*Result*: Sub-chronic administration of AM6545 enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice.
Title:
Sub-chronic administration of AM6545 enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice.
Authors:
Bergadà-Martínez A; Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain., de Los Reyes-Ramírez L; Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.; Research Group in Biology of Cognition, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain., Martínez-Torres S; Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain., Ciaran-Alfano L; Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.; Research Group in Biology of Cognition, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain., Martínez-Gallego I; Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Seville, Spain., Maldonado R; Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.; Research Programme in Neurosciences, IMIM Hospital del Mar Research Institute, Barcelona, Spain., Rodríguez-Moreno A; Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Seville, Spain., Ozaita A; Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.; Research Group in Biology of Cognition, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.; Research Programme in Neurosciences, IMIM Hospital del Mar Research Institute, Barcelona, Spain.
Source:
British journal of pharmacology [Br J Pharmacol] 2025 Jul; Vol. 182 (13), pp. 2914-2929. Date of Electronic Publication: 2025 Mar 18.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE
Imprint Name(s):
Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.
Original Publication: London, Macmillian Journals Ltd.
MeSH Terms:
References:
Adams, B., Fitch, T., Chaney, S., & Gerlai, R. (2002). Altered performance characteristics in cognitive tasks: Comparison of the albino ICR and CD1 mouse strains. Behavioural Brain Research, 133, 351–361. https://doi.org/10.1016/S0166-4328(02)00020–7.
Alexander, S. P. H., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., & Davies, J. A. (2023). The concise guide to PHARMACOLOGY 2023/24: G protein‐coupled receptors. British Journal of Pharmacology, 180, S23–S144.
Alexander, S. P. H., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Buneman, O. P., Faccenda, E., Harding, S. D., Spedding, M., & Cidlowski, J. A. (2023). The concise guide to pharmacology 2023/24: Introduction and other protein targets. British Journal of Pharmacology, 180, S1–S22.
Alexander, S. P. H., Mathie, A. A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Aldrich, R. W., Attali, B., Baggetta, A. M., Becirovic, E., Biel, M., Bill, R. M., Caceres, A. I., Catterall, W. A., Conner, A. C., … Zhu, M. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. British Journal of Pharmacology, 180(Suppl 2), S145–S222. https://doi.org/10.1111/bph.16181.
Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Mangum, J., Wonnacott, S., & Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology. British Journal of Pharmacology, 175, 407–411. https://doi.org/10.1111/bph.14112.
Arguello, P. A., & Jentsch, J. D. (2004). Cannabinoid CB1 receptor‐mediated impairment of visuospatial attention in the rat. Psychopharmacology, 177, 141–150. https://doi.org/10.1007/s00213-004-1953-0.
Barna, I., Soproni, K., Arszovszki, A., Csabai, K., & Haller, J. (2007). WIN‐55,212–2 chronically implanted into the CA3 region of the dorsal hippocampus impairs learning: A novel method for studying chronic, brain‐area‐specific effects of cannabinoids. Behavioural Pharmacology, 18, 515–520. https://doi.org/10.1097/FBP.0b013e3282d9e9f9.
Beletskiy, A., Zolotar, A., Fortygina, P., Chesnokova, E., Uroshlev, L., Balaban, P., & Kolosov, P. (2024). Downregulation of ribosomal protein genes is revealed in a model of rat hippocampal neuronal culture activation with GABA(A)R/GlyRa2 antagonist Picrotoxin. Cells, 13, 383. https://doi.org/10.3390/cells13050383.
Borrie, S. C., Brems, H., Legius, E., & Bagni, C. (2017). Cognitive dysfunctions in intellectual disabilities: The Contributions of the Ras‐MAPK and PI3K‐AKT‐mTOR pathways. Annual Review of Genomics and Human Genetics, 18, 115–142. https://doi.org/10.1146/annurev-genom-091416–035332.
Bridi, M., Schoch, H., Florian, C., Poplawski, S. G., Banerjee, A., Hawk, J. D., Porcari, G. S., Lejards, C., Hahn, C. G., Giese, K. P., Havekes, R., Spruston, N., & Abel, T. (2020). Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling. JCI Insight, 5, e92385. https://doi.org/10.1172/jci.insight.92385.
Butler, C. W., Keiser, A. A., Kwapis, J. L., Berchtold, N. C., Wall, V. L., Wood, M. A., & Cotman, C. W. (2019). Exercise opens a temporal window for enhanced cognitive improvement from subsequent physical activity. Learning & Memory, 26, 485–492. https://doi.org/10.1101/lm.050278.119.
Curtis, M. J., Alexander, S. P. H., Cirino, G., George, C. H., Kendall, D. A., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Patel, H. H., Sobey, C. G., Stanford, S. C., Stanley, P., Stefanska, B., Stephens, G. J., Teixeira, M. M., Vergnolle, N., & Ahluwalia, A. (2022). Planning experiments: Updated guidance on experimental design and analysis and their reporting III. British Journal of Pharmacology, 179, 3907–3913. https://doi.org/10.1111/bph.15868.
Da Silva, G. E., & Takahashi, R. N. (2002). SR 141716A prevents Δ9‐tetrahydrocannabinol‐induced spatial learning deficit in a Morris‐type water maze in mice. Progress in Neuro‐Psychopharmacology & Biological Psychiatry, 26, 321–325. https://doi.org/10.1016/S0278-5846(01)00275–5.
Dupret, D., Revest, J.‐M., Koehl, M., Ichas, F., De Giorgi, F., Costet, P., Abrous, D. N., & Piazza, P. V. (2008). Spatial relational memory requires hippocampal adult neurogenesis. PLoS ONE, 3, e1959. https://doi.org/10.1371/journal.pone.0001959.
