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Cited by 122Cannabis and Cannabinoid ResearchAutism Spectrum Disorder ResearchNeuroendocrine regulation and behavior

Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment

Open access
Wei, Don, Dinh, Drake, Lee, DaYeon, Li, Dandan, Anguren, Allison, Moreno-Sanz, Guillermo, Gall, Christine M., Piomelli, Daniele·2016·Cannabis and Cannabinoid Research
DOI 10.1089/can.2015.0008PMC PMC5549436
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Abstract

Introduction: We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD—social impairment—we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1−/− (model of Fragile X Syndrome). Methods: We used the established three-chambered social approach test. We specifically increased the activity of anandamide by administering the compound URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the hydrolytic enzyme for anandamide. Results: Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice. These results were likely independent of effects on anxiety, as FAAH inhibition did not alter the performance of BTBR mice in the elevated plus maze. Conclusions: The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.

AI snapshot

Written from the paper’s full text.

TL;DR

In two mouse models of autism-related social impairment, pharmacological inhibition of FAAH with URB597 increased anandamide signaling and corrected social approach deficits; the effect in BTBR mice was blocked by CB1 antagonism and was not explained by reduced anxiety. These findings identify FAAH as a candidate therapeutic target for ASD-related social impairment.

Key findings

  • URB597 (0.3 or 1 mg/kg i.p., 3 h before testing) significantly increased social chamber time and sniffing in BTBR mice to levels comparable to C57Bl6J controls; concomitant AM251 (2 mg/kg i.p.) prevented this prosocial effect (n=12–16).
  • In fmr1−/− mice, URB597 (0.3 mg/kg i.p.) increased social chamber time and sniffing to control levels, while no effect was seen in wild-type fmr1+/+ (FVB/NJ) mice; the baseline fmr1−/− social deficit was not statistically significant in this study (n=12–14 per group).
  • URB597 inhibited FAAH and substantially increased forebrain anandamide in BTBR mice without affecting 2-AG. In the elevated plus maze, URB597 (1 mg/kg i.p.) did not alter open-arm time or entries in BTBR mice (n=10 per group), suggesting the prosocial effect was not due to general anxiolysis.
  • In socially normal C57Bl6J mice, neither AM251 (2 mg/kg i.p.) nor URB597 (1 mg/kg i.p.) altered social chamber time or sniffing.

Methods

  • Preclinical proof-of-principle study using male mice (8–10 weeks) bred at UC Irvine, group-housed and naive for each behavioral experiment. Models included BTBR, fmr1−/− (FVB/NJ), C57Bl6J, and wild-type fmr1+/+.
  • Behavioral testing used the three-chamber social approach test (10-min test; choice between novel object and a sex-, age-, and weight-matched 129/SvImJ mouse; 5 lux lighting; automated chamber-time scoring and blinded sniffing scoring) and the elevated plus maze. Biochemical assays included a FAAH enzymatic activity assay and LC/MS lipid quantification.
  • URB597 and AM251 were administered i.p. 3 h before testing. Statistical analysis used two-tailed Student’s t-test and one-way or two-way ANOVA with Tukey’s post hoc test; significance was p<0.05 (GraphPad Prism).

Limitations

  • Stated in the paper: interpretation of BTBR data is limited by possible polygenetic contributions to this inbred strain’s phenotype; fmr1−/− mice were not tested in the elevated plus maze because they display an innate open-arm preference that could confound interpretation; the social approach test may have a ceiling effect and is typically a screening tool rather than a continuous measure of sociability.
  • Evident from the text: only male mice were studied, drug treatment was acute, and no chronic dosing, safety, or human data are reported.
  • Evident from the text: the fmr1−/− baseline social deficit was not statistically significant in this study, and the proposed oxytocin–anandamide reward mechanism was not directly tested in these ASD models.

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

Integrity signals

Registry

Crossref · 10.1089/can.2015.0008

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 44 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    URB597 inhibited FAAH in the forebrain of BTBR mice.

