Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle
Open accessAbstract
The cannabinoid CB1 receptor has been shown to be critically involved in the extinction of fear memory. Systemic injection of a CB1 receptor antagonist prior to extinction training blocked extinction. Conversely, administration of the cannabinoid uptake inhibitor AM404 facilitated extinction in a dose-dependent manner. Here we show that bilateral infusion of CB1 receptor agonists into the amygdala after memory reactivation blocked reconsolidation of fear memory measured with fear-potentiated startle. The effect was dose-dependent and could be blocked by AM251, a specific CB1 receptor antagonist. In contrast, the effect of CB1 agonists on reconsolidation was no longer seen if memory reactivation was omitted. Concomitant with block of reconsolidation, CB1 agonist-treated animals did not exhibit shock-induced reinstatement or spontaneous recovery of fear. The absence of recovery was not attributable to permanent damage to the amygdala in WIN-treated rats, nor did the effect result from alteration of baseline startle or shock reactivity. These results suggest that CB1 agonists could impair fear memory via blocking reconsolidation.
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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].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [81]
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“although somewhat controversial, several authors have shown that the reconsolidation of memories created by either appetitive or aversively motivated learning requires protein synthesis or the function of specific molecules in the amygdala (Nader et al. 2000b; Koh and Bernstein 2003; Duvarci and Nader 2004; Wang et al…”
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“…reconsolidation and facilitates extinction of contextual fear measured with freezing response in rats (De Oliveira Alvares et al, 2008), and when administered by intra-amygdala injection, WIN55212-2 blocks reconsolidation of fear memory measured with fear-potentiated startle (Lin et al, 2006).”
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“…or FAAH inhibition (with AM3506), either in the BLA, or in at least some studies, the mPFC or infralimbic subregion, promotes fear extinction and prevents stress-induced extinction deficits (Lin et al., 2006; 2009b; Do Monte et al., 2013; Ganon-Elazar and Akirav, 2013; Gunduz-Cinar et al., 2013).”
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Activity in prelimbic cortex subserves fear memory reconsolidation over timePreprint
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“…showing the absence of this memory extinction-related feature after impairing the reconsolidation process in other aversive memory paradigms, such as fear-potentiated startle (Lin et al. 2006), inhibitory avoidance (Taubenfeld et al. 2009), and auditory fear conditioning (Maddox and Schafe 2011).”
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“…with exposure therapy is made even more intriguing by findings in rats showing that intraamygdala infusion of CB1 receptor agonists after a memory reactivation session actually blocks reconsolidation of fear memory, as well as reinstatement and spontaneous recovery of fear (Lin et al., 2006).”
Role of cortical cannabinoid CB1 receptor in conditioned taste aversion memory
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“Further, CB1 antagonists have been shown to block reconsolidation (Lin et al., 2006).”
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“In agreement with this premise, the activation of CB1 receptors into the aforementioned sites has facilitated aversive memory extinction (Lin et al., 2006; de Oliveira Alvares et al., 2008; Lin et al., 2009; Do Monte et al., 2013; Sachser et al., 2015).”
BackgroundInfluentialManwell, L. A., Satvat, E., Lang, S. T., Allen, C. P., Leri, F., & Parker, L. A. (2009) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2009.08.002 · Cited by 48 · see citing works
Ratano, P., Everitt, B. J., & Milton, A. L. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.103 · Cited by 49 · see citing works
“However, less is known about endocannabinoid signaling in reconsolidation (De Oliveira Alvares et al , 2008; Kobilo et al , 2007), especially within the amygdala (Bucherelli et al , 2006; Lin et al , 2006).”
Amaral, O. B., Osan, R. M., Roesler, R., & Tort, A. B. L. (2008) · Hippocampus · doi:10.1002/hipo.20420 · Cited by 47 · see citing works
“…al., 2004, 2005, 2006; Debiec and LeDoux, 2004; Duvarci and Nader, 2004; Lee et al., 2004; Suzuki et al., 2004; Miller and Marshall, 2005; Tronel et al., 2005; Bustos et al., 2006; Lin et al., 2006; Rossato et al., 2006; Valjent et al., 2006; Jin et al., 2007; Tronel and Alberini, 2007) (Table 2).”