Falcón‐Moya, R., Martínez‐Gallego, I., & Rodríguez‐Moreno, A. (2021). Kainate receptor modulation of glutamatergic synaptic transmission in the CA2 region of the hippocampus. Journal of Neurochemistry, 158, 1083–1093.
Gibon, J., & Barker, P. A. (2017). Neurotrophins and proneurotrophins: Focus on synaptic activity and plasticity in the brain. The Neuroscientist, 23, 587–604. https://doi.org/10.1177/1073858417697037.
Gomis‐González, M., Galera‐López, L., Ten‐Blanco, M., Busquets‐Garcia, A., Cox, T., Maldonado, R., & Ozaita, A. (2021). Protein kinase C‐gamma knockout mice show impaired hippocampal short‐term memory while preserved long‐term memory. Molecular Neurobiology, 58, 617–630. https://doi.org/10.1007/s12035-020-02135-6.
Hafner, A. S., Donlin‐Asp, P. G., Leitch, B., Herzog, E., & Schuman, E. M. (2019). Local protein synthesis is a ubiquitous feature of neuronal pre‐ and postsynaptic compartments. Science (New York, N.Y.), 364(6441), eaau3644. https://doi.org/10.1126/science.aau3644.
Horner, A. E., Heath, C. J., Hvoslef‐Eide, M., Kent, B. A., Kim, C. H., Nilsson, S. R. O., Alsiö, J., Oomen, C. A., Holmes, A., Saksida, L. M., & Bussey, T. J. (2013). The touchscreen operant platform for testing learning and memory in rats and mice. Nature Protocols, 8, 1961–1984. https://doi.org/10.1038/nprot.2013.122.
Ishac, E. J. N., Jiang, L., Lake, K. D., Varga, K., Abood, M. E., & Kunos, G. (1996). Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. British Journal of Pharmacology, 118, 2023–2028. https://doi.org/10.1111/j.1476–5381.1996.tb15639.x.
Jessberger, S., Clark, R. E., Broadbent, N. J., Clemenson, G. D., Consiglio, A., Lie, D. C., Squire, L. R., & Gage, F. H. (2009). Dentate gyrus‐specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learning & Memory, 16(2), 147–154. https://doi.org/10.1101/lm.1172609.
Joiner, M. A., Lisé, M.‐F., Yuen, E. Y., Kam, A. Y. F., Zhang, M., Hall, D. D., Malik, Z. A., Qian, H., Chen, Y., Ulrich, J. D., & Burette, A. C. (2010). Assembly of a beta2‐adrenergic receptor‐‐gluR1 signalling complex for localized cAMP signalling. The EMBO Journal, 29, 482–495.
Kale, V. P., Gibbs, S., Taylor, J. A., Zmarowski, A., Novak, J., Patton, K., Sparrow, B., Gorospe, J., Anand, S., Cinar, R., Kunos, G., Chorvat, R. J., & Terse, P. S. (2019). Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis. Regulatory Toxicology and Pharmacology, 109, 104483. https://doi.org/10.1016/j.yrtph.2019.104483.
King, S. O., & Williams, C. L. (2009). Novelty‐induced arousal enhances memory for cued classical fear conditioning: Interactions between peripheral adrenergic and brainstem glutamatergic systems. Learning & Memory, 16, 625–634.
Kruk‐Slomka, M., & Biala, G. (2016). CB1 receptors in the formation of the different phases of memory‐related processes in the inhibitory avoidance test in mice. Behavioural Brain Research, 301, 84–95. https://doi.org/10.1016/j.bbr.2015.12.023.
Lilley, E., Stanford, S. C., Kendall, D. E., Alexander, S. P. H., Cirino, G., Docherty, J. R., George, C. H., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Sobey, C. G., Stefanska, B., Stephens, G., Teixeira, M., & Ahluwalia, A. (2020). ARRIVE 2.0 and the British Journal of pharmacology: Updated guidance for 2020. British Journal of Pharmacology, 177, 3611–3616. https://doi.org/10.1111/bph.15178.
Lim, Y., Wu, L. L. Y., Chen, S., Sun, Y., Vijayaraj, S. L., Yang, M., Bobrovskaya, L., Keating, D., Li, X. J., & Zhou, X. F. (2018). HAP1 is required for endocytosis and signalling of BDNF and its receptors in neurons. Molecular Neurobiology, 55, 1815–1830. https://doi.org/10.1007/s12035-016-0379-0.
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real‐time quantitative PCR and the 2−ΔΔCT method. Methods, 25, 402–408. https://doi.org/10.1006/meth.2001.1262.
Love, M. I., Huber, W., & Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA‐seq data with DESeq2. Genome Biology, 15, 550. https://doi.org/10.1186/s13059-014-0550-8.
Maccarrone, M., Valverde, O., Barbaccia, M. L., Castañé, A., Maldonado, R., Ledent, C., Parmentier, M., & Finazzi‐Agrò, A. (2002). Age‐related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: Correlation with behaviour. The European Journal of Neuroscience, 15, 1178–1186.
Marsicano, G., Wotjak, C. T., Azad, S. C., Bisogno, T., Rammes, G., Cascioll, M. G., Hermann, H., Tang, J., Hofmann, C., Zieglgänsberger, W., Di Marzo, V., & Lutz, B. (2002). The endogenous cannabinoid system controls extinction of aversive memories. Nature, 418, 530–534.
Martínez‐Torres, S., Bergadà‐Martínez, A., Ortega, J. E., Galera‐López, L., Hervera, A., los, de Reyes‐Ramírez, L., Ortega‐Álvaro, A., Remmers, F., Muñoz‐Moreno, E., Soria, G., & Del Río, J. A. (2023). Peripheral CB1 receptor blockade acts as a memory enhancer through a noradrenergic mechanism. Neuropsychopharmacology, 48, 341–350.
