Integrated cannabinoid CB1 receptor transmission within the amygdala–prefrontal cortical pathway modulates neuronal plasticity and emotional memory encoding
Abstract
The cannabinoid CB1 receptor system is functionally involved in the processing and encoding of emotionally salient sensory information, learning and memory. The CB1 receptor is found in high concentrations in brain structures that are critical for emotional processing, including the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC). In addition, synaptic plasticity in the form of long-term potentiation (LTP) within the BLA > mPFC pathway is an established correlate of exposure to emotionally salient events. We performed a series of in vivo LTP studies by applying tetanic stimulation to the BLA combined with recordings of local field potentials within prelimbic cortical (PLC) region of the rat mPFC. Systemic pretreatment with AM-251 dose dependently blocked LTP along the BLA-PLC pathway and also the behavioral acquisition of conditioned fear memories. We next performed a series of microinfusion experiments wherein CB1 receptor transmission within the BLA > PLC circuit was pharmacologically blocked. Asymmetrical, interhemispheric blockade of CB1 receptor transmission along the BLA > PLC pathway prevented the acquisition of emotionally salient associative memory. Our results indicate that coordinated CB1 receptor transmission within the BLA > PLC pathway is critically involved in the encoding of emotional fear memories and modulates neural plasticity related to the encoding of emotionally salient associative learning.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
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].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [85]
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.”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [85]
Cites
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
Cannabinoid receptor localization in brain.
Herkenham, M., Lynn, A. B., Little, M. D., Johnson, M. R., Melvin, L. S., de Costa, B. R., & Rice, K. C. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.5.1932 · Cited by 2,321 · see citing works
Neurons in medial prefrontal cortex signal memory for fear extinction
Milad, M. R., & Quirk, G. J. (2002) · Nature · doi:10.1038/nature01138 · Cited by 1,836 · cited 6× · see citing works
“Post hoc analyses were performed with Fisher’s least significant difference tests or Newman--Keuls tests.”
BackgroundMethodInfluentialThe endogenous cannabinoid system controls extinction of aversive memories
Marsicano, G., Wotjak, C. T., Azad, S. C., Bisogno, T., Rammes, G., Cascio, M. G., Hermann, H., Tang, J., Hofmann, C., Zieglgänsberger, W., et al. (2002) · Nature · doi:10.1038/nature00839 · Cited by 1,728 · see citing works
Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system
Tsou, K., Brown, S., Sañudo-Peña, M. C., Mackie, K., & Walker, J. M. (1998) · Neuroscience · doi:10.1016/s0306-4522(97)00436-3 · Cited by 1,586 · see citing works
Differential projections of the infralimbic and prelimbic cortex in the rat
Vertes, R. P. (2004) · Synapse · doi:10.1002/syn.10279 · Cited by 1,550 · see citing works
Goal-directed instrumental action: contingency and incentive learning and their cortical substrates
Balleine, B. W., & Dickinson, A. (1998) · Neuropharmacology · doi:10.1016/s0028-3908(98)00033-1 · Cited by 1,541 · see citing works
The Amygdala: a functional analysis
Aggleton, J. P. (2000) · Cited by 964 · see citing works
Katona, I., Rancz, E. A., Acsády, L., Ledent, C., Mackie, K., Hájos, N., & Freund, T. F. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-23-09506.2001 · Cited by 668 · cited 1× · see citing works
“Within the BLA, CB1 receptors are highly expressed on inhibitory local c-aminobutyric acidergic (GABAergic) interneurons but are absent in the adjacent central nucleus (Herkenham et al. 1990; Tsou et al. 1998; Katona et al. 2001).”