    “Using an enzymatic activity assay and LC/MS, we confirmed that URB597 inhibited FAAH and substantially increased the levels of anandamide in the forebrain of BTBR mice (Fig. 2a, b), without affecting levels of the other endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) (Fig. 2c).”
    Quote in the paperSubstantial claim
  • Findingown data

    Administration of URB597 (0.3 or 1 mg/kg i.p., 3 h before testing) significantly increased the time BTBR mice spent in the social chamber and sniffing, to levels comparable to those displayed by control, socially normal C57Bl6J mice.

    “However, administration of URB597 (0.3 or 1 mg kg−1, i.p., 3 h before testing) significantly increased the time BTBR mice spent in the social chamber and sniffing, to levels that were comparable to those displayed by control, socially normal C57Bl6J mice (Fig. 1c, d).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] source

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  • Findingown data

    URB597 did not affect levels of 2-arachidonoyl-sn-glycerol (2-AG) in the forebrain of BTBR mice.

    “Using an enzymatic activity assay and LC/MS, we confirmed that URB597 inhibited FAAH and substantially increased the levels of anandamide in the forebrain of BTBR mice (Fig. 2a, b), without affecting levels of the other endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) (Fig. 2c).”
    Quote in the paperSubstantial claim
  • Findingown data

    Concomitant administration of AM251 (2 mg/kg i.p.) prevented the effect of FAAH inhibition on social approach in BTBR mice.

    “The effect of FAAH inhibition on social approach depended on CB1 receptors and, thus, presumably on anandamide accumulation, because it was prevented by concomitant administration of AM251 (2 mg kg−1, i.p.) (Fig. 1c, d).”
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  • Findingcitation

    BTBR mice show no social preference in the three-chambered social approach test.

    “In contrast to C57Bl6J mice, BTBR mice show no social preference in the test (Fig. 1c, d).20,21”
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    • cites [21] Silverman JL, 2012, Sci Transl Med source

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  • May combine two claims. 11
  • Classified as probably not a substantial claim. 25

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    Findingown data

    URB597 (1 mg/kg i.p.) administered to BTBR mice did not alter the time spent in the open arms or the number of open-arm entries in the elevated plus maze under dim lighting conditions (5 lux).

    “We found that URB597 (1 mg kg−1, i.p.) administered to BTBR mice did not alter the time spent in the open arms, or the number of open-arm entries (Fig. 3a–c), suggesting that the prosocial effect of this compound cannot be attributed to reduced anxiety.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither AM251 (2 mg/kg i.p.) nor URB597 (1 mg/kg i.p.) altered the time spent in the social chamber or the time spent sniffing the target mouse in socially normal C57Bl6J mice.

    “We first evaluated maximally effective doses of AM251 (2 mg kg−1, i.p.)29 or URB597 (1 mg kg−1, i.p.)25 in socially normal C57Bl6J mice and found that neither drug altered the two outcome measures of the test, namely the time spent in the social chamber and the time spent sniffing the target mouse (Fig. 1a, b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Findingown data

    Acute administration of URB597 (0.3 mg/kg i.p.) increased the time spent by fmr1−/− mice in the social chamber and the time spent sniffing to levels displayed by control mice.

    “Nevertheless, we found that acute administration of URB597 (0.3 mg kg−1, i.p.), which did not alter the time spent in the social chamber or sniffing in wild-type fmr1+/+ (FVB/NJ) mice (Fig. 4a–c), increased the time spent by fmr1−/− mice in the social chamber and the time spent sniffing to levels to those displayed by control mice (Fig. 4a–c).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The social motivation theory posits that the psychopathology of ASD is rooted in a decreased desire to be social.

    “One theory—the social motivation theory—posits that the psychopathology of ASD is rooted in a decreased desire to be social.3,4”
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    Premisecitation

    People with ASD restrict themselves to repetitive behaviors and show deficits in social reciprocity and communication.

    “People with ASD restrict themselves to repetitive behaviors and show deficits in social reciprocity and communication.1”
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    Premisecitation

    Consequent activation of CB1 receptors is necessary and sufficient to regulate social reward.

    “Consequent activation of CB1 receptors is necessary and sufficient to regulate social reward.”
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    • cites [15] source

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    Premisecitation

    Oxytocin is crucial in many aspects of social behavior, including affiliation and reward.

