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Cited by 120Cannabis and Cannabinoid ResearchPosttraumatic Stress Disorder ResearchStress Responses and Cortisol

Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress

Open access
Ganon-Elazar, Eti, Akirav, Irit·2012·Neuropsychopharmacology
DOI 10.1038/npp.2011.204PMC PMC3242307
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Abstract

Cannabinoids have recently emerged as a possible treatment of stress- and anxiety-related disorders such as post-traumatic stress disorder (PTSD). Here, we examined whether cannabinoid receptor activation could prevent the effects of traumatic stress on the development of behavioral and neuroendocrine measures in a rat model of PTSD, the single-prolonged stress (SPS) model. Rats were injected with the CB1/CB2 receptor agonist WIN55,212-2 (WIN) systemically or into the basolateral amygdala (BLA) at different time points following SPS exposure and were tested 1 week later for inhibitory avoidance (IA) conditioning and extinction, acoustic startle response (ASR), hypothalamic-pituitary-adrenal (HPA) axis function, and anxiety levels. Exposure to SPS enhanced conditioned avoidance and impaired extinction while enhancing ASR, negative feedback on the HPA axis, and anxiety. WIN (0.5 mg/kg) administered intraperitoneally 2 or 24 h (but not 48 h) after SPS prevented the trauma-induced alterations in IA conditioning and extinction, ASR potentiation, and HPA axis inhibition. WIN microinjected into the BLA (5 μg/side) prevented SPS-induced alterations in IA and ASR. These effects were blocked by intra-BLA co-administration of the CB1 receptor antagonist AM251 (0.3 ng/side), suggesting the involvement of CB1 receptors. These findings suggest that (i) there may be an optimal time window for intervention treatment with cannabinoids after exposure to a highly stressful event, (ii) some of the preventive effects induced by WIN are mediated by an activation of CB1 receptors in the BLA, and (iii) cannabinoids could serve as a pharmacological treatment of stress- and trauma-related disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

Systemic or intra-basolateral amygdala (BLA) cannabinoid receptor activation with WIN55,212-2 prevented several behavioral and endocrine consequences of single-prolonged stress (SPS) in rats, including impaired inhibitory avoidance extinction, enhanced acoustic startle, and enhanced HPA-axis negative feedback. The preventive effects depended on timing after SPS and were blocked by the CB1 antagonist AM251 in the BLA, but WIN did not prevent SPS-induced anxiety.

Key findings

  • SPS increased conditioned avoidance, impaired extinction, enhanced acoustic startle response (ASR), enhanced HPA-axis negative feedback, and increased anxiety. Systemic WIN (0.5 mg/kg) given 2 min, 2 h, or 24 h after SPS prevented the trauma-induced alterations in inhibitory avoidance conditioning/extinction, ASR potentiation, and HPA-axis inhibition; WIN given 48 h after SPS did not prevent these effects and impaired extinction.
  • Intra-BLA WIN (5 mg/side) given 2 min after SPS prevented SPS-induced alterations in inhibitory avoidance and ASR, but intra-BLA WIN given 2 h after SPS did not prevent the effects on extinction. Intra-BLA AM251 (0.3 ng/side) co-administered with WIN blocked WIN’s effects on inhibitory avoidance and ASR.
  • Systemic WIN given 2 or 24 h, but not 2 min, after SPS prevented enhanced HPA-axis inhibition in the dexamethasone suppression test; intra-BLA WIN given 2 min or 2 h did not prevent this HPA-axis effect.
  • WIN did not prevent SPS-induced anxiety: in the open-field test, the vehicle group spent more time in the center than all other groups (p<0.05), and in the light-dark test, the vehicle group spent more time in the light side than all other groups (p<0.05).

