Anxiety, stress, and fear response in mice with reduced endocannabinoid levels
Abstract
Background Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB1 receptors has been linked to depression in humans and depression-like behaviors in mice. The two main endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), are produced on demand from phospholipids. The pathways and enzymes involved in endocannabinoid biosynthesis thus play a major role in regulating the activity of this system. This study investigates the role of the main 2-AG producing enzyme diacylglycerol lipase α (DAGL-α).Methods We generated and used knockout mice lacking DAGL-α (Dagla(-/-)) to assess the behavioral consequences of reduced endocannabinoid levels in the brain. We performed different behavior tests to determine anxiety- and depression-related behavioral changes in Dagla(-/-) mice. We also analyzed expression of genes related to the endocannabinoid system via real-time polymerase chain reaction and used the mitotic marker 5-bromo-2'-deoxyuridine to analyze adult neurogenesis.Results Dagla(-/-) animals show an 80% reduction of brain 2-AG levels but also a reduction in cortical and amygdalar anandamide. The behavioral changes induced by Dagla deletion include a reduced exploration of the central area of the open field, a maternal neglect behavior, a fear extinction deficit, increased behavioral despair, increased anxiety-related behaviors in the light/dark box, and reduced hippocampal neurogenesis. Some of these behavioral changes resemble those observed in animals lacking the CB1 receptor.Conclusions Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses.
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In mice lacking the 2-AG synthesising enzyme diacylglycerol lipase, anxiety-related behaviour is enhanced.
“and in mice lacking the 2-AG synthesising enzyme diacylglycerol lipase anxiety-related behaviour is enhanced (Jenniches et al., 2016;Shonesy et al., 2014).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Jenniches et al., 2016
Mice with genetic deletion of DAGL and reductions in 2-AG signaling show increases in anxiety-like behavior.
“in mice with genetic deletion of DALG and reductions in 2-AG signaling, increases in anxiety-like behavior are evident (Jenniches et al., 2016; Shonesy et al., 2014).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Jenniches et al., 2016
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Kessler, R. C., Chiu, W. T., Demler, O., & Walters, E. E. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.617 · Cited by 12,052 · see citing works
THE EFFECTS OF STRESSFUL LIFE EVENTS ON DEPRESSION
Kessler, R. C. (1997) · Annual Review of Psychology · doi:10.1146/annurev.psych.48.1.191 · Cited by 2,111 · see citing works
Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms
Pittenger, C., & Duman, R. S. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301574 · Cited by 1,795 · see citing works
The 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
Self-citationMyers, K. M., & Davis, M. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001939 · Cited by 1,277 · see citing works
Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials
Christensen, R., Kristensen, P. K., Bartels, E. M., Bliddal, H., & Astrup, A. (2007) · The Lancet · doi:10.1016/s0140-6736(07)61721-8 · Cited by 1,097 · see citing works
The endocannabinoid system and its therapeutic exploitation
Marzo, V. D., Bifulco, M., & Petrocellis, L. D. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1495 · Cited by 1,090 · see citing works
Bisogno, T., Howell, F., Williams, G., Minassi, A., Cascio, M. G., Ligresti, A., Matias, I., Schiano-Moriello, A., Paul, P., Williams, E.-J., et al. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200305129 · Cited by 1,039 · see citing works
The stress system in the human brain in depression and neurodegeneration
Swaab, D. F., Bao, A.-M., & Lucassen, P. J. (2005) · Ageing Research Reviews · doi:10.1016/j.arr.2005.03.003 · Cited by 984 · see citing works
Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation
Nomura, D. K., Morrison, B. E., Blankman, J. L., Long, J. Z., Kinsey, S. G., Marcondes, M. C. G., Ward, A. M., Hahn, Y. K., Lichtman, A. H., Conti, B., et al. (2011) · Science · doi:10.1126/science.1209200 · Cited by 727 · see citing works
Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system
Schlosburg, J. E., Blankman, J. L., Long, J. Z., Nomura, D. K., Pan, B., Kinsey, S. G., Nguyen, P. T., Ramesh, D., Booker, L., Burston, J. J., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2616 · Cited by 641 · see citing works
