Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance
Open accessAbstract
Despite the efficacy of behavior therapy for human anxiety disorders, extinction-like treatments require repeated cue exposures and are vulnerable to reversal by a number of environmental factors, particularly stress. The endocannabinoid system has recently emerged as important in the regulation of extinction learning and in the regulation of the hypothalamic-pituitary-adrenal axis. Here, we aimed to examine the involvement of the cannabinoid CB(1) receptor in the basolateral amygdala (BLA) in inhibitory avoidance (IA) conditioning and extinction and to test whether cannabinoid activation would reverse the effects of stress on these memory processes. The synthetic full agonist of the CB(1)/CB(2) receptor WIN55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4- benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] (5 microg/0.5 microl) microinjected into the BLA had no effect on IA conditioning or extinction by itself. However, microinjecting WIN55,212-2 into the BLA before exposing the rats to a stressor reversed the enhancing effects of the stressor on IA conditioning and its impairing effects on IA extinction. Importantly, WIN55,212-2 microinjected into the BLA reduced stress-induced elevations in corticosterone levels. Control experiments demonstrated the following: (1) the effects of WIN55,212-2 could not be attributed to sensorimotor deficits, because these parameters seemed unchanged by WIN55,212-2 microinjected into the BLA; and (2) the CB(1) receptor in the BLA is crucially involved in the extinction of IA, because the CB(1) receptor antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (6 ng/0.5 microl) microinjected into the BLA significantly blocked extinction. Together, our findings may support a wide therapeutic application for cannabinoids in the treatment of conditions associated with the inappropriate retention of aversive memories and stress-related disorders.
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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].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [65]
Cannabinoid receptor activation in the basolateral amygdala (BLA) using WIN55,212-2 can prevent stress-induced enhancement of inhibitory avoidance (IA) conditioning.
“We have recently found that cannabinoid receptor activation in the basolateral amygdala (BLA) using the CB1/2 receptor agonist WIN55,212-2 (WIN) can prevent the stress-induced enhancement of inhibitory avoidance (IA) conditioning as well as the stress-induced disruption of IA extinction.”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-Elazar and Akirav, 2009
Cannabinoid receptor activation in the basolateral amygdala (BLA) using WIN55,212-2 can prevent stress-induced disruption of inhibitory avoidance (IA) extinction.
“We have recently found that cannabinoid receptor activation in the basolateral amygdala (BLA) using the CB1/2 receptor agonist WIN55,212-2 (WIN) can prevent the stress-induced enhancement of inhibitory avoidance (IA) conditioning as well as the stress-induced disruption of IA extinction.”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-Elazar and Akirav, 2009
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).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-Elazar and Akirav, 2009
Intra-BLA WIN inhibited the stress-induced increase in plasma corticosterone (CORT) levels.
“This reversal effect was found to be associated with alterations in the HPA axis, as intra-BLA WIN inhibited the stress-induced increase in plasma corticosterone (CORT) levels (Ganon-Elazar and Akirav, 2009).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-Elazar and Akirav, 2009
Our findings that intra-BLA WIN reduces the CORT response to stress.
“Together with our findings that intra-BLA WIN reduces the CORT response to stress (Ganon-Elazar and Akirav, 2009)”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-Elazar and Akirav, 2009
Cannabinoids in the amygdala serve to attenuate neuronal and behavioral responses to aversive environmental stimuli.
“This is consistent with studies suggesting that cannabinoids in the amygdala serve to attenuate neuronal and behavioral responses to aversive environmental stimuli (Patel et al, 2005;Ganon-Elazar and Akirav, 2009).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-Elazar and Akirav, 2009
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).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-Elazar and Akirav, 2009
Cannabinoid modulation in the BLA of HPA axis activation occurs in proximity to stress exposure.
“Together with our findings that intra-BLA WIN reduces the CORT response to stress (Ganon-Elazar and Akirav, 2009), these studies suggest cannabinoid modulation in the BLA of HPA axis activation in proximity to stress exposure.”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-Elazar and Akirav, 2009
We have previously shown that intra-BLA WIN reversed the stress-induced increase in CORT levels.
“We have previously shown that intra-BLA WIN reversed the stress-induced increase in CORT levels (Ganon-elazar and Akirav, 2009).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Ganon-elazar and Akirav, 2009
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References 68 · Cited by 173
- Authors
- Ganon-Elazar, E., & Akirav, I.
- Affiliations
- University of Haifa (IL)
- Corresponding author
- Akirav, Irit
- ORCID
- Akirav, Irit
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-09-09
- Volume
- 29
- Issue
- 36
- Pages
- 11078-11088
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6665931
- OpenAlex
- W2061001906
- Cited by
- 173
- References
- 68
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 8 · 2019: 9 · 2018: 8 · 2017: 17 · 2016: 14 · 2015: 22 · 2014: 11 · 2013: 16 · 2012: 10
- FWCI
- 9.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- CB1 receptor, basolateral amygdala, passive avoidance, extinction learning, stress, endocannabinoid system, WIN 55,212-2, AM251, corticosterone, anxiety disorders, aversive memory, hypothalamic-pituitary-adrenal axis
- MeSH terms
- Amygdala, Animals, Avoidance Learning, Cannabinoids, Conditioning, Psychological, Extinction, Psychological, Male, Microinjections, Morpholines, Naphthalenes, Stress, Psychological, Rats, Sprague-Dawley, Receptors, Cannabinoid, Benzoxazines, Rats, Cannabinoid Receptor Agonists
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