Methods

  • A total of 637 male Sprague Dawley rats (about 60 days old, 250–300 g) were used. SPS consisted of 2 h restraint, 15 min forced swim, and isoflurane exposure until loss of consciousness.
  • WIN55,212-2 was administered systemically (0.5 mg/kg or 3 mg/kg i.p.) or into the BLA (5 mg/side) at 2 min, 2 h, 24 h, or 48 h after SPS; AM251 (0.3 ng/side) was co-administered intra-BLA in some experiments. Rats were tested 1 week later for inhibitory avoidance conditioning/extinction, acoustic startle response, HPA-axis function via corticosterone ELISA and dexamethasone suppression test, open-field behavior, and light-dark test.
  • Statistical analysis used t-tests, one-way ANOVA, and mixed-design ANOVA, with LSD post hoc comparisons; values are reported as mean ± SEM.

Limitations

  • The paper states that other targets of WIN, such as CB2 receptors, cannot be completely ruled out, and that injection spread to other structures, especially the central amygdala, cannot be completely ruled out. It also states that the precise mechanism by which cannabinoid receptor activation prevents stress-induced behavioral and neuroendocrine modifications remains to be clarified.
  • Evident from the text: the study used only male Sprague Dawley rats, so sex differences and generalization to females are not addressed; findings are from an animal model of PTSD and may not directly translate to humans.
  • Evident from the text: WIN did not prevent SPS-induced anxiety, indicating that cannabinoid treatment did not block all stress effects.

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

Integrity signals

Registry

Crossref · 10.1038/npp.2011.204

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 49 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    WIN (0.5 mg/kg) administered intraperitoneally 48 h after SPS did not prevent the effects of stress on fear retrieval or extinction in the IA paradigm.

    “This suggests that WIN administered 48 h post-SPS did not prevent the effects of stress on fear retrieval or extinction.”
    Quote in the paperSubstantial claim
  • Findingown data

    WIN (0.5 mg/kg) administered intraperitoneally 24 h after SPS prevented SPS-induced HPA axis inhibition.

    “WIN (0.5 mg/kg) administered intraperitoneally 2 or 24 h (but not 48 h) after SPS prevented the trauma-induced alterations in IA conditioning and extinction, ASR potentiation, and HPA axis inhibition.”
    Quote in the paperSubstantial claim
  • Findingown data

    SPS exposure by itself does not change the CORT response to subsequent elevated platform stress when no dexamethasone is injected.

    “Next, we demonstrated that SPS exposure by itself does not change the responsiveness to subsequent EP stress when no Dex is injected.”
    • Also stated in: § The Effects of SPS and WIN55,212-2 on HPA Axis Function · plain
      “Hence, a similar response was observed in rats that were exposed to SPS and EP and rats that were exposed to EP without prior SPS exposure.”
    Quote in the paperSubstantial claim
  • Findingown data

    Intra-BLA WIN administered 2 min or 2 h after SPS did not prevent the SPS-induced enhanced inhibition of the HPA axis in response to DST.

    “Hence, the SPS group showed enhanced inhibition of the HPA axis in response to DST and WIN administered into the BLA 2 min or 2 h after SPS exposure did not prevent this enhanced inhibition.”
    • Also stated in: § Systemic Cannabinoid Receptor Activation Prevents the Effects of Stress on HPA axis Function · plain
      “However, WIN microinjected into the BLA 2 min or 2 h after SPS exposure did not prevent the stress-induced alterations to HPA axis function.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reduced CORT levels in response to DST indicate HPA axis inhibition.
  • Findingown data

    AM251 by itself had no effect on extinction.

    “suggesting that AM by itself had no effect on extinction.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 13
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    Systemic WIN administered 48 h after SPS did not prevent the stress-induced disruption of extinction learning and enhancement of ASR; it impaired extinction.

    “When WIN was injected 48 h after trauma exposure, it was too late to reverse the effects of stress, and in fact resulted in the impairment of extinction.”
    • Also stated in: § DISCLOSURE · plain
      “WIN administered 48 h after SPS exposure did not prevent the SPS-induced alterations in fear retrieval or extinction”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The 24-h SPS group showed high CORT levels (367 ± 79) compared with the control group (100±37), and the difference was significant by independent samples t-test.

