] Azad SC Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling J. Neurosci 2004 24 9953 9961 15525780 PMC6730232 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Stress rapidly mobilizes FAAH, depletes the signaling pool of AEA, and increases BLA excitability to drive anxiety.

    “Collectively, these findings support a model in which stress rapidly mobilizes FAAH, depletes the signaling pool of AEA, and increases BLA excitability to drive anxiety [67] (Figure 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Hill MN Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output J. Neurosci 2010 30 14980 14986 21068301 PMC3073528 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB1R antagonism increases BLA excitability, activates the HPA axis, and increases anxiety-like behavior.

    “First, presumably by removing AEA-mediated tonic inhibitory activity, CB1R antagonism increases BLA excitability [61–63], activates the hypothalamic–pituitary–adrenal (HPA) axis and increases anxiety-like behavior [58,64,65].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [61] Patel S Synergistic interactions between cannabinoids and environmental stress in the activation of the central amygdala Neuropsychopharmacology 2005 30 497 507 15280883 source

      Not checked in the free run.

    • cites [62] Meye FJ Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity Mol. Psychiatry 2013 http://dx.doi.org/10.1038/mp.2012.145 23070073 source

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    • cites [63] Newsom RJ Cannabinoid receptor type 1 antagonism significantly modulates basal and loud noise induced neural and hypothalamic–pituitary–adrenal axis responses in male Sprague–Dawley rats Neuroscience 2012 204 64 73 22138156 PMC3288505 source

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    • cites [58] Hill MN Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic–pituitary–adrenal axis Neuropsychopharmacology 2009 34 2733 2745 19710634 PMC3197779 source

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    • cites [64] Dono LM Currie PJ The cannabinoid receptor CB1 inverse agonist AM251 potentiates the anxiogenic activity of urocortin I in the basolateral amygdala Neuropharmacology 2012 62 192 199 21736884 source

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    • cites [65] Ganon-Elazar E Akirav I Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance J. Neurosci 2009 29 11078 11088 19741114 PMC6665931 source

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  • May combine two claims.

    Premisecitation

    Stress produces divergent effects on AEA and 2-AG levels in the BLA, with an elevation in 2-AG levels and a rapid induction of FAAH activity and resultant decline in the AEA pool following exposure to various types of stress.

    “Interestingly, stress appears to produce divergent effects on AEA and 2-AG levels in the BLA – with an elevation in 2-AG levels [57], but a rapid induction of FAAH activity and a resultant decline in the pool of AEA [58–60] were reported following exposure to various types of stress.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [57] Patel S Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala Neuropsychopharmacology 2009 34 2699 2709 19675536 PMC2881681 source

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    • cites [58] Hill MN Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic–pituitary–adrenal axis Neuropsychopharmacology 2009 34 2733 2745 19710634 PMC3197779 source

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    • cites [59] Rademacher DJ Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice Neuropharmacology 2008 54 108 116 17675104 source

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    • cites [60] Patel S Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling Eur. J. Neurosci 2005 21 1057 1069 15787710 source

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  • May combine two claims.

    Premisecitation

    Chronically administered MAGL inhibitors prevent chronic stress-induced increases in anxiety-like behavior and impairments in BLA synaptic plasticity.

    “and when administered chronically, to prevent chronic stress-induced increases in anxiety-like behavior and impairments in BLA synaptic plasticity [75]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Sumislawski JJ Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: a potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation Neuropsychopharmacology 2011 36 2750 2761 21849983 PMC3230498 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of ECBs on fear are not restricted to the BLA but involve a pathway between the BLA and mPFC.

    “These effects on fear are not restricted to the BLA but involve a pathway between the BLA and mPFC.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [83] Laviolette SR Grace AA Cannabinoids potentiate emotional learning plasticity in neurons of the medial prefrontal cortex through basolateral amygdala inputs J. Neurosci 2006 26 6458 6468 16775133 PMC6674051 source

      Not checked in the free run.

    • cites [84] Tan H Cannabinoid transmission in the basolateral amygdala modulates fear memory formation via functional inputs to the prelimbic cortex J. Neurosci 2011 31 5300 5312 21471365 PMC6622725 source

      Not checked in the free run.