BackgroundYu, L., Wang, X., Zhao, M., Liu, Y., Li, Y., Li, F.-Q., Wang, X., Xue, Y.-X., & Lü, L. (2009) · Psychopharmacology · doi:10.1007/s00213-008-1450-y · Cited by 48 · see citing works
“…are more frequently described to cause disruptive effects on learning and memory (Ameri 1999; Hernandez-Tristan et al. 2000; Kobilo et al. 2007; Lin et al. 2006), but disrupted extinction learning in both the conditioned freezing and passive avoidance tasks has been found in rats treated with…”
InfluentialEndocannabinoid regulation of relapse mechanisms
Fattore, L., Fadda, P., & Fratta, W. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.09.004 · Cited by 48 · see citing works
“[11] Lin HC, Mao SC, Gean PW.”
Rabinak, C. A., & Phan, K. L. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990437 · Cited by 46 · see citing works
“Moreover, Lin and colleagues have found that local injections of WIN 55–212,2 [46, 53] or AM404 [46] into the IL cortex prior to training improves the extinction of fear-potentiated startle and local injections of HUB210 and/or WIN 55–212,2 into the AMYG during fear extinction blocks the return of extinguished fear-po…”
BackgroundInhibition and enhancement of contextual fear memory destabilization
Lee, J. L. C., & Flavell, C. R. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00144 · Cited by 42 · see citing works
Locci, A., & Pinna, G. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.12.014 · Cited by 42 · see citing works
Wesley, M. J., Lile, J. A., Hanlon, C. A., & Porrino, L. J. (2015) · Psychopharmacology · doi:10.1007/s00213-015-4180-y · Cited by 40 · see citing works
“For example, cannabinoid agonists injected directly into the rodent amygdala prevented the reconsolidation of fear memories (Lin et al. 2006) or extinguished them altogether (Marsicano et al. 2002).”
Hammoud, M. Z., Peters, C., Hatfield, J. R. B., Gorka, S. M., Phan, K. L., Milad, M. R., & Rabinak, C. A. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0416-6 · Cited by 40 · see citing works
The endocannabinoid system in the amygdala and modulation of fear
Gunduz‐Cinar, O. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110116 · Cited by 38 · see citing works
“Intra-BLA infusion of CB1R agonists enhanced consolidation of conditioned fear (Lin et al., 2006) while intra-BLA infusions of CB1R antagonists attenuated short term extinction of fear (Roche et al.”
Papini, S., Sullivan, G. M., Hien, D. A., Shvil, E., & Neria, Y. (2014) · Biological Psychology · doi:10.1016/j.biopsycho.2014.10.010 · Cited by 37 · see citing works
“These two types of effects were blocked in rats by systemic (Ganon-Elazar & Akirav, 2012), intra-BLA, or intra-hippocampal—but not intra-infralimbic—(Ganon-Elazar & Akirav, 2013) infusions of a CB1 agonist.”
BackgroundInfluentialMemory labilization in reconsolidation and extinction – Evidence for a common plasticity system?
Almeida-Corrêa, S., & Amaral, O. B. (2014) · Journal of Physiology-Paris · doi:10.1016/j.jphysparis.2014.08.006 · Cited by 36 · see citing works
Cannabinoids: Revealing their complexity and role in central networks of fear and anxiety
Murkar, A., Koninck, J. D., & Merali, Z. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.09.002 · Cited by 34 · see citing works
Sachser, R. M., Crestani, A. P., Quillfeldt, J. A., Souza, T. M. E., & Alvares, L. D. O. (2015) · Learning & Memory · doi:10.1101/lm.039891.115 · Cited by 31 · see citing works
“Additionally, when infused into the amygdala, the cannabinoid receptor agonist WIN blocks fear memory reconsolidation (Lin et al. 2006), the same effect found here using CP55940.”
BackgroundMethodEndocannabinoids underlie reconsolidation of hedonic memories in Wistar rats
de Carvalho, C. R., Pamplona, F. A., Cruz, J. S., & Takahashi, R. N. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3331-2 · Cited by 30 · see citing works
“On the other hand, aversive memory reconsolidation can be disrupted by post-retrieval treatment with CB1 antagonists (Bucherelli et al. 2006), which supports a role for endocannabinoid on memory reconsolidation (Lin et al. 2006; Kobilo et al. 2007; Suzuki et al. 2008).”