McIntyre, C. K., McGaugh, J. L., & Williams, C. L. (2012). Interacting brain systems modulate memory consolidation. Neuroscience and Biobehavioral Reviews, 36, 1750–1762. https://doi.org/10.1016/j.neubiorev.2011.11.001.
Merlo, S. A., Belluscio, M. A., Pedreira, M. E., & Merlo, E. (2024). Memory persistence: From fundamental mechanisms to translational opportunities. Translational Psychiatry, 14, 98. https://doi.org/10.1038/s41398-024-02808-z.
Monfort, P., & Felipo, V. (2007). Hippocampal long‐term potentiation is reduced in mature compared to young male rats but not in female rats. Neuroscience, 146, 504–508. https://doi.org/10.1016/j.neuroscience.2007.02.008.
Morris, R. G. M. (2006). Elements of a neurobiological theory of hippocampal function: The role of synaptic plasticity, synaptic tagging and schemas. The European Journal of Neuroscience, 23, 2829–2846. https://doi.org/10.1111/j.1460–9568.2006.04888.x.
Navarro‐Romero, A., Galera‐López, L., Ortiz‐Romero, P., Llorente‐Ovejero, A., los, de Reyes‐Ramírez, L., de Tena, I. B., Garcia‐Elias, A., Mas‐Stachurska, A., Reixachs‐Solé, M., Pastor, A., & De La Torre, R. (2022). Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams‐Beuren syndrome. eLife, 11, e72560.
Navarro‐Romero, A., Vázquez‐Oliver, A., Gomis‐González, M., Garzón‐Montesinos, C., Falcón‐Moya, R., Pastor, A., Martín‐García, E., Pizarro, N., Busquets‐Garcia, A., Revest, J. M., Piazza, P. V., Bosch, F., Dierssen, M., de la Torre, R., Rodríguez‐Moreno, A., Maldonado, R., & Ozaita, A. (2019). Cannabinoid type‐1 receptor blockade restores neurological phenotypes in two models for down syndrome. Neurobiology of Disease, 125, 92–106. https://doi.org/10.1016/j.nbd.2019.01.014.
Niederhoffer, N., Hansen, H. H., Fernandez‐Ruiz, J. J., & Szabo, B. (2001). Effects of cannabinoids on adrenaline release from adrenal medullary cells. British Journal of Pharmacology, 134, 1319–1327. https://doi.org/10.1038/sj.bjp.0704359.
Oh, M. C., Derkach, V. A., Guire, E. S., & Soderling, T. R. (2006). Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long‐term potentiation. Journal of Biological Chemistry, 281, 752–758. https://doi.org/10.1074/jbc.M509677200.
Ohno‐Shosaku, T., & Kano, M. (2014). Endocannabinoid‐mediated retrograde modulation of synaptic transmission. Current Opinion in Neurobiology, 29, 1–8. https://doi.org/10.1016/j.conb.2014.03.017.
Pacher, P., Bátkai, S., & Kunos, G. (2006). The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews, 58, 389–462. https://doi.org/10.1124/pr.58.3.2.
Pamplona, F. A., & Takahashi, R. N. (2006). WIN 55212‐2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors. Neuroscience Letters, 397, 88–92. https://doi.org/10.1016/j.neulet.2005.12.026.
Papaleonidopoulos, V., & Papatheodoropoulos, C. (2018). β‐Adrenergic receptors reduce the threshold for induction and stabilization of LTP and enhance its magnitude via multiple mechanisms in the ventral but not the dorsal hippocampus. Neurobiology of Learning and Memory, 151, 71–84. https://doi.org/10.1016/j.nlm.2018.04.010.
Patel, S., & Hillard, C. J. (2006). Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. The Journal of pharmacology and experimental therapeutics, 318(1), 304–311. https://doi.org/10.1124/jpet.106.101287.
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A., & Kingsford, C. (2017). Salmon: Fast and bias‐aware quantification of transcript expression using dual‐phase inference. Nature Methods, 14, 417.
Pennington, Z. T., Diego, K. S., Francisco, T. R., LaBanca, A. R., Lamsifer, S. I., Liobimova, O., Shuman, T., & Cai, D. J. (2021). EzTrack—A step‐by‐step guide to behavior tracking. Current Protocols, 1, e255.
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., Emerson, M., Garner, P., Holgate, S. T., Howells, D. W., Karp, N. A., Lazic, S. E., Lidster, K., MacCallum, C. J., Macleod, M., … Würbel, H. (2020). The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biology, 18, e3000410. https://doi.org/10.1371/journal.pbio.3000410.
Pérez‐Rodríguez, M., Arroyo‐García, L. E., Prius‐Mengual, J., Andrade‐Talavera, Y., Armengol, J. A., Pérez‐Villegas, E. M., Duque‐Feria, P., Flores, G., & Rodríguez‐Moreno, A. (2019). Adenosine receptor‐mediated developmental loss of spike timing‐dependent depression in the hippocampus. Cerebral Cortex, 29, 3266–3281. https://doi.org/10.1093/cercor/bhy194.
Puighermanal, E., Marsicano, G., Busquets‐Garcia, A., Lutz, B., Maldonado, R., & Ozaita, A. (2009). Cannabinoid modulation of hippocampal long‐term memory is mediated by mTOR signaling. Nature Neuroscience, 12, 1152–1158.
Qi, X., Zhang, K., Xu, T., Yamaki, V. N., Wei, Z., Huang, M., Rose, G. M., & Cai, X. (2016). Sex differences in long‐term potentiation at temporoammonic‐CA1 synapses: Potential implications for memory consolidation. PLoS ONE, 11, e0165891. https://doi.org/10.1371/journal.pone.0165891.