    • cites [85] Tan H Integrated cannabinoid CB1 receptor transmission within the amygdala–prefrontal cortical pathway modulates neuronal plasticity and emotional memory encoding Cereb. Cortex 2010 20 1486 1496 19880592 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The BLA is activated during the formation, expression, and extinction of conditioned fear memories, and damage to the BLA disrupts one or more of these processes.

    “The BLA is activated during the formation, expression, and extinction of conditioned fear memories, and damage to the BLA disrupts one or more of these processes [79,80].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Orsini CA Maren S Neural and cellular mechanisms of fear and extinction memory formation Neurosci. Biobehav. Rev 2012 36 1773 1802 22230704 PMC3345303 source

      Not checked in the free run.

    • cites [80] Herry C Neuronal circuits of fear extinction Eur. J. Neurosci 2010 31 599 612 20384807 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB1R knockout or systemic antagonist (SR141716A) administration produces impairments in extinction learning but not fear conditioning.

    “and produced impairments in extinction learning (but not fear conditioning) by CB1R KO or systemic antagonist (SR141716A) administration [28,86]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Cannich A CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice Learn. Mem 2004 11 625 632 15466318 PMC523082 source

      Not checked in the free run.

    • cites [86] Marsicano G The endogenous cannabinoid system controls extinction of aversive memories Nature 2002 418 530 534 12152079 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Responses to fear cues in mPFC neurons receiving inputs from BLA were potentiated by the CB1R agonist WIN55212-2, and CB1R blockade/inverse agonism with AM251 in these regions disrupts fear learning and learning-related long-term potentiation.

    “Responses to fear cues in mPFC neurons receiving inputs from BLA were potentiated by the CB1R agonist WIN55212-2, and CB1R blockade/inverse agonism (with AM251) in these regions disrupts fear learning and learning-related synaptic plasticity (long-term potentiation) [83–85].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [83] Laviolette SR Grace AA Cannabinoids potentiate emotional learning plasticity in neurons of the medial prefrontal cortex through basolateral amygdala inputs J. Neurosci 2006 26 6458 6468 16775133 PMC6674051 source

      Not checked in the free run.

    • cites [84] Tan H Cannabinoid transmission in the basolateral amygdala modulates fear memory formation via functional inputs to the prelimbic cortex J. Neurosci 2011 31 5300 5312 21471365 PMC6622725 source

      Not checked in the free run.

    • cites [85] Tan H Integrated cannabinoid CB1 receptor transmission within the amygdala–prefrontal cortical pathway modulates neuronal plasticity and emotional memory encoding Cereb. Cortex 2010 20 1486 1496 19880592 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Injecting a CB1R agonist (WIN55212-2) into the BLA enhanced the consolidation of conditioned fear but impaired fear reconsolidation, whereas CB1R antagonism/inverse agonism (AM251) impaired fear memory formation.

    “Implicating BLA ECB signaling in fear conditioning, several studies have shown that injecting a CB1R agonist (WIN55212-2) into the BLA enhanced the consolidation of conditioned fear (but impaired fear reconsolidation [81]), whereas CB1R antagonism/inverse agonism (AM251) had the opposite effect, impairing fear memory formation [82].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Lin HC Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle Learn. Mem 2006 13 316 321 16705137 PMC1475812 source

      Not checked in the free run.

    • cites [82] Campolongo P Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory Proc. Natl. Acad. Sci. U.S.A 2009 106 4888 4893 19255436 PMC2660732 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CB1R signalling in the BLA is both necessary and sufficient for FAAH inhibitors to facilitate fear extinction.

    “Thus, these data show that CEA–CB1R signalling in the BLA is both necessary and sufficient for FAAH inhibitors to facilitate fear extinction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Systemic administration of AM3506 prior to extinction training augmented extinction-induced BLA AEA levels and reduced fear on extinction retrieval in a mouse model of impaired extinction.

    “More recently, systemic administration of a novel, potent FAAH inhibitor, AM3506 [100], prior to extinction training augmented extinction-induced BLA AEA levels and reduced fear on extinction retrieval in a mouse model of impaired extinction [50].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [100] Godlewski G Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects Chem Biol 2010 17 1256 1266 21095576 PMC3003779 source

      Not checked in the free run.

    • cites [50] Gunduz-Cinar O Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity Mol. Psychiatry 2013 18 813 823 22688188 PMC3549323 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A CB1R-dependent form of synaptic plasticity in the BLA, long-term depression of inhibitory GABAergic transmission (LTDi), is enhanced by FAAH knockout and by the FAAH inhibitor AM3506 at doses that promote extinction.