InfluentialZubedat, S., & Akirav, I. (2017) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.01.011 · Cited by 30 · see citing works
“Others found that intra-amygdala post-reactivation injection of the cannabinoid agonists WIN55,212–2 and HU210 disrupted reconsolidation (Lin et al., 2006) whereas the fatty acid amide hydrolase inhibitor URB597 produced a small, transient enhancement of memory re-stabilization (Ratano et al.,…”
BackgroundNiloy, N., Hediyal, T. A., Vichitra, C., Sharma, S., Chidambaram, S. B., Gorantla, V. R., & Mahalakshmi, A. M. (2023) · Biomolecules · doi:10.3390/biom13010162 · Cited by 28 · see citing works
“Intraamygdala CB1 agonist infusion disrupted fear memory by hampering the reconsolidation (past consolidated memories being recalled and actively consolidated) [170].”
BackgroundRoche, M., Johnston, P., Mhuircheartaigh, O. N., Olango, W. M., Mackie, K., & Finn, D. P. (2009) · European Journal of Pain · doi:10.1016/j.ejpain.2009.08.009 · Cited by 29 · see citing works
Endocannabinoid signaling and memory dynamics: A synaptic perspective
Drumond, A., Madeira, N., & Fonseca, R. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.07.031 · Cited by 27 · see citing works
Murkar, A., Kent, P., Cayer, C., James, J., Durst, T., & Merali, Z. (2019) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2019.00174 · Cited by 28 · see citing works
“The distribution of central receptors in the ECB system has already been implicated in human PTSD. Evidence from positron emission tomography (PET) imaging suggests that among those with PTSD there is a widespread upregulation of CB1 receptor density particularly in regions implicated in learned fear (the amygdala, hi…”
InfluentialFattore, L., Piva, A., Zanda, M. T., Fumagalli, G. F., & Chiamulera, C. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4793-4 · Cited by 26 · see citing works
“Although some studies found that activation of CB1 receptors in the amygdala (Lin et al. 2006) or in the”
BackgroundMethodResultInfluentialSantana, F., Sierra, R. O., Haubrich, J., Crestani, A. P., Duran, J. M., Cassini, L. F., Alvares, L. D. O., & Quillfeldt, J. A. (2015) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2015.11.016 · Cited by 26 · see citing works
Bach, D. R., Naef, M., Deutschmann, M., Tyagarajan, S. K., & Quednow, B. B. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1285-19.2019 · Cited by 24 · see citing works
“This is not (or less so) the case for reconsolidation blockade, which thus appears to lastingly modify memory (Duvarci and Nader, 2004; Lin et al., 2006).”
BackgroundNeuroanatomical substrates involved in cannabinoid modulation of defensive responses
Moreira, F. A., Aguiar, D., Resstel, L. B. M., Lisboa, S. F. D. S., Campos, A. C., Gomes, F. V., & Guimarães, F. S. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111400651 · Cited by 22 · see citing works
“…and several studies suggest that it is involved in the effects of cannabinoids on consolidation and extinction of aversive memories (Bucherelli et al. 2006; Cannich et al. 2004; Campolongo et al., 2009; Ganon-Elazar and Akirav, 2009; Lin et al., 2006; Marsicano et al., 2002; Roche et al., 2007).”
BackgroundFlavell, C. R., & Lee, J. L. C. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05338-5 · Cited by 21 · see citing works
Higginbotham, J. A., Jones, N. M., Wang, R., Christian, R. J., Ritchie, J. L., McLaughlin, R. J., & Fuchs, R. A. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-00919-x · Cited by 20 · see citing works
Fotio, Y., Tagne, A. M., Jung, K., & Piomelli, D. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06358-y · Cited by 19 · see citing works
“CB 1 cannabinoid receptors in the prefrontal cortex (PFC) and amygdala are critical modulators of emotional and neurochemical responses to fear and stress (Hill et al. 2009; Lin et al. 2006, 2009; Ramot and Akirav 2012).”