    “Since the 24-h SPS group showed high CORT levels (367 ± 79) compared with the control group (100±37), the two groups were compared using an independent samples t-test (t (13) ¼ 4.30, po0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Resting CORT levels following SPS exposure were extremely high immediately after trauma and remained significantly high up to 24 h thereafter.

    “Interestingly, resting CORT levels measured at different time points following SPS exposure were extremely high immediately after the trauma and remained significantly high up to 24 h thereafter.”
    • Also stated in: § DISCLOSURE · plain
      “Rats decapitated 2 min, 2, or 24 h, but not 1 week (1W), after SPS exposure showed significantly increased levels of CORT compared with control rats.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    SPS exposure induced disruption of extinction learning and enhancement of ASR.

    “The SPS + Veh groups demonstrated a significantly longer latency until they crossed over to the dark side of the IA apparatus on conditioning (Cond) day, fear retrieval (Ext1) and extinction (Ext2) than the Veh groups.”
    • Also stated in: § DISCLOSURE · boosted
      “The SPS + Veh groups demonstrated a significantly enhanced ASR than the Veh groups”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The cannabinoid system is part of the complex circuitry that regulates anxiety and stress and is a crucial mediator of emotional learning.

    “The cannabinoid system is part of the complex circuitry that regulates anxiety and stress and is a crucial mediator of emotional learning (Marsicano et al, 2002;Viveros et al, 2005;Patel et al, 2005Patel et al, , 2005a; Laviolette and Grace, 2006;Varvel et al, 2007;Ganon-Elazar and Akirav, 2009;Lutz, 2009;Hill et al, 2009;Abush and Akirav, 2010;Akirav, 2011).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Marsicano et al, 2002 source

      Not checked in the free run.

    • cites Viveros et al, 2005 source

      Not checked in the free run.

    • cites Patel et al, 2005

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Cannula placements were verified histologically, and only data from animals with correct cannula placements were included in the analyses.

    “Placements of the cannulae were found to be incorrect in o10% of injected rats.Only data from animals with correct cannula placements were included in the analyses (Figure 1).”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Drug concentrations were based on reports in the literature and the authors' previous results.

    “Drug concentrations were based on reports in the literature and our previous results (Martin et al, 1999;Ganon-Elazar and Akirav, 2009;Campolongo et al, 2009;Abush and Akirav, 2010;Segev and Akirav, 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Martin et al, 1999 source

      Not checked in the free run.

    • cites Ganon-Elazar and Akirav, 2009 source

      Not checked in the free run.

    • cites Campolongo et al, 2009 source

      Not checked in the free run.

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

    Premisecitation

    WIN administered into the CA1 has no effect on conditioned avoidance.

    “We have recently shown that WIN administered into the CA1 facilitates IA extinction, with no effect on conditioned avoidance (Abush and Akirav, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Abush and Akirav, 2010 source

      Not checked in the free run.

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

    Study design and conductnone given

    The experiments were approved by the University of Haifa Ethics and Animal Care Committee, and adequate measures were taken to minimize pain or discomfort.

    “The experiments were approved by the University of Haifa Ethics and Animal Care Committee, and adequate measures were taken to minimize pain or discomfort.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    WIN administered into the CA1 facilitates IA extinction.

    “We have recently shown that WIN administered into the CA1 facilitates IA extinction, with no effect on conditioned avoidance (Abush and Akirav, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Abush and Akirav, 2010 source

      Not checked in the free run.

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

    Premisecitation

    Milad et al. (2008) showed deficient extinction recall, measured by skin conductance response, in a 2-day fear conditioning and extinction procedure in PTSD patients.

    “For example, Milad et al (2008) have shown deficient extinction recall as measured in skin conductance response in a 2-day fear conditioning and extinction procedure in PTSD patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Milad et al, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AEA content in the BLA is reduced at the termination of restraint stress and is negatively correlated with the magnitude of the CORT response to stress.