Hardwiring the Brain: Endocannabinoids Shape Neuronal Connectivity
Berghuis, P., Rajnicek, A. M., Morozov, Y. M., Ross, R. A., Mulder, J., Urbán, G. M., Monory, K., Marsicano, G., Matteoli, M., Canty, A. J., et al. (2007) · Science · doi:10.1126/science.1137406 · Cited by 551 · see citing works
Self-citationInvolvement of CB1 cannabinoid receptors in emotional behaviour
Martín, M., Ledent, C. A., Parmentier, M., Maldonado, R. J., & Valverde, O. (2002) · Psychopharmacology · doi:10.1007/s00213-001-0946-5 · Cited by 507 · see citing works
Gao, Y., Vasilyev, D. V., Goncalves, M. B., Howell, F. V., Hobbs, C., Reisenberg, M., Shen, R., Zhang, M.-Y., Strassle, B. W., Lu, P., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5693-09.2010 · Cited by 473 · see citing works
Tanimura, A., Yamazaki, M., Hashimotodani, Y., Uchigashima, M., Kawata, S., Abe, M., Kita, Y., Hashimoto, K., Shimizu, T., Watanabe, M., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.01.021 · Cited by 472 · see citing works
Conditional control of gene expression in the mouse
Lewandoski, M. (2001) · Nature reviews genetics · doi:10.1038/35093537 · Cited by 442 · see citing works
Lallemand, Y., Luria, V. A., Haffner‐Krausz, R., & Lonai, P. (1998) · Transgenic Research · doi:10.1023/a:1008868325009 · Cited by 393 · see citing works
Hill, M. N., Miller, G. E., Carrier, E. J., Gorzalka, B. B., & Hillard, C. J. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.03.013 · Cited by 328 · see citing works
Serum Endocannabinoid Content is Altered in Females with Depressive Disorders: A Preliminary Report
Hill, M., Miller, G., Ho, W.-S., Gorzalka, B., & Hillard, C. (2008) · Pharmacopsychiatry · doi:10.1055/s-2007-993211 · Cited by 292 · see citing works
Haller, J., Varga, B., Ledent, C., Barna, I., & Freund, T. F. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03293.x · Cited by 284 · see citing works
Moreira, F. A., Kaiser, N., Monory, K., & Lutz, B. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.07.005 · Cited by 282 · see citing works
Self-citationDifferential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses
Busquets-Garcia, A., Puighermanal, E., Pastor, A., de la Torre, R., Maldonado, R., & Ozaita, A. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.04.022 · Cited by 273 · see citing works
Feil, S. C., Valtcheva, N., & Feil, R. (2009) · Methods in molecular biology · doi:10.1007/978-1-59745-471-1_18 · Cited by 268 · see citing works
Bornstein, S. R., Schuppenies, A., Wong, M., & Licinio, J. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001873 · Cited by 267 · see citing works
The endocannabinoid system in anxiety, fear memory and habituation
Ruehle, S., Rey, A. A., Remmers, F., & Lutz, B. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111408958 · Cited by 236 · see citing works
Self-citationRademacher, D. J., Meier, S. E., Shi, L., Vanessa Ho, W.-S., Jarrahian, A., & Hillard, C. J. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.06.012 · Cited by 233 · see citing works
Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors
Urigüen, L., Pérez-Rial, S., Ledent, C., Palomo, T., & Manzanares, J. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.01.003 · Cited by 218 · see citing works
Cannabinoid CB1 Receptor Mediates Fear Extinction via Habituation-Like Processes
Kamprath, K., Marsicano, G., Tang, J., Monory, K., Bisogno, T., Marzo, V. D., Lutz, B., & Wotjak, C. T. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0153-06.2006 · Cited by 217 · see citing works
Self-citationDepression and Cardiovascular Disease
Rumsfeld, J. S., & Ho, P. M. (2005) · Circulation · doi:10.1161/01.cir.0000154573.62822.89 · Cited by 208 · see citing works
Nonassociative learning processes determine expression and extinction of conditioned fear in micePreprint
Kamprath, K., & Wotjak, C. T. (2004) · Learning & Memory · doi:10.1101/lm.86104 · Cited by 188 · see citing works
Sciolino, N. R., Zhou, W., & Hohmann, A. G. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.04.010 · Cited by 179 · see citing works
Goncalves, M. B. C. V., Suetterlin, P., Yip, P. K., Molina‐Holgado, F., Walker, D. J., Oudin, M. J., Zentar, M. P., Pollard, S. M., Yáñez‐Muñoz, R. J., Williams, G. H., et al. (2008) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2008.05.001 · Cited by 177 · see citing works
Patel, S., & Hillard, C. J. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06266.x · Cited by 162 · see citing works
CB1 receptor-deficient mice as a model for depression