    “This neuropeptide is crucial in many aspects of social behavior, including affiliation6 and reward.7”
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    Premisecitation

    Acutely intoxicated marijuana users enjoy interacting more and feel more connected and empathetic.

    “Acutely intoxicated marijuana users enjoy interacting more and feel more connected and empathetic.16,17”
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    Premisecitation

    Fatty acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the endocannabinoid anandamide.

    “Fatty acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the endocannabinoid anandamide.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Pharmacological FAAH inhibition promotes social play in juvenile rats.

    “Trezza et al. noted that pharmacological FAAH inhibition promotes social play in juvenile rats.14”
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    Premisecitation

    A polymorphism in the CB1 cannabinoid receptor gene modulates social gaze.

    “Chakrabarti and Baron-Cohen reported that a polymorphism in the CB1 cannabinoid receptor gene modulates social gaze.18”
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    Premisecitation

    FAAH inhibition results in anxiolytic-like effects only under high-light conditions.

    “This result is in line with previous reports showing that FAAH inhibition results in anxiolytic-like effects only under “high-light” conditions.42”
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    Premisecitation

    CB1 receptors are present on presynaptic terminals of both glutamatergic projection neurons and GABAergic interneurons.

    “This view is consistent with the presence of CB1 receptors on presynaptic terminals of both glutamatergic projection neurons and GABAergic interneurons.11”
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    Interpretationown data

    FAAH inhibition is an appropriate strategy to elevate levels of anandamide, and thus anandamide signaling, in BTBR mice.

    “We confirm that FAAH inhibition is an appropriate strategy to elevate levels of anandamide, and thus, anandamide signaling, in BTBR mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The prosocial action of increased anandamide activity through FAAH inhibition is generalizable across at least two distinct models of ASD-related social impairment, without affecting socially normal animals.

    “These results suggest that the prosocial action of increased anandamide activity (through FAAH inhibition) is generalizable across at least two distinct models of ASD-related social impairment, without affecting socially normal animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CB1 overexpression in the medial prefrontal cortex alters social interactions without overtly changing the anxiety-related phenotype.

    “In line with this notion, CB1 overexpression in the medial prefrontal cortex alters social interactions without overtly changing the anxiety-related phenotype.43”
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    CB1 agonists impair social play in rats.

    “CB1 agonists impair social play in rats.39”
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    Premisecitation

    Deletion of FMRP impairs the formation of a key signaling complex that links mGluR5 and DGL-α.

    “In a related example, we found that deletion of FMRP, the mRNA-trafficking protein missing in Fragile X Syndrome, impairs the formation of a key signaling complex that links metabotropic glutamate receptor-5 (mGluR5) and the 2-AG-synthesizing enzyme diacylglycerol lipase-α (DGL-α).28”
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    • cites [28] Jung K-M, 2012, Nat Commun

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    Study design and conductnone given

    All procedures met the National Institute of Health guidelines for the care and use of laboratory animals and were approved by the Institutional Animal Care and Use Committee at the University of California, Irvine.

    “All procedures met the National Institute of Health guidelines for the care and use of laboratory animals and were approved by the Institutional Animal Care and Use Committee at the University of California, Irvine.”
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    Interpretationcitation

    The bidirectional modulation of social behavior likely depends on the dose and the identity of the affected circuits.

    “Thus, the bidirectional modulation of social behavior likely depends on the dose and the identity of the affected circuits.”
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    Premisecitation

    Genetic removal of CB1 receptors alters social interactions in mice in a context-dependent manner.

    “Genetic removal of CB1 receptors alters social interactions in mice in a context-dependent manner,32 which may be related to social anxiety and/or cognition.37,38”
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    Study design and conductnone given

    Sniffing time was scored by trained assistants who were unaware of treatment conditions.

    “Sniffing time was scored by trained assistants who were unaware of treatment conditions.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Human studies have found that marijuana may enhance sociability.

    “In addition, human studies have found that marijuana may enhance sociability16,17 and a polymorphism in the CB1 cannabinoid receptor gene modulates social gaze.18”
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    Premisecitation

    Chronic isolation increases both 2-AG and anandamide in the piriform cortex.

