Berberine Alleviates Anxiety, Depression, and Motor Impairment Associated with Alcohol Withdrawal in Mice: A Preclinical Study
DOI:
https://doi.org/10.71193/jpci.20250017Keywords:
Berberine, Alcohol withdrawal, Anxiety, Depression, Motor coordinationAbstract
Alcohol withdrawal is a serious condition that often leads to heightened anxiety, depressive symptoms, and problems with motor coordination, all of which can significantly affect quality of life. These effects are largely tied to chemical imbalances in the brain, particularly involving GABA and glutamate systems, as well as oxidative stress. Berberine, a natural plant alkaloid long recognized for its therapeutic potential, is known to have calming, mood-stabilizing, and neuroprotective properties. In this study, mice were exposed to repeated alcohol intake (10% v/v, 2 g/kg p.o) followed by withdrawal, which produced marked behavioral changes resembling anxiety, depression, and poor motor performance. When treated with berberine (10 or 30 mg/kg p.o.) , however, these animals showed a clear reversal of withdrawal-induced problems. At both lower and higher doses, berberine reduced anxiety-like behavior, improved exploratory activity, lessened depressive signs, and improved motor coordination, with the higher dose offering stronger benefits. Importantly, berberine by itself did not cause any harmful effects, suggesting that it is safe in this context. These findings indicate that berberine may offer meaningful protection against the emotional and motor disturbances caused by alcohol withdrawal. Its ability to ease anxiety and depression while supporting brain function makes it a promising candidate for managing alcohol withdrawal syndrome.
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Angoa-Pérez, M., Kane, M. J., Briggs, D. I., Francescutti, D. M., & Kuhn, D. M. (2013). Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice. Journal of Visualized Experiments : JoVE, 82, 50978. https://doi.org/10.3791/50978 DOI: https://doi.org/10.3791/50978
Becker, H. C., & Lopez, M. F. (2004). Increased ethanol drinking after repeated chronic ethanol exposure and withdrawal experience in C57BL/6 mice. Alcoholism: Clinical and Experimental Research,28(12),1829–1838. https://doi.org/10.1097/01.ALC.0000149977.95306.3A DOI: https://doi.org/10.1097/01.ALC.0000149977.95306.3A
Campos-Cardoso, R., Godoy, L. D., Lazarini-Lopes, W., Novaes, L. S., dos Santos, N. B., Perfetti, J. G., Garcia-Cairasco, N., Munhoz, C. D., & Padovan, C. M. (2023). Exploring the light/dark box test: Protocols and implications for neuroscience research. Journal of Neuroscience Methods, 384, 109748. https://doi.org/10.1016/j.jneumeth.2022.109748 DOI: https://doi.org/10.1016/j.jneumeth.2022.109748
Celada, P., Bortolozzi, A., & Artigas, F. (2013). Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: Rationale and current status of research. CNS Drugs, 27(9), 703–716. https://doi.org/10.1007/S40263-013-0071-0 DOI: https://doi.org/10.1007/s40263-013-0071-0
Chandler, L. J., Harris, R. A., & Crews, F. T. (1998). Ethanol tolerance and synaptic plasticity. Trends in Pharmacological Sciences, 19(12), 491–495. https://doi.org/10.1016/S0165-6147(98)01268-1. /ASSET/99A4C487-66EF-4BFF-B8BF-E3B4E1245071/MAIN.ASSETS/GR1.SML DOI: https://doi.org/10.1016/S0165-6147(98)01268-1
Cicero, A. F. G., & Baggioni, A. (2016). Berberine and its role in chronic disease. Advances in Experimental Medicine and Biology, 928, 27–45. https://doi.org/10.1007/978-3-319-41334-1_2, DOI: https://doi.org/10.1007/978-3-319-41334-1_2
Deacon, R. M. J. (2006). Digging and marble burying in mice: Simple methods for in vivo identification of biological impacts. Nature Protocols, 1(1), 122–124. https://doi.org/10.1038/NPROT.2006.20 DOI: https://doi.org/10.1038/nprot.2006.20
Fan, X., Liu, B., Zhou, J., Gu, X., Zhou, Y., Yang, Y., Guo, F., Wei, X., Wang, H., Si, N., Yang, J., Bian, B., & Zhao, H. (2021). High-Fat Diet Alleviates Neuroinflammation and Metabolic Disorders of APP/PS1 Mice and the Intervention With Chinese Medicine. Frontiers in Aging Neuroscience, 13, 658376. https://doi.org/10.3389/fnagi.2021.658376 DOI: https://doi.org/10.3389/fnagi.2021.658376
File, S. E., & Wardill, A. G. (1975). Validity of head-dipping as a measure of exploration in a modified hole-board. Psychopharmacologia, 44(1), 53–59. https://doi.org/10.1007/BF00421184 DOI: https://doi.org/10.1007/BF00421184
Goldfine, C. E., Tom, J. J., Im, D. D., Yudkoff, B., Anand, A., Taylor, J. J., Chai, P. R., & Suzuki, J. (2023). The therapeutic use and efficacy of ketamine in alcohol use disorder and alcohol withdrawal syndrome: a scoping review. Frontiers in Psychiatry, 14, 1141836. https://doi.org/10.3389/FPSYT.2023.1141836 DOI: https://doi.org/10.3389/fpsyt.2023.1141836
Joshi, D., Naidu, P. S., Singh, A., & Kulkarni, S. K. (2005). Protective effect of quercetin on alcohol abstinence-induced anxiety and convulsions. Journal of Medicinal Food, 8(3), 392–396. https://doi.org/10.1089 DOI: https://doi.org/10.1089/jmf.2005.8.392
Klein, S. (2023). The role of the neurotransmitter Glutamate for the development and maintenance of alcohol use disorder. http://dx.doi.org/10.17169/refubium-38673
Koob, G. F., & Le Moal, M. (2001). Drug Addiction, Dysregulation of Reward, and Allostasis. Neuropsychopharmacology, 24(2), 97–129. https://doi.org/10.1016/S0893-133X(00)00195-0 DOI: https://doi.org/10.1016/S0893-133X(00)00195-0
Kranzler, H. R. (2023). Overview of Alcohol Use Disorder. The American Journal of Psychiatry, 180(8),565–572. https://doi.org/10.1176/APPI.AJP.20230488 DOI: https://doi.org/10.1176/appi.ajp.20230488