Reibaud, M., Obinu, M. C., Ledent, C., Parmentier, M., Böhme, G. A., & Imperato, A. (1999). Enhancement of memory in cannabinoid CB1 receptor knock‐out mice. European Journal of Pharmacology, 379, R1–R2. https://doi.org/10.1016/S0014-2999(99)00496–3.
Roberts, C. J., & Hillard, C. J. (2020). Peripherally restricted cannabinoid type 1 receptor (CB1R) antagonist, AM6545, potentiates stress‐induced hypothalamic–pituitary–adrenal axis activation via a non‐CB1R mechanism. Endocrine, 72, 297–300.
Roozendaal, B., McEwen, B. S., & Chattarji, S. (2009). Stress, memory and the amygdala. Nature Reviews. Neuroscience, 10, 423–433. https://doi.org/10.1038/nrn2651.
Rouach, N., Byrd, K., Petralia, R. S., Elias, G. M., Adesnik, H., Tomita, S., Karimzadegan, S., Kealey, C., Bredt, D. S., & Nicoll, R. A. (2005). TARP γ‐8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nature Neuroscience, 8, 1525–1533. https://doi.org/10.1038/nn1551.
Salgado‐Mendialdúa, V., Aguirre‐Plans, J., Guney, E., Reig‐Viader, R., Maldonado, R., Bayés, A., Oliva, B., & Ozaita, A. (2018). Δ9‐tetrahydrocannabinol modulates the proteasome system in the brain. Biochemical Pharmacology, 157, 159–168.
Saxe, M. D., Battaglia, F., Wang, J.‐W., Malleret, G., David, D. J., Monckton, J. E., Garcia, A. D. R., Sofroniew, M. V., Kandel, E. R., Santarelli, L., Hen, R., & Drew, M. R. (2006). Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proceedings of the National Academy of Sciences, 103, 17501–17506. https://doi.org/10.1073/pnas.0607207103.
Sengar, A. S., Li, H., Zhang, W., Leung, C., Ramani, A. K., Saw, N. M., Wang, Y., Tu, Y. S., Ross, P. J., Scherer, S. W., Ellis, J., Brudno, M., Jia, Z., & Salter, M. W. (2019). Control of long‐term synaptic potentiation and learning by alternative splicing of the NMDA receptor subunit GluN1. Cell Reports, 29, 4285–4294.e5. https://doi.org/10.1016/j.celrep.2019.11.087.
Soneson, C., Love, M. I., & Robinson, M. D. (2016). Differential analyses for RNA‐seq: Transcript‐level estimates improve gene‐level inferences. F1000Res, 4, 1521.
Takahashi, R. N., Pamplona, F. A., & Fernandes, M. S. (2005). The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T‐maze. Neuroscience Letters, 380, 270–275. https://doi.org/10.1016/j.neulet.2005.01.049.
Tam, J., Vemuri, V. K., Liu, J., Bátkai, S., Mukhopadhyay, B., Godlewski, G., Osei‐Hyiaman, D., Ohnuma, S., Ambudkar, S. V., Pickel, J., Makriyannis, A., & Kunos, G. (2010). Peripheral cb1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. Journal of Clinical Investigation, 120, 2953–2966.
Terranova, J. P., Storme, J. J., Lafon, N., Péŕio, A., Rinaldi‐Carmona, M., Le Fur, G., & Soubrie, P. (1996). Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716. Psychopharmacology, 126, 165–172. https://doi.org/10.1007/BF02246352.
Vanhoose, A. M., & Winder, D. G. (2003). NMDA and beta1‐adrenergic receptors differentially signal phosphorylation of glutamate receptor type 1 in area CA1 of hippocampus. The Journal of Neuroscience, 23, 5827–5834. https://doi.org/10.1523/JNEUROSCI.23-13-05827.2003.
Wolff, M. C., & Leander, J. D. (2003). SR141716A, a cannabinoid CB1 receptor antagonist, improves memory in a delayed radial maze task. European Journal of Pharmacology, 477, 213–217. https://doi.org/10.1016/j.ejphar.2003.08.025.
Xu, X., Jiang, S., Xu, E., Wu, X., & Zhao, R. (2019). Inhibition of CB1 receptor ameliorates spatial learning and memory impairment in mice with traumatic brain injury. Neuroscience Letters, 696, 127–131. https://doi.org/10.1016/j.neulet.2018.12.024.
Yang, C., Liu, J.‐F., Chai, B.‐S., Fang, Q., Chai, N., Zhao, L.‐Y., Xue, Y. X., Luo, Y. X., Jian, M., Han, Y., Shi, H. S., Lu, L., Wu, P., & Wang, J. S. (2013). Stress within a restricted time window selectively affects the persistence of long‐term memory. PLoS ONE, 8, e59075. https://doi.org/10.1371/journal.pone.0059075.
Yu, G., Wang, L. G., Han, Y., & He, Q. Y. (2012). clusterProfiler: An R package for comparing biological themes among gene clusters. Omics, 16, 284–287. https://doi.org/10.1089/omi.2011.0118.
Zanettini, C., Panlilio, L. V., Alicki, M., Goldberg, S. R., Haller, J., & Yasar, S. (2011). Effects of endocannabinoid system modulation on cognitive and emotional behavior. Frontiers in Behavioral Neuroscience, 5, 57.
Alexander, S. P. H., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., & Davies, J. A. (2023). The concise guide to PHARMACOLOGY 2023/24: G protein‐coupled receptors. British Journal of Pharmacology, 180, S23–S144.
Alexander, S. P. H., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Buneman, O. P., Faccenda, E., Harding, S. D., Spedding, M., & Cidlowski, J. A. (2023). The concise guide to pharmacology 2023/24: Introduction and other protein targets. British Journal of Pharmacology, 180, S1–S22.