BackgroundActivity in Prelimbic Cortex Is Necessary for the Expression of Learned, But Not Innate, Fears
Corcoran, K., & Quirk, G. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.5327-06.2007 · Cited by 580 · see citing works
Giuffrida, A., Leweke, F. M., Gerth, C. W., Schreiber, D., Koethe, D., Faulhaber, J., Klosterkötter, J., & Piomelli, D. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300558 · Cited by 481 · see citing works
Structure−Activity Relationships of Pyrazole Derivatives as Cannabinoid Receptor Antagonists
Lan, R., Liu, Q., Fan, P., Lin, S., Fernando, S. R., McCallion, D. S. E., Pertwee, R. G., & Makriyannis, A. (1999) · Journal of Medicinal Chemistry · doi:10.1021/jm980363y · Cited by 447 · see citing works
Rosenkranz, J. A., & Grace, A. A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-01-00324.2002 · Cited by 392 · see citing works
Rosenkranz, J. A., Moore, H., & Grace, A. A. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-35-11054.2003 · Cited by 344 · see citing works
Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure
Schneider, M. (2008) · Addiction Biology · doi:10.1111/j.1369-1600.2008.00110.x · Cited by 330 · see citing works
Maroun, M., & Richter-Levin, G. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-11-04406.2003 · Cited by 293 · see citing works
Zavitsanou, K., Garrick, T. M., & Huang, X. (2003) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2003.11.005 · Cited by 264 · see citing works
Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling
Azad, S. C., Monory, K., Marsicano, G., Cravatt, B. F., Lutz, B., Zieglgänsberger, W., & Rammes, G. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.2134-04.2004 · Cited by 263 · cited 6× · see citing works
“demonstrated a role for CB1 receptor transmission during the processing of neuronal plasticity and emotional associative learning behaviors within this neural circuit (Azad et al. 2004; Laviolette and Grace 2006b; Roche et al. 2007).”
BackgroundResultInfluentialMolecular Components and Functions of the Endocannabinoid System in Mouse Prefrontal Cortex
Lafourcade, M., Elezgarai, I., Mato, S., Bakiri, Y., Grandes, P., & Manzoni, O. J. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000709 · Cited by 249 · see citing works
Laviolette, S. R., Lipski, W. J., & Grace, A. A. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1168-05.2005 · Cited by 235 · see citing works
Self-citationAzad, S. C., Eder, M., Marsicano, G., Lutz, B., Zieglgänsberger, W., & Rammes, G. (2003) · Learning & Memory · doi:10.1101/lm.53303 · Cited by 220 · see citing works
Hoffman, A. F., & Lupica, C. R. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.85.1.72 · Cited by 194 · see citing works
Amygdala input to medial prefrontal cortex (mPFC) in the rat: A light and electron microscope study
Bacon, S. J., Headlam, A. J. N., Gabbott, P. L. A., & Smith, A. D. (1996) · Brain Research · doi:10.1016/0006-8993(96)00155-2 · Cited by 191 · see citing works
Laviolette, S. R., & Grace, A. A. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0707-06.2006 · Cited by 189 · see citing works
Self-citationIncreased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia
Newell, K. A., Deng, C., & Huang, X. (2006) · Experimental Brain Research · doi:10.1007/s00221-006-0503-x · Cited by 179 · see citing works
Anandamide elevation in cerebrospinal fluid in initial prodromal states of psychosis
Koethe, D., Giuffrida, A., Schreiber, D., Hellmich, M., Schultze‐Lutter, F., Ruhrmann, S., Klosterkötter, J., Piomelli, D., & Leweke, F. M. (2009) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.108.053843 · Cited by 178 · see citing works
Laviolette, S. R., & Grace, A. A. (2006) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-006-6027-5 · Cited by 170 · see citing works
Self-citationMcDonald, A. J., & Mascagni, F. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00380-3 · Cited by 157 · cited 4× · see citing works
“found localized on a subpopulation of inhibitory interneurons (McDonald and Mascagni 2001) suggesting an important regulatory role for CB1 receptor transmission within the BLA through endocannabinoid signaling.”
