Chronic Cannabis Extract Modulates Anxiety Behavior in Wistar Rats: VTA Histology and Catecholamine Analysis
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Abstract
Cannabis, derived from the Cannabis sativa plant, has seen a surge in global use, particularly in medicinal and recreational contexts, over the past decade. The VTA, a critical component of the brain’s reward system, plays a pivotal role in motivation and addiction through its dopaminergic pathways. While research has examined the behavioral and neurochemical effects of cannabis, there is limited exploration of cannabis-induced histological changes in the VTA, thus, this study investigated the effects of chronic cannabis ethanol extract exposure on anxiety behavior, ventral tegmental area (VTA) histology, and catecholamine levels in Wistar rats. Using the Elevated Plus Maze (EPM) test, anxiety behavior was assessed across four groups exposed to varying doses (0, 50, 100, and 150 mg/kg) of cannabis extract. Histological analysis of the VTA and catecholamine quantification were conducted to evaluate structural and biochemical changes. Behavioral results indicated dose-dependent increases in anxiety, with Group 3 (100 mg/kg) showing the highest anxiety-related behaviors, evidenced by reduced open-arm exploration and increased closed-arm preference (p < 0.05). Histological analysis revealed fatty changes and inflammatory cell infiltration in the VTA, with severity increasing at higher doses. Catecholamine levels declined dose-dependent (p < 0.05), suggesting suppressed neurotransmitter synthesis or metabolism. These findings align with previous reports of cannabis-induced neurotoxicity and its biphasic effects on anxiety, extending understanding of its behavioral, structural, and biochemical impacts. The results highlight the potential risks of chronic cannabis use, particularly at higher doses, on anxiety regulation and neural integrity in the VTA.
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References
I. Allain CC, Poon LS, Chan CS, Richmond W and Fu PC, (1974). Enzymatic determination of total serum cholesterol. Clinical Chemistry, 20 (19):470-475.
II. Beier, K. T., Xie, S., Gao, X. J., DeLoach, K. E., Malenka, R. C., & Luo, L. (2019). Topological organization of ventral tegmental area connectivity revealed by viral-genetic dissection of input-output relations. Cell Reports, 26(1), 1-9.
III. Blessing, E. M., Steenkamp, M. M., Manzanares, J., & Marmar, C. R. (2015). Cannabidiol is a potential treatment for anxiety disorders. Neurotherapeutics, 12(4), 825-836.
IV. Bloomfield, M. A. P., Ashok, A. H., Volkow, N. D., & Howes, O. D. (2016). The effects of cannabis on the dopamine system. Nature, 539(7629), 369–377.
V. Bouarab, C., Rancillac, A., Monier, C., & Hamon, M. (2019). VTA GABAergic neurons and their modulation of reward pathways. Journal of Neuroscience, 39(1), 123-138.
VI. Brown, A., & Thompson, C. (2019). The role of the Ventral Tegmental Area in reward processing. Journal of Neuroscience, 43(2), 123-135.
VII. Cassano Tommaso, Calcagnini Silvio, Pace Lorenzo, Marco Federico De, Romano Adele and Gaetani Silvana, (2017).Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target. Frontiers in Neuroscience, 11:30.
VIII. Cohen Koby, Weizman Abraham, Weinstein Aviv, (2019). Modulatory effects of cannabinoids on brain neurotransmission. European Journal of Neuroscience, 50(3):2322-2345.
IX. Davis, M., & Kim, H. (2021). Cannabinoid effects on dopamine: Implications for reward. Neuropsychopharmacology, 46(7), 1054-1067.
X. Dong Mei-xue, Chen Guang-Hui, Hu Ling, (2020). Dopaminergic System Alteration in Anxiety and Compulsive Disorders: A Systematic Review of Neuroimaging Studies. Frontiers in Neuroscience, 14:608520.
XI. Gonzalez-Cuevas, Gabriel, Tostes, Ricardo C., Moreira, Fabricio A., Fogaça, Mariana V., Ramos, Angela, Nascimento, Jéssica M., Andrade, João R. and De Jesus, Renata P, (2018). Cannabinoids induce oxidative stress and fatty degeneration in neurons. Neuropharmacology, 146, 100–110.
XII. Hasin Deborah and Walsh Claire, (2021). Trends over time in adult cannabis use: A review of recent findings. Current Opinion Journals, 38: 80–85.
XIII. Hurd Yasmin L., Manzoni Olivier J., Pletnikov Mikhail V., Lee Francis S., Bhattacharyya Sagnik and Melis Miriam, (2019). Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects. Journal of Neuroscience, 39 (42) 8250-8258.