Alexander, S. P. H., Mathie, A. A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Aldrich, R. W., Attali, B., Baggetta, A. M., Becirovic, E., Biel, M., Bill, R. M., Caceres, A. I., Catterall, W. A., Conner, A. C., … Zhu, M. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. British Journal of Pharmacology, 180(Suppl 2), S145–S222. https://doi.org/10.1111/bph.16181.
Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Mangum, J., Wonnacott, S., & Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology. British Journal of Pharmacology, 175, 407–411. https://doi.org/10.1111/bph.14112.
Arguello, P. A., & Jentsch, J. D. (2004). Cannabinoid CB1 receptor‐mediated impairment of visuospatial attention in the rat. Psychopharmacology, 177, 141–150. https://doi.org/10.1007/s00213-004-1953-0.
Barna, I., Soproni, K., Arszovszki, A., Csabai, K., & Haller, J. (2007). WIN‐55,212–2 chronically implanted into the CA3 region of the dorsal hippocampus impairs learning: A novel method for studying chronic, brain‐area‐specific effects of cannabinoids. Behavioural Pharmacology, 18, 515–520. https://doi.org/10.1097/FBP.0b013e3282d9e9f9.
Beletskiy, A., Zolotar, A., Fortygina, P., Chesnokova, E., Uroshlev, L., Balaban, P., & Kolosov, P. (2024). Downregulation of ribosomal protein genes is revealed in a model of rat hippocampal neuronal culture activation with GABA(A)R/GlyRa2 antagonist Picrotoxin. Cells, 13, 383. https://doi.org/10.3390/cells13050383.
Borrie, S. C., Brems, H., Legius, E., & Bagni, C. (2017). Cognitive dysfunctions in intellectual disabilities: The Contributions of the Ras‐MAPK and PI3K‐AKT‐mTOR pathways. Annual Review of Genomics and Human Genetics, 18, 115–142. https://doi.org/10.1146/annurev-genom-091416–035332.
Bridi, M., Schoch, H., Florian, C., Poplawski, S. G., Banerjee, A., Hawk, J. D., Porcari, G. S., Lejards, C., Hahn, C. G., Giese, K. P., Havekes, R., Spruston, N., & Abel, T. (2020). Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling. JCI Insight, 5, e92385. https://doi.org/10.1172/jci.insight.92385.
Butler, C. W., Keiser, A. A., Kwapis, J. L., Berchtold, N. C., Wall, V. L., Wood, M. A., & Cotman, C. W. (2019). Exercise opens a temporal window for enhanced cognitive improvement from subsequent physical activity. Learning & Memory, 26, 485–492. https://doi.org/10.1101/lm.050278.119.
Curtis, M. J., Alexander, S. P. H., Cirino, G., George, C. H., Kendall, D. A., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Patel, H. H., Sobey, C. G., Stanford, S. C., Stanley, P., Stefanska, B., Stephens, G. J., Teixeira, M. M., Vergnolle, N., & Ahluwalia, A. (2022). Planning experiments: Updated guidance on experimental design and analysis and their reporting III. British Journal of Pharmacology, 179, 3907–3913. https://doi.org/10.1111/bph.15868.
Da Silva, G. E., & Takahashi, R. N. (2002). SR 141716A prevents Δ9‐tetrahydrocannabinol‐induced spatial learning deficit in a Morris‐type water maze in mice. Progress in Neuro‐Psychopharmacology & Biological Psychiatry, 26, 321–325. https://doi.org/10.1016/S0278-5846(01)00275–5.
Dupret, D., Revest, J.‐M., Koehl, M., Ichas, F., De Giorgi, F., Costet, P., Abrous, D. N., & Piazza, P. V. (2008). Spatial relational memory requires hippocampal adult neurogenesis. PLoS ONE, 3, e1959. https://doi.org/10.1371/journal.pone.0001959.
Falcón‐Moya, R., Martínez‐Gallego, I., & Rodríguez‐Moreno, A. (2021). Kainate receptor modulation of glutamatergic synaptic transmission in the CA2 region of the hippocampus. Journal of Neurochemistry, 158, 1083–1093.
Gibon, J., & Barker, P. A. (2017). Neurotrophins and proneurotrophins: Focus on synaptic activity and plasticity in the brain. The Neuroscientist, 23, 587–604. https://doi.org/10.1177/1073858417697037.
Gomis‐González, M., Galera‐López, L., Ten‐Blanco, M., Busquets‐Garcia, A., Cox, T., Maldonado, R., & Ozaita, A. (2021). Protein kinase C‐gamma knockout mice show impaired hippocampal short‐term memory while preserved long‐term memory. Molecular Neurobiology, 58, 617–630. https://doi.org/10.1007/s12035-020-02135-6.
Hafner, A. S., Donlin‐Asp, P. G., Leitch, B., Herzog, E., & Schuman, E. M. (2019). Local protein synthesis is a ubiquitous feature of neuronal pre‐ and postsynaptic compartments. Science (New York, N.Y.), 364(6441), eaau3644. https://doi.org/10.1126/science.aau3644.
Horner, A. E., Heath, C. J., Hvoslef‐Eide, M., Kent, B. A., Kim, C. H., Nilsson, S. R. O., Alsiö, J., Oomen, C. A., Holmes, A., Saksida, L. M., & Bussey, T. J. (2013). The touchscreen operant platform for testing learning and memory in rats and mice. Nature Protocols, 8, 1961–1984. https://doi.org/10.1038/nprot.2013.122.
Ishac, E. J. N., Jiang, L., Lake, K. D., Varga, K., Abood, M. E., & Kunos, G. (1996). Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. British Journal of Pharmacology, 118, 2023–2028. https://doi.org/10.1111/j.1476–5381.1996.tb15639.x.