BackgroundInfluentialDiscriminative fear conditioning to context expressed by multiple measures of fear in the rat
Antoniadis, E. A., & McDonald, R. J. (1999) · Behavioural Brain Research · doi:10.1016/s0166-4328(98)00056-4 · Cited by 151 · see citing works
Gatley, S. J., Lan, R., Pyatt, B. E., Gifford, A. N., Volkow, N. D., & Makriyannis, A. (1997) · Life Sciences · doi:10.1016/s0024-3205(97)00690-5 · Cited by 140 · see citing works
Pistis, M., Perra, S., Pillolla, G., Melis, M., Gessa, G., & Muntoni, A. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2003.08.003 · Cited by 124 · see citing works
Cannabinoids inhibit GABAergic synaptic transmission in mice nucleus accumbens
Manzoni, O. J., & Bockaert, J. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(01)00723-3 · Cited by 103 · see citing works
Bangalore, S. S., Prasad, K. M. R., Montrose, D. M., Goradia, D. D., Diwadkar, V. A., & Keshavan, M. S. (2008) · Schizophrenia Research · doi:10.1016/j.schres.2007.11.029 · Cited by 100 · see citing works
The rodent amygdala contributes to the production of cannabinoid-induced antinociception
Manning, B. H., Martin, W. J., & Meng, I. D. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00356-7 · Cited by 94 · see citing works
Cannabis, Cannabinoids and Schizophrenia: Integration of the Evidence
Cohen, M. A., Solowij, N., & Carr, V. J. (2008) · Australian & New Zealand Journal of Psychiatry · doi:10.1080/00048670801961156 · Cited by 90 · see citing works
Roche, M., O'Connor, E., Diskin, C., & Finn, D. P. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05861.x · Cited by 83 · see citing works
Maroun, M. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05169.x · Cited by 82 · see citing works
Finn, D. P., Beckett, S. R. G., Richardson, D., Kendall, D. A., Marsden, C. A., & Chapman, V. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03509.x · Cited by 66 · see citing works
McGinty, V. B., & Grace, A. A. (2007) · Cerebral Cortex · doi:10.1093/cercor/bhm223 · Cited by 54 · see citing works
Thiemann, G., Marzo, V. D., Molleman, A., & Hasenöhrl, R. U. (2008) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2008.01.010 · Cited by 44 · see citing works
Hasanein, P., Parviz, M., Keshavarz, M., & Javanmardi, K. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04592.x · Cited by 43 · see citing works
Hodge, J., Bow, J. P., Plyler, K. S., Vemuri, K. V., Wisniecki, A., Salamone, J. D., Makriyannis, A., & McLaughlin, P. J. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.06.010 · Cited by 40 · see citing works
Finn, D. P., Jhaveri, M. D., Beckett, S. R. G., Madjd, A., Kendall, D. A., Marsden, C. A., & Chapman, V. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2005.11.063 · Cited by 40 · see citing works
Orozco-Cabal, L. F., Pollandt, S., Liu, J., Vergara, L. A., Shinnick‐Gallagher, P., & Gallagher, J. P. (2005) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2005.07.002 · Cited by 33 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress
Milad, M. R., & Quirk, G. J. (2012) · Annual Review of Psychology · doi:10.1146/annurev.psych.121208.131631 · Cited by 1,466 · see citing works
Prefrontal control of fear: more than just extinction
Sotres-Bayon, F., & Quirk, G. J. (2010) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2010.02.005 · Cited by 625 · see citing works
“This suggests that the amygdala may recruit IL and PL [41–43], which in turn regulate amygdala output.”
BackgroundAmygdala FAAH and anandamide: mediating protection and recovery from stress
Gunduz-Cinar, O., Hill, M. N., McEwen, B. S., & Holmes, A. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.08.008 · Cited by 229 · see citing works
Tan, H., Lauzon, N. M., Bishop, S. F., Chi, N., Bechard, M., & Laviolette, S. R. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4718-10.2011 · Cited by 92 · see citing works
Self-citationRamikie, T. S., & Patel, S. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2011.08.037 · Cited by 62 · see citing works
Serotonergic neuromodulation of synaptic plasticity
Higa, G. S. V., Viana, F. J. C., Francis-Oliveira, J., Cruvinel, E., Franchin, T. S., Marcourakis, T., Ulrich, H., & De Pasquale, R. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110036 · Cited by 29 · 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
- Authors
- Tan, H., Lauzon, N. M., Bishop, S. F., Bechard, M. A., & Laviolette, S. R.
- Affiliations
- Western University (CA)
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-10-30
- Volume
- 20
- Issue
- 6
- Pages
- 1486-1496
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- OpenAlex
- W2137721816
- Cited by
- 81
- References
- 44
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 2 · 2018: 2 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 10 · 2013: 9 · 2012: 6
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cerebral Cortex (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CB1 receptor, amygdala, medial prefrontal cortex, basolateral amygdala, prelimbic cortex, long-term potentiation, synaptic plasticity, emotional memory, fear memory, fear conditioning, AM251, cannabinoid signaling, associative learning
- MeSH terms
- Amygdala, Animals, Brain Mapping, Electric Stimulation, Emotions, Male, Memory, Neural Pathways, Synaptic Transmission, Neuronal Plasticity, Piperidines, Pyrazoles, Rats, Sprague-Dawley, Prefrontal Cortex, Long-Term Potentiation, Receptor, Cannabinoid, CB1, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