XIV. Ishrat S, Levey DF, Gelernter J, Ebmeier K, Topiwala A., (2024). Association between cannabis use and brain structure and function: an observational and Mendelian randomisation study. BMJ Mental Health, 27(1):e301065.
XV. Johnson, L., & Lee, S. (2020). Therapeutic benefits of cannabis: A growing evidence base. Clinical Pharmacology and Therapeutics, 107(5), 861-871.
XVI. Kasten CR, Carrey SE, Mulligan GL, Scholl AD, Zhang LE, Andricioaei BP, Hsieh KC, and Patel S, (2021). Dose-dependent biphasic effects of cannabinoids on anxiety. Frontiers in Behavioral Neuroscience, 15, 689450.
XVII. Kim, S., et al. (2021). Histological changes in the brain following long-term cannabis exposure. Journal of Neuroscience Research, 89(6), 1670-1682.
XVIII. Kumar, A., Singh, A., & Ekavali. (2011). A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacological Reports, 67(2), 195-203.
XIX. Lisboa SF, Gomes FV, Terzian AL, Aguiar DC, Moreira FA, Resstel LB, Guimarães FS, (2017). The Endocannabinoid System and Anxiety. Vitam Horm, 103:193-279.
XX. López-Moreno, J. A., González-Cuevas, G., Moreno, G., & Navarro, M. (2008). The pharmacology of the endocannabinoid system: functional and structural interactions with other neurotransmitter systems and their repercussions on behavioral addiction. Addiction Biology, 13(2), 160-187.
XXI. López-Moreno, J. A., González-Cuevas, G., Moreno, G., & Navarro, M. (2008). Cannabinoid impact on dopaminergic and noradrenergic systems. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 32(7), 1385-1392.
XXII. Lingegowda, H., Williams, B.J., Spiess, K.G. et al. Role of the endocannabinoid system in the pathophysiology of endometriosis and therapeutic implications. J Cannabis Res 4, 54 (2022).
XXIII. National Research Council, (2011). Guide for the care and use of Laboratory Animals. Eight Edition, Washington DC. Accessed on 18 August, 2024.
XXIV. 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. Journal of Pharmacology and Experimental Therapeutics, 318(1), 304-311.
XXV. Patricio F, Morales-Andrade AA, Patricio-Martínez A and Limón ID (2020) Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson’s Disease. Frontiers in Pharmacology, 11:595635.
XXVI. Polter, A. M., & Kauer, J. A. (2014). In vivo synaptic plasticity in the VTA and its role in addiction. Neuropharmacology, 76(Part B), 291-299.
XXVII. Sadaka AH, Canuel J, Febo M, Johnson CT, Bradshaw HB, Ortiz R, Ciumo F, Kulkarni P, Gitcho MA and Ferris CF (2023) Effects of inhaled cannabis high in Δ9-THC or CBD on the aging brain: A translational MRI and behavioral study. Frontiers in Aging Neuroscience, 15:1055433.
XXVIII. Treit D, Menard J, Royan C, (1993). Anxiogenic stimuli in the elevated plus-maze. Pharmacology Biochemistry and Behavior, 44:463-469.
XXIX. Urban Nina BL, Slifstein Mark, Thompson Judy L, Xiaoyan Xu, Ragy R Girgis, Sonia Raheja, Margaret Haney, Anissa Abi-Dargham, (2013). Dopamine release in chronic cannabis users: a [11C]raclopride Positron Emission Tomography study. Biological Psychiatry, 71(8):677–683.
XXX. Umoren EB, Obembe AO, Odo MO, and Osim EE, (2014). Effect of nevirapine administration on biliary Secretion/ its Biochemical composition in albino Wistar rats. Journal of Antivirus and Antiretrovirus 6:45-49.
XXXI. van den Hoogen NJ, Harding EK, Davidson CED and Trang T (2022) Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation. Frontiers in Neural Circuits, 15:816747.
XXXII. Volkow, Nora D., Swanson, James M., Evins, A. Eden, et al., (2016). Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review. JAMA Psychiatry. 73(3):292-297.
XXXIII. Yu, X., Zhang, Y., Sun, Y., Wang, Y., & Li, S. (2021). Ventral tegmental area glutamate neurons regulate reward consumption and stress responses. Frontiers in Neural Circuits, 15, 667477
XXXIV. Zehra Amna, Burns Jamie, Liu Christopher Kure, Manza Peter, Wiers Corinde E., Volkow Nora D., Wang Gene-Jack, (2018). Cannabis Addiction and the Brain: a Review. Journal of Neuroimmune Pharmacology, 13:438–452
XXXV. Zhang, H. Y., Gao, M., Liu, Q. R., & Wu, J. (2014). Cannabinoid CB2 receptor: a potential therapeutic target for chronic pain. Brain Research Reviews, 67(1-2), 140-151.