Jessberger, S., Clark, R. E., Broadbent, N. J., Clemenson, G. D., Consiglio, A., Lie, D. C., Squire, L. R., & Gage, F. H. (2009). Dentate gyrus‐specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learning & Memory, 16(2), 147–154. https://doi.org/10.1101/lm.1172609.
Joiner, M. A., Lisé, M.‐F., Yuen, E. Y., Kam, A. Y. F., Zhang, M., Hall, D. D., Malik, Z. A., Qian, H., Chen, Y., Ulrich, J. D., & Burette, A. C. (2010). Assembly of a beta2‐adrenergic receptor‐‐gluR1 signalling complex for localized cAMP signalling. The EMBO Journal, 29, 482–495.
Kale, V. P., Gibbs, S., Taylor, J. A., Zmarowski, A., Novak, J., Patton, K., Sparrow, B., Gorospe, J., Anand, S., Cinar, R., Kunos, G., Chorvat, R. J., & Terse, P. S. (2019). Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis. Regulatory Toxicology and Pharmacology, 109, 104483. https://doi.org/10.1016/j.yrtph.2019.104483.
King, S. O., & Williams, C. L. (2009). Novelty‐induced arousal enhances memory for cued classical fear conditioning: Interactions between peripheral adrenergic and brainstem glutamatergic systems. Learning & Memory, 16, 625–634.
Kruk‐Slomka, M., & Biala, G. (2016). CB1 receptors in the formation of the different phases of memory‐related processes in the inhibitory avoidance test in mice. Behavioural Brain Research, 301, 84–95. https://doi.org/10.1016/j.bbr.2015.12.023.
Lilley, E., Stanford, S. C., Kendall, D. E., Alexander, S. P. H., Cirino, G., Docherty, J. R., George, C. H., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Sobey, C. G., Stefanska, B., Stephens, G., Teixeira, M., & Ahluwalia, A. (2020). ARRIVE 2.0 and the British Journal of pharmacology: Updated guidance for 2020. British Journal of Pharmacology, 177, 3611–3616. https://doi.org/10.1111/bph.15178.
Lim, Y., Wu, L. L. Y., Chen, S., Sun, Y., Vijayaraj, S. L., Yang, M., Bobrovskaya, L., Keating, D., Li, X. J., & Zhou, X. F. (2018). HAP1 is required for endocytosis and signalling of BDNF and its receptors in neurons. Molecular Neurobiology, 55, 1815–1830. https://doi.org/10.1007/s12035-016-0379-0.
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real‐time quantitative PCR and the 2−ΔΔCT method. Methods, 25, 402–408. https://doi.org/10.1006/meth.2001.1262.
Love, M. I., Huber, W., & Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA‐seq data with DESeq2. Genome Biology, 15, 550. https://doi.org/10.1186/s13059-014-0550-8.
Maccarrone, M., Valverde, O., Barbaccia, M. L., Castañé, A., Maldonado, R., Ledent, C., Parmentier, M., & Finazzi‐Agrò, A. (2002). Age‐related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: Correlation with behaviour. The European Journal of Neuroscience, 15, 1178–1186.
Marsicano, G., Wotjak, C. T., Azad, S. C., Bisogno, T., Rammes, G., Cascioll, M. G., Hermann, H., Tang, J., Hofmann, C., Zieglgänsberger, W., Di Marzo, V., & Lutz, B. (2002). The endogenous cannabinoid system controls extinction of aversive memories. Nature, 418, 530–534.
Martínez‐Torres, S., Bergadà‐Martínez, A., Ortega, J. E., Galera‐López, L., Hervera, A., los, de Reyes‐Ramírez, L., Ortega‐Álvaro, A., Remmers, F., Muñoz‐Moreno, E., Soria, G., & Del Río, J. A. (2023). Peripheral CB1 receptor blockade acts as a memory enhancer through a noradrenergic mechanism. Neuropsychopharmacology, 48, 341–350.
McIntyre, C. K., McGaugh, J. L., & Williams, C. L. (2012). Interacting brain systems modulate memory consolidation. Neuroscience and Biobehavioral Reviews, 36, 1750–1762. https://doi.org/10.1016/j.neubiorev.2011.11.001.
Merlo, S. A., Belluscio, M. A., Pedreira, M. E., & Merlo, E. (2024). Memory persistence: From fundamental mechanisms to translational opportunities. Translational Psychiatry, 14, 98. https://doi.org/10.1038/s41398-024-02808-z.
Monfort, P., & Felipo, V. (2007). Hippocampal long‐term potentiation is reduced in mature compared to young male rats but not in female rats. Neuroscience, 146, 504–508. https://doi.org/10.1016/j.neuroscience.2007.02.008.
Morris, R. G. M. (2006). Elements of a neurobiological theory of hippocampal function: The role of synaptic plasticity, synaptic tagging and schemas. The European Journal of Neuroscience, 23, 2829–2846. https://doi.org/10.1111/j.1460–9568.2006.04888.x.
Navarro‐Romero, A., Galera‐López, L., Ortiz‐Romero, P., Llorente‐Ovejero, A., los, de Reyes‐Ramírez, L., de Tena, I. B., Garcia‐Elias, A., Mas‐Stachurska, A., Reixachs‐Solé, M., Pastor, A., & De La Torre, R. (2022). Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams‐Beuren syndrome. eLife, 11, e72560.
Navarro‐Romero, A., Vázquez‐Oliver, A., Gomis‐González, M., Garzón‐Montesinos, C., Falcón‐Moya, R., Pastor, A., Martín‐García, E., Pizarro, N., Busquets‐Garcia, A., Revest, J. M., Piazza, P. V., Bosch, F., Dierssen, M., de la Torre, R., Rodríguez‐Moreno, A., Maldonado, R., & Ozaita, A. (2019). Cannabinoid type‐1 receptor blockade restores neurological phenotypes in two models for down syndrome. Neurobiology of Disease, 125, 92–106. https://doi.org/10.1016/j.nbd.2019.01.014.