    “For instance, we found that chronic isolation increases 2-AG in the prefrontal cortex, without affecting anandamide, and increases both 2-AG and anandamide in the piriform cortex.35”
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    Study design and conductnone given

    Subjects with outlying inactivity were excluded.

    “Excluded were subjects with outlying inactivity.”
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    Study design and conductnone given

    Object/mouse side placement was counterbalanced between trials.

    “Object/mouse side placement was counterbalanced between trials.”
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    Premisecitation

    Mutations in neuroligins impair tonic endocannabinoid signaling.

    “For example, mutations in neuroligins, a family of ASD-linked synaptic adhesion proteins, impair tonic endocannabinoid signaling.34”
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    Premisecitation

    Developmental treatment with valproic acid reduces hippocampal mRNA levels of the 2-AG-hydrolyzing enzyme monoacylglycerol lipase.

    “Furthermore, developmental treatment with valproic acid reduces cerebellar mRNA levels of DGL-α and reduces hippocampal mRNA levels of the 2-AG-hydrolyzing enzyme monoacylglycerol lipase.36”
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    • cites [36] Kerr DM, 2013, Behav Brain Res

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    Premisecitation

    Developmental treatment with valproic acid reduces cerebellar mRNA levels of DGL-α.

    “Furthermore, developmental treatment with valproic acid reduces cerebellar mRNA levels of DGL-α and reduces hippocampal mRNA levels of the 2-AG-hydrolyzing enzyme monoacylglycerol lipase.36”
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    Study design and conductnone given

    The apparatus was thoroughly cleaned with SCOE 10X odor eliminator between trials to preclude olfactory confounders.

    “The apparatus was thoroughly cleaned with SCOE 10X odor eliminator (BioFOG) between trials to preclude olfactory confounders.”
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    Study design and conductnone given

    Naive mice were used for each behavioral experiment.

    “Naive mice were used for each behavioral experiment.”
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    Study design and conductcitation

    Previously established methods were followed for the three-chambered social approach task.

    “Previously established methods were followed.21”
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    • cites [21] Silverman JL, 2012, Sci Transl Med source

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    Study design and conductcitation

    The elevated plus maze procedure was based on previously published methods.

    “The procedure was based on previously published methods.28”
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    • cites [28] Jung K-M, 2012, Nat Commun

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33 of 33

  • The paper relies on this without support.

    The underlying basis for social impairment in ASD is unknown, and no pharmacological treatment is available.

    “The underlying basis for social impairment in ASD is unknown, and no pharmacological treatment is available.”

  • The paper relies on this without support.

    Social reward is a key aspect of social functioning that is disrupted in ASD.

    “social reward is a key aspect of social functioning that is thought to be disrupted in ASD.”
2 of 2

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Cites

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1 of the 51 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Jung K-M, 2012, Nat Commun, 3, 108
  2. Kerr DM, 2013, Behav Brain Res, 30, 680

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Authors
Wei, D., Dinh, D., Lee, D., Li, D., Anguren, A., Moreno-Sanz, G., Gall, C. M., & Piomelli, D.
Affiliations
  • Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California.
  • University of California, Irvine (US)
  • Harbin Medical University (CN)
Corresponding author
Piomelli, Daniele
ORCID
Venue
Cannabis and Cannabinoid Research
Publisher
SAGE Publications
Published
2016-12
Volume
1
Issue
1
Pages
81-89
ISSN
2378-8763 (ISSN-L)
DOI
10.1089/can.2015.0008
PMC
PMC5549436
OpenAlex
W2293191501
Cited by
122
References
51
Citations by year
2026: 4 · 2025: 17 · 2024: 15 · 2023: 14 · 2022: 11 · 2021: 25 · 2020: 11 · 2019: 14 · 2018: 3 · 2017: 4 · 2016: 4
FWCI
6.75
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cannabis and Cannabinoid Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Autism Science Foundation
  • National Institutes of Health
  • University of California, Irvine
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Keywords
anandamide, endocannabinoid system, autism spectrum disorder, social dysfunction, oxytocin, social reward, fatty acid amide hydrolase, FAAH inhibition, URB597, CB1 receptor, BTBR mice, Fmr1 knockout mice, fragile X syndrome, therapeutic target

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