Valverde, O., & Torrens, M. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.09.031 · Cited by 153 · see citing works
Lomazzo, E., Bîndilă, L., Remmers, F., Lerner, R., Schwitter, C., Hoheisel, U., & Lutz, B. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.198 · Cited by 141 · see citing works
Self-citationZhong, P., Wang, W., Pan, B., Liu, X., Zhang, Z., Long, J. Z., Zhang, H., Cravatt, B. F., & Liu, Q.-S. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.24 · Cited by 137 · see citing works
Zhang, Z., Wang, W., Zhong, P., Liu, S. J., Long, J. Z., Zhao, L., Gao, H., Cravatt, B. F., & Liu, Q. (2015) · Hippocampus · doi:10.1002/hipo.22344 · Cited by 89 · see citing works
Bisogno, T., Mahadevan, A., Coccurello, R., Chang, J. W., Allarà, M., Chen, Y., Giacovazzo, G., Lichtman, A. H., Cravatt, B. F., Moles, A., et al. (2012) · British Journal of Pharmacology · doi:10.1111/bph.12013 · Cited by 74 · see citing works
Analysis of the Endocannabinoid System by Using CB1 Cannabinoid Receptor Knockout Mice
Valverde, O., Karsak, M., & Zimmer, A. (2005) · Springer eBooks · doi:10.1007/3-540-26573-2_4 · Cited by 61 · see citing works
Self-citationSmaga, I., Bystrowska, B., Gawliński, D., Pomierny, B., Stankowicz, P., & Filip, M. (2014) · Neurotoxicity Research · doi:10.1007/s12640-014-9465-0 · Cited by 61 · see citing works
Schechter, M., Pinhasov, A., Weller, A., & Fride, E. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.10.016 · Cited by 38 · see citing works
Gorzalka, B. B., & Hill, M. N. (2009) · Current topics in behavioral neurosciences · doi:10.1007/978-3-540-88955-7_12 · Cited by 37 · see citing works
Schechter, M., Weller, A., Pittel, Z., Gross, M., Zimmer, A., & Pinhasov, A. (2013) · Journal of Neuroendocrinology · doi:10.1111/jne.12082 · Cited by 23 · see citing works
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Lutz, B., Marsicano, G., Maldonado, R., & Hillard, C. J. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn4036 · Cited by 506 · see citing works
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Garcia, R. (2017) · Learning & Memory · doi:10.1101/lm.044115.116 · Cited by 239 · see citing works
Sartori, S. B., & Singewald, N. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107402 · Cited by 236 · see citing works
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Maccarrone, M., Di Marzo, V., Gertsch, J., Grether, U., Howlett, A. C., Hua, T., Makriyannis, A., Piomelli, D., Ueda, N., & van der Stelt, M. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000600 · Cited by 183 · see citing works
Locci, A., & Pinna, G. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13843 · Cited by 132 · see citing works
Bosch-Bouju, C., Larrieu, T., Linders, L., Manzoni, O. J., & Layé, S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.082 · Cited by 100 · see citing works
Schneider, P., Bindila, L., Schmahl, C., Bohus, M., Meyer-Lindenberg, A., Lutz, B., Spanagel, R., & Schneider, M. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00203 · Cited by 89 · see citing works
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Lisboa, S. F., Vila-Verde, C., Rosa, J., Uliana, D. L., Stern, C. A. J., Bertoglio, L. J., Resstel, L. B., & Guimaraes, F. S. (2019) · Psychopharmacology · doi:10.1007/s00213-018-5127-x · Cited by 54 · see citing works
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- Authors
- Jenniches, I., Ternes, S., Albayram, O., Otte, D. M., Bach, K., Bindila, L., Michel, K., Lutz, B., Bilkei-Gorzo, A., & Zimmer, A.
- Affiliations
- University of Bonn (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Zimmer, Andreas
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 79
- Issue
- 10
- Pages
- 858-868
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2041094930
- Cited by
- 169
- References
- 44
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 12 · 2023: 11 · 2022: 20 · 2021: 27 · 2020: 17 · 2019: 12 · 2018: 11 · 2017: 17 · 2016: 18 · 2015: 7
- FWCI
- 12.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- endocannabinoid system, diacylglycerol lipase alpha, 2-arachidonoylglycerol, anandamide, CB1 receptor, anxiety, depression-like behavior, fear extinction, maternal neglect, hippocampal neurogenesis, stress response, amygdala, open field exploration, behavioral despair
- MeSH terms
- Animals, Anxiety, Brain, Exploratory Behavior, Extinction, Psychological, Fear, Female, Lipoprotein Lipase, Male, Maternal Behavior, Mice, Inbred C57BL, Motor Activity, Social Behavior, Stress, Psychological, Cohort Studies, Mice, Knockout, Neurogenesis, Endocannabinoids
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