Niederhoffer, N., Hansen, H. H., Fernandez‐Ruiz, J. J., & Szabo, B. (2001). Effects of cannabinoids on adrenaline release from adrenal medullary cells. British Journal of Pharmacology, 134, 1319–1327. https://doi.org/10.1038/sj.bjp.0704359.
Oh, M. C., Derkach, V. A., Guire, E. S., & Soderling, T. R. (2006). Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long‐term potentiation. Journal of Biological Chemistry, 281, 752–758. https://doi.org/10.1074/jbc.M509677200.
Ohno‐Shosaku, T., & Kano, M. (2014). Endocannabinoid‐mediated retrograde modulation of synaptic transmission. Current Opinion in Neurobiology, 29, 1–8. https://doi.org/10.1016/j.conb.2014.03.017.
Pacher, P., Bátkai, S., & Kunos, G. (2006). The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews, 58, 389–462. https://doi.org/10.1124/pr.58.3.2.
Pamplona, F. A., & Takahashi, R. N. (2006). WIN 55212‐2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors. Neuroscience Letters, 397, 88–92. https://doi.org/10.1016/j.neulet.2005.12.026.
Papaleonidopoulos, V., & Papatheodoropoulos, C. (2018). β‐Adrenergic receptors reduce the threshold for induction and stabilization of LTP and enhance its magnitude via multiple mechanisms in the ventral but not the dorsal hippocampus. Neurobiology of Learning and Memory, 151, 71–84. https://doi.org/10.1016/j.nlm.2018.04.010.
Patel, S., & Hillard, C. J. (2006). Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. The Journal of pharmacology and experimental therapeutics, 318(1), 304–311. https://doi.org/10.1124/jpet.106.101287.
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A., & Kingsford, C. (2017). Salmon: Fast and bias‐aware quantification of transcript expression using dual‐phase inference. Nature Methods, 14, 417.
Pennington, Z. T., Diego, K. S., Francisco, T. R., LaBanca, A. R., Lamsifer, S. I., Liobimova, O., Shuman, T., & Cai, D. J. (2021). EzTrack—A step‐by‐step guide to behavior tracking. Current Protocols, 1, e255.
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., Emerson, M., Garner, P., Holgate, S. T., Howells, D. W., Karp, N. A., Lazic, S. E., Lidster, K., MacCallum, C. J., Macleod, M., … Würbel, H. (2020). The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biology, 18, e3000410. https://doi.org/10.1371/journal.pbio.3000410.
Pérez‐Rodríguez, M., Arroyo‐García, L. E., Prius‐Mengual, J., Andrade‐Talavera, Y., Armengol, J. A., Pérez‐Villegas, E. M., Duque‐Feria, P., Flores, G., & Rodríguez‐Moreno, A. (2019). Adenosine receptor‐mediated developmental loss of spike timing‐dependent depression in the hippocampus. Cerebral Cortex, 29, 3266–3281. https://doi.org/10.1093/cercor/bhy194.
Puighermanal, E., Marsicano, G., Busquets‐Garcia, A., Lutz, B., Maldonado, R., & Ozaita, A. (2009). Cannabinoid modulation of hippocampal long‐term memory is mediated by mTOR signaling. Nature Neuroscience, 12, 1152–1158.
Qi, X., Zhang, K., Xu, T., Yamaki, V. N., Wei, Z., Huang, M., Rose, G. M., & Cai, X. (2016). Sex differences in long‐term potentiation at temporoammonic‐CA1 synapses: Potential implications for memory consolidation. PLoS ONE, 11, e0165891. https://doi.org/10.1371/journal.pone.0165891.
Reibaud, M., Obinu, M. C., Ledent, C., Parmentier, M., Böhme, G. A., & Imperato, A. (1999). Enhancement of memory in cannabinoid CB1 receptor knock‐out mice. European Journal of Pharmacology, 379, R1–R2. https://doi.org/10.1016/S0014-2999(99)00496–3.
Roberts, C. J., & Hillard, C. J. (2020). Peripherally restricted cannabinoid type 1 receptor (CB1R) antagonist, AM6545, potentiates stress‐induced hypothalamic–pituitary–adrenal axis activation via a non‐CB1R mechanism. Endocrine, 72, 297–300.
Roozendaal, B., McEwen, B. S., & Chattarji, S. (2009). Stress, memory and the amygdala. Nature Reviews. Neuroscience, 10, 423–433. https://doi.org/10.1038/nrn2651.
Rouach, N., Byrd, K., Petralia, R. S., Elias, G. M., Adesnik, H., Tomita, S., Karimzadegan, S., Kealey, C., Bredt, D. S., & Nicoll, R. A. (2005). TARP γ‐8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nature Neuroscience, 8, 1525–1533. https://doi.org/10.1038/nn1551.
Salgado‐Mendialdúa, V., Aguirre‐Plans, J., Guney, E., Reig‐Viader, R., Maldonado, R., Bayés, A., Oliva, B., & Ozaita, A. (2018). Δ9‐tetrahydrocannabinol modulates the proteasome system in the brain. Biochemical Pharmacology, 157, 159–168.
Saxe, M. D., Battaglia, F., Wang, J.‐W., Malleret, G., David, D. J., Monckton, J. E., Garcia, A. D. R., Sofroniew, M. V., Kandel, E. R., Santarelli, L., Hen, R., & Drew, M. R. (2006). Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proceedings of the National Academy of Sciences, 103, 17501–17506. https://doi.org/10.1073/pnas.0607207103.