    “One notable finding is that a CB1R-dependent form of synaptic plasticity in BLA [51,86], long-term depression of inhibitory GABAergic transmission (LTDi), is enhanced by FAAH KO [51] and by the FAAH inhibitor AM3506 at doses that promote extinction [50].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51] Azad SC Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling J. Neurosci 2004 24 9953 9961 15525780 PMC6730232 source

      Not checked in the free run.

    • cites [86] Marsicano G The endogenous cannabinoid system controls extinction of aversive memories Nature 2002 418 530 534 12152079 source

      Not checked in the free run.

    • cites [50] Gunduz-Cinar O Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity Mol. Psychiatry 2013 18 813 823 22688188 PMC3549323 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of AM3506 were attributed to the BLA by the finding that infusing the drug directly into the BLA promoted extinction, and intra-BLA infusion of SR141716A blocked the pro-extinction effect of systemically delivered AM3506.

    “The effects of AM3506 were attributed to the BLA by the finding that infusing the drug directly into the BLA promoted extinction, and the demonstration that intra-BLA infusion of SR141716A blocked the pro-extinction effect of systemically delivered AM3506 [50].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Gunduz-Cinar O Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity Mol. Psychiatry 2013 18 813 823 22688188 PMC3549323 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Preliminary clinical trials with selective FAAH inhibitors, including PF04457845 and URB597, are either underway or being planned.

    “Encouragingly, preliminary clinical trials with selective FAAH inhibitors, including PF04457845 and URB597, are either underway (www.clinicaltrials.gov/ct2/show/NCT01665573) or being planned.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites www.clinicaltrials.gov/ct2/show/NCT01665573

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The refined mechanism of action of FAAH inhibitors would avoid the widespread activity of THC or CB1R agonism and is expected to produce fewer clinically unwanted side effects and be less liable to CB1R downregulation after repeated dosing.

    “This refined mechanism of action would avoid the widespread activity of THC or CB1R agonism and, as a result, is expected to produce fewer clinically unwanted side effects and be less liable to CB1R downregulation after repeated dosing.”
    Quote in the paperSubstantial claim
31 of 31

  • The paper relies on this without support.

    Findings from rodent models of stress, anxiety, and fear extinction are predictive of human anxiety disorders and treatment response.

    “These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.”
    “Taken together, these findings encourage the development of novel anxiolytics based around restoring deficient AEA levels by pharmacologically inhibiting FAAH.”
1 of 1

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References 121 · Cited by 229

Authors
Gunduz-Cinar, O., Hill, M. N., McEwen, B. S., & Holmes, A.
Affiliations
  • University of Calgary (CA)
  • Rockefeller University (US)
  • National Institutes of Health (US)
Corresponding author
Hill, Matthew N.
ORCID
Venue
Trends in Pharmacological Sciences
Publisher
Elsevier BV
Published
2013-11
Volume
34
Issue
11
Pages
637-644
ISSN
0165-6147 (ISSN-L)
DOI
10.1016/j.tips.2013.08.008
PMC
PMC4169112
OpenAlex
W2004981165
Semantic Scholar
1390b2f3fb5af8687254bfc31a445735984d3b65
Cited by
229
References
121
Citations by year
2026: 14 · 2025: 13 · 2024: 11 · 2023: 17 · 2022: 15 · 2021: 24 · 2020: 18 · 2019: 16 · 2018: 15 · 2017: 20 · 2016: 25 · 2015: 29 · 2014: 11 · 2013: 1
FWCI
2.78
Type
journal article
Language
en
Open access
Locations
  • Trends in Pharmacological Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Canadian Institutes of Health Research
  • National Institute on Alcohol Abuse and Alcoholism (ZIAAA000411)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
fatty acid amide hydrolase, anandamide, endocannabinoids, basolateral amygdala, stress, anxiety, fear extinction, traumatic stress, FAAH inhibition, CB1 receptor, synaptic plasticity, anxiolytics
MeSH terms
Fatty Acid Amide Hydrolases, Amidohydrolases, Amygdala, Animals, Anxiety Disorders, Arachidonic Acids, Enzyme Inhibitors, Humans, Stress, Physiological, Stress, Psychological, Polyunsaturated Alkamides, Endocannabinoids

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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