Ghasemi, M., Abrari, K., Goudarzi, I., & Rashidy‐Pour, A. (2017) · Basic and Clinical Neuroscience Journal · doi:10.29252/nirp.bcn.8.6.493 · Cited by 19 · see citing works
“There are conflicting evidence that administration of cannabinoid agonists and their reuptake inhibitors before extinction training affects the acquisition and retrieval of memory extinction (Kamprath et al., 2006; Lin, 2006).”
Najar, F., Nasehi, M., Haeri-Rouhani, S.-A., & Zarrindast, M. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881115609021 · Cited by 18 · see citing works
Social recognition memory requires protein synthesis after reactivation.
Perrin, G., Ferreira, G., Meurisse, M., Verdin, S., Mouly, A., & Lévy, F. (2007) · Behavioral Neuroscience · doi:10.1037/0735-7044.121.1.148 · Cited by 18 · see citing works
The Neurobiology of Fear Memory Reconsolidation and Psychoanalytic Theory
Gorman, J. M., & Roose, S. P. (2011) · Journal of the American Psychoanalytic Association · doi:10.1177/0003065111427724 · Cited by 17 · see citing works
Developmental differences in the effects of CB1/2R agonist WIN55212-2 on extinction of learned fear
Bisby, M. A., Richardson, R., & Baker, K. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109834 · Cited by 15 · see citing works
Peripheral CB1 receptor blockade acts as a memory enhancer through a noradrenergic mechanism
Martínez‐Torres, S., Bergadà‐Martínez, A., Ortega, J. E., Galera-López, L., Hervera, A., Reyes‐Ramírez, L. D. L., Ortega-Álvaro, A., Remmers, F., Muñoz‐Moreno, E., Sòria, G., et al. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01436-9 · Cited by 15 · see citing works
“On the contrary, infusions of CB1R agonists in the basolateral amygdala prevented fear memory by preventing reconsolidation [33], and the administration of CB1R agonists directly into infralimbic cortex and CA1 hippocampus region improved fear memory reconsolidation [34].”
BackgroundMoore, N. L. T., Gauchan, S., & Genovese, R. F. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2014.01.011 · Cited by 15 · see citing works
“It is known that AM404 microinjections into the amygdala, periaqueductal gray, and hippocampus aid in extinction of freezing behavior (Lin et al., 2006; Resstel et al., 2008; Tan et al., 2011).”
The effects of anandamide and oleamide on cognition depend on diurnal variations
Rueda‐Orozco, P. E., Montes-Rodríguez, C. J., Ruiz‐Contreras, A. E., Méndez‐Díaz, M., & Prospero-Garcia, O. E. (2017) · Brain Research · doi:10.1016/j.brainres.2017.08.002 · Cited by 15 · see citing works
Lee, J. L. C., Amorim, F. E., Cassini, L. F., & Amaral, O. B. (2019) · PLoS ONE · doi:10.1371/journal.pone.0205781 · Cited by 14 · see citing works
Gastrin-releasing peptide attenuates fear memory reconsolidation
Murkar, A., Kent, P., Cayer, C., James, J., & Merali, Z. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.11.037 · Cited by 12 · see citing works
Extracellular matrix: a new player in memory maintenance and psychiatric disorders
Bach, D. R., Brown, S. A., Kleim, B., & Tyagarajan, S. K. (2019) · Swiss Medical Weekly · doi:10.4414/smw.2019.20060 · Cited by 11 · see citing works
Cannabidiol and the corticoraphe circuit in post-traumatic stress disorder
Alexander, C., & Vasefi, M. (2021) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2021.08.001 · Cited by 11 · see citing works
“This mechanism of CBD was observed in rodent models of depression (Silote et al., 2019; Linge et al., 2016), however this mechanism slightly differs for PTSD. Due to enhanced endocannabinoid signaling, we suggest that corticoraphe signaling will be stabilized by AEA regulation of 5-HT release in…”
BackgroundInfluentialBayer, H., Bertoglio, L. J., Maren, S., & Stern, C. A. J. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106198 · Cited by 11 · see citing works
The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics
Ahmed, M., Boileau, I., Le Foll, B., Carvalho, A. F., & Kloiber, S. (2022) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2021-1926 · Cited by 11 · see citing works
Scienza-Martin, K., Lotz, F. N., Zanona, Q. K., Santana, F., Crestani, A. P., Boos, F. Z., Calcagnotto, M. E., & Quillfeldt, J. A. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.04.009 · Cited by 10 · see citing works
Enhancing Fear Extinction: Pharmacological Approaches
Ponomareva, O. Y., Fenster, R. J., & Ressler, K. J. (2023) · Current topics in behavioral neurosciences · doi:10.1007/7854_2023_443 · Cited by 7 · see citing works
Matias, M. E., Radulski, D. R., da Silva, T. R., Raymundi, A. M., Stern, C. A. J., & Zampronio, A. R. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110745 · Cited by 9 · see citing works
The Hippocampal Endocannabinoid System in Different Memory Phases: Unveiling the CA1 Circuitry
Quillfeldt, J. A., & Alvares, L. D. O. (2015) · Springer eBooks · doi:10.1007/978-1-4939-2294-9_3 · Cited by 6 · see citing works
Cannabis for posttraumatic stress disorder
Krumm, B. A. (2015) · The Nurse Practitioner · doi:10.1097/01.npr.0000434091.34348.3c · Cited by 6 · see citing works
Murkar, A., Cayer, C., James, J., Durst, T., Arnason, J. T., Sanchez-Vindas, P. E., Rojas, M. O., & Merali, Z. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01496 · Cited by 6 · see citing works
“This technique has been used in preclinical research to help identify potential therapeutic targets (Debiec and LeDoux, 2006; Lin et al., 2006; Pitman et al., 2011; Murkar et al., 2017).”
Methodde Carvalho, C. R., Stern, C. A. J., Bertoglio, L. J., & Takahashi, R. N. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800213-1.00075-4 · Cited by 4 · see citing works
Endocannabinoids and psychopathology: The therapy inside
Drago, F. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.09.007 · Cited by 4 · see citing works
PROGRAMA DE PÓS-GRADUAÇÃO EM NEUROCIÊNCIAS
Saúde, B. D. (2010) · Cited by 2 · see citing works
Endocannabinoid System Contributions to Psychiatric Risk
Lunge, A. R., Tansey, R. C., Elliott, G., Ferger, M. D., & Mayo, L. M. (2025) · Springer eBooks · doi:10.1007/978-3-031-87990-6_15 · Cited by 1 · see citing works
The role of endocannabinoid function in posttraumatic stress disorder
Gabbay, F. H., Choi, K. H., Wynn, G. H., & Ursano, R. J. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-417041-4.00011-4 · Cited by 1 · see citing works
Manwell, L. A. (2013) · The Atrium (University of Guelph) · Cited by 1 · see citing works
- Authors
- Lin, H.-C., Mao, S.-C., & Gean, P.-W.
- Affiliations
- National Cheng Kung University (TW)
- Venue
- Learning & Memory
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2006-05
- Volume
- 13
- Issue
- 3
- Pages
- 316-321
- ISSN
- 1072-0502 (ISSN-L)
- 1549-5485
- PMC
- PMC1475812
- OpenAlex
- W2093170247
- Cited by
- 107
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 9 · 2018: 1 · 2017: 7 · 2016: 3 · 2015: 11 · 2014: 9 · 2013: 6 · 2012: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Learning & Memory (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council (NSC94-2752-B-006-001-PAE)
- National Health Research Institutes
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- CB1 receptor agonists, fear memory reconsolidation, fear-potentiated startle, memory reactivation, CB1 receptor, AM251, fear extinction, reinstatement, spontaneous recovery
- MeSH terms
- Amygdala, Analysis of Variance, Animals, Arachidonic Acids, Association Learning, Cannabinoids, Conditioning, Classical, Dose-Response Relationship, Drug, Extinction, Psychological, Fear, Memory, Microinjections, Morpholines, Naphthalenes, Piperidines, Pyrazoles, Reflex, Startle, Dronabinol, Receptor, Cannabinoid, CB1, Benzoxazines, Rats
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