Sengar, A. S., Li, H., Zhang, W., Leung, C., Ramani, A. K., Saw, N. M., Wang, Y., Tu, Y. S., Ross, P. J., Scherer, S. W., Ellis, J., Brudno, M., Jia, Z., & Salter, M. W. (2019). Control of long‐term synaptic potentiation and learning by alternative splicing of the NMDA receptor subunit GluN1. Cell Reports, 29, 4285–4294.e5. https://doi.org/10.1016/j.celrep.2019.11.087.
Soneson, C., Love, M. I., & Robinson, M. D. (2016). Differential analyses for RNA‐seq: Transcript‐level estimates improve gene‐level inferences. F1000Res, 4, 1521.
Takahashi, R. N., Pamplona, F. A., & Fernandes, M. S. (2005). The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T‐maze. Neuroscience Letters, 380, 270–275. https://doi.org/10.1016/j.neulet.2005.01.049.
Tam, J., Vemuri, V. K., Liu, J., Bátkai, S., Mukhopadhyay, B., Godlewski, G., Osei‐Hyiaman, D., Ohnuma, S., Ambudkar, S. V., Pickel, J., Makriyannis, A., & Kunos, G. (2010). Peripheral cb1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. Journal of Clinical Investigation, 120, 2953–2966.
Terranova, J. P., Storme, J. J., Lafon, N., Péŕio, A., Rinaldi‐Carmona, M., Le Fur, G., & Soubrie, P. (1996). Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716. Psychopharmacology, 126, 165–172. https://doi.org/10.1007/BF02246352.
Vanhoose, A. M., & Winder, D. G. (2003). NMDA and beta1‐adrenergic receptors differentially signal phosphorylation of glutamate receptor type 1 in area CA1 of hippocampus. The Journal of Neuroscience, 23, 5827–5834. https://doi.org/10.1523/JNEUROSCI.23-13-05827.2003.
Wolff, M. C., & Leander, J. D. (2003). SR141716A, a cannabinoid CB1 receptor antagonist, improves memory in a delayed radial maze task. European Journal of Pharmacology, 477, 213–217. https://doi.org/10.1016/j.ejphar.2003.08.025.
Xu, X., Jiang, S., Xu, E., Wu, X., & Zhao, R. (2019). Inhibition of CB1 receptor ameliorates spatial learning and memory impairment in mice with traumatic brain injury. Neuroscience Letters, 696, 127–131. https://doi.org/10.1016/j.neulet.2018.12.024.
Yang, C., Liu, J.‐F., Chai, B.‐S., Fang, Q., Chai, N., Zhao, L.‐Y., Xue, Y. X., Luo, Y. X., Jian, M., Han, Y., Shi, H. S., Lu, L., Wu, P., & Wang, J. S. (2013). Stress within a restricted time window selectively affects the persistence of long‐term memory. PLoS ONE, 8, e59075. https://doi.org/10.1371/journal.pone.0059075.
Yu, G., Wang, L. G., Han, Y., & He, Q. Y. (2012). clusterProfiler: An R package for comparing biological themes among gene clusters. Omics, 16, 284–287. https://doi.org/10.1089/omi.2011.0118.
Zanettini, C., Panlilio, L. V., Alicki, M., Goldberg, S. R., Haller, J., & Yasar, S. (2011). Effects of endocannabinoid system modulation on cognitive and emotional behavior. Frontiers in Behavioral Neuroscience, 5, 57.
Grant Information:
PID2021-123482OB-I00 Ministerio de Ciencia e Innovación; PID2019-107677GB-I00 Agencia Estatal de Investigación; PID2022-136597NB-I00 Agencia Estatal de Investigación; P20-0881 Junta de Andalucía; 2021 SGR 00912 Agència de Gestió d'Ajuts Universitaris i de Recerca
Contributed Indexing:
Keywords: CB1 receptor; cognitive enhancement; hippocampal synaptic plasticity; peripheral‐to‐central
Substance Nomenclature:
0 (Receptor, Cannabinoid, CB1)
Entry Date(s):
Date Created: 20250319 Date Completed: 20250604 Latest Revision: 20250604
Update Code:
20260130
DOI:
10.1111/bph.70015
PMID:
40102206
Database:
MEDLINE
*Further Information*
*Background and Purpose: There is evidence of crosstalk between the brain and peripheral tissues. However, how the periphery contributes to brain function is not well understood. The cannabinoid CB <subscript>1</subscript> receptor is classically pictured to have a relevant role in cognitive function. We previously demonstrated a novel mechanism where acute administration of the CB <subscript>1</subscript> receptor antagonist AM6545, largely restricted to the periphery, prolonged memory persistence in mice. Here, we have assessed the effects of repeated exposure to AM6545 on cognitive improvements.
Experimental Approach: We evaluated, in young adult male and female mice, the behavioural consequences of sub-chronic treatment with AM6545. An unbiased transcriptomic analysis, as well as electrophysiological and biochemical studies, was carried out to elucidate the central cellular and molecular consequences of such action at peripheral receptors.
Key Results: Sub-chronic AM6545 enhanced memory in low and high arousal conditions in male and female mice. Executive function was facilitated after repeated AM6545 administration in male mice. Transcriptional analysis of hippocampal synaptoneurosomes from treated mice revealed a preliminary, sex-dependent, modulation of synaptic transcripts by AM6545. Notably, AM6545 occluded long-term potentiation in CA3-CA1 synapses while enhancing input-output relation in male mice. This was accompanied by an increase in hippocampal expression of Bdnf and Ngf.
Conclusion and Implications: Our results showed that repeated administration of AM6545 contributed to the modulation of memory persistence, executive function and hippocampal synaptic plasticity in mice, further indicating that peripheral CB <subscript>1</subscript> receptors could act as a target for a novel class of nootropic compounds.
(© 2025 British Pharmacological Society.)*