    “Hill et al (2009) have recently shown that the content of AEA in the BLA is reduced at the termination of restraint stress (also see Patel et al, 2005a andRademacher et al, 2008) and that AEA content is negatively correlated with the magnitude of the CORT response to stress.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hill et al, 2009 source

      Not checked in the free run.

    • cites Patel et al, 2005a

      Not checked in the free run.

    • cites Rademacher et al, 2008 source

      Not checked in the free run.

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

    Premisecitation

    CB1 receptor expression in the central amygdala is less clear.

    “but their expression in the central amygdala is less clear (Katona et al, 2001;Tsou et al, 1997;Cota et al, 2007; but see Kamprath et al, 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Katona et al, 2001 source

      Not checked in the free run.

    • cites Tsou et al, 1997 source

      Not checked in the free run.

    • cites Cota et al, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Rats injected with WIN after SPS are still anxious, but do not demonstrate the two main PTSD-like symptoms (enhanced ASR and HPA-negative feedback).

    “Hence, rats that were injected with WIN after SPS are still anxious, but do not demonstrate the two main PTSD-like symptoms (ie, enhanced ASR and HPA-negative feedback).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The open field and light-dark tests measure anxiety.
    • Rests on an assumption: The IA, ASR, and DST measures are valid PTSD-like behavioral and neuroendocrine measures.

  • May combine two claims.

    Interpretationown data

    The effects of WIN in preventing PTSD-like symptoms are not due to a general 'relaxation effect' or to an erasure of the stressful event, since rats injected with WIN after SPS still exhibit unconditioned anxiety.

    “Importantly, this result suggests that the effects of WIN in preventing PTSD-like symptoms are not due to a general 'relaxation effect' or to an erasure of the stressful event, since rats injected with WIN after SPS still exhibit unconditioned anxiety.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The open field and light-dark tests measure anxiety.

  • May combine two claims.

    Interpretationown data

    The results extend previous findings to another stress model and to a post-trauma treatment configuration that are more relevant to clinical context and add to the growing body of data pointing to a therapeutic potential of cannabinoids for treatment of PTSD.

    “Furthermore, the results extend previous findings to another stress model and to a post-trauma treatment configuration that are more relevant to clinical context and add to the growing body of data pointing to a therapeutic potential of cannabinoids for treatment of PTSD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The SPS model is a valid model of PTSD.

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

    Study design and conductreasoning

    The cannulae were implanted into the BLA, but the possibility of injection spread to other structures, especially the central amygdala nucleus, cannot be completely ruled out.

    “The cannulae were implanted into the BLA and although we used a small volume of infusion (0.5 ml), the possibility of injection spread to other structures, especially the central amygdala nucleus, cannot be completely ruled out.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Activating CB1 receptors or increasing AEA signaling prevents some effects of stress in the amygdala and hippocampus and can reduce stress-induced HPA axis activation.

    “Several studies have shown that activating CB1 receptors or increasing N-arachidonylethanolamine (AEA) signaling prevents some of the effects of stress in the amygdala and hippocampus and can reduce stress-induced HPA axis activation (Ganon-Elazar and Akirav, 2009;Patel et al, 2004;Gorzalka et al, 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ganon-Elazar and Akirav, 2009 source

      Not checked in the free run.

    • cites Patel et al, 2004 source

      Not checked in the free run.

    • cites Gorzalka et al, 2008 source

      Not checked in the free run.

18 of 18

  • The paper relies on this without support.

    Inhibiting FAAH activity within the BLA reduces the CORT response to stress, and AEA content in the BLA constrains HPA axis activation.

    “Inhibiting fatty acid amide hydrolase (an endocannabinoid-deactivating enzyme) activity within the BLA reduces the CORT response to stress, suggesting that AEA content in the BLA has a function in constraining HPA axis activation.”

  • The paper relies on this without support.

    Reduced CORT levels in response to DST indicate HPA axis inhibition.

    “Reduced levels of CORT in response to DST indicate HPA axis inhibition.”
    “The DST assesses CORT levels following negative feedback to the pituitary to suppress the secretion of adrenocorticotropic hormone.”

  • The paper relies on this without support.

    The open field and light-dark tests measure anxiety.

    “We used the open field arena and the light-dark test to examine the effects of SPS and WIN (0.5 mg/kg) on anxiety and locomotion.”

  • The paper relies on this without support.

    The SPS model is a valid model of PTSD.

    “The main findings of the current study are that exogenous systemic or intra-BLA administration of the CB1/CB2 cannabinoid receptor agonist WIN55,212-2 normalizes behavioral and neuroendocrine abnormalities resulting from prior stress exposure in a rat model of PTSD.”

  • The paper relies on this without support.

    The IA, ASR, and DST measures are valid PTSD-like behavioral and neuroendocrine measures.

    “cannabinoid receptor activation reverses the effects of SPS on PTSD-like behavioral and neuroendocrine measures (ie, disrupted extinction, enhanced ASR, and HPA inhibition)”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Animal experiments showed that systemic and intracranial injection of cannabinoids, resulting in an increase in EC signaling, prevented the effects of intense stress in animal models of PTSD.

    “In line with this assumption, animal experiments showed that the systemic and intracranial injection of cannabinoids, resulting in an increase in EC signaling, prevented the effects of intense stress in animal models of PTSD [40].”

    From Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder (2013) · cites this paper as [40]

  • Deficient fear extinction caused by a restraint/swim stressor was rescued by intra-BLA or hippocampal, but not mPFC, injection of a CB1R agonist (WIN55212-2) immediately after stress.

    “Interestingly in this context, deficient fear extinction caused by a restraint/swim stressor was recently shown to be rescued by intra-BLA (or hippocampal, but not mPFC) injection of a CB1R agonist (WIN55212-2) immediately after stress [105,106].”

    From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [105]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • WIN at 24 h did not prevent the conditioning alteration

    Major

    The abstract says WIN given 24 h after SPS prevented alterations in IA conditioning. In the results, the SPS + WIN24 h group still had a significantly longer conditioning latency than the non-stressed vehicle group.

  • Wrong group-effect degrees of freedom in intra-BLA analyses

    Minor

    The stated three-group analysis requires 2 numerator degrees of freedom for its group effect, not the reported 1. The same mismatch appears in the corresponding 2 h intra-BLA analysis, which also reports F (1,29) for a three-group design.

    Reported 1 · recomputed 2

2 of 2

Cites

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1 of the 39 references couldn’t be matched to a known paper.

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Related

Authors
Ganon-Elazar, E., & Akirav, I.
Affiliations
University of Haifa (IL)
Corresponding author
Akirav, Irit
ORCID
Akirav, Irit
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2011-09-14
Volume
37
Issue
2
Pages
456-466
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2011.204
PMC
PMC3242307
OpenAlex
W2065711685
Cited by
120
References
39
Citations by year
2026: 2 · 2025: 6 · 2024: 1 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 8 · 2018: 8 · 2017: 12 · 2016: 15 · 2015: 15 · 2014: 9 · 2013: 12 · 2012: 8
FWCI
6.79
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
cannabinoids, post-traumatic stress disorder, single prolonged stress, CB1 receptor, CB2 receptor, WIN 55,212-2, basolateral amygdala, passive avoidance, extinction, acoustic startle response, hypothalamic-pituitary-adrenal axis, anxiety, intervention timing, trauma-related disorders
MeSH terms
Amygdala, Animals, Anxiety, Avoidance Learning, Cannabinoids, Dexamethasone, Disease Models, Animal, Extinction, Psychological, Humans, Hypothalamo-Hypophyseal System, Injections, Intraperitoneal, Male, Microinjections, Morpholines, Naphthalenes, Piperidines, Pituitary-Adrenal Function Tests, Pituitary-Adrenal System, Pyrazoles, Reflex, Startle, Stress, Physiological, Stress Disorders, Post-Traumatic, Rats, Sprague-Dawley, Benzoxazines, Rats, Sensory Gating, Cannabinoid Receptor Agonists, Cannabinoid Receptor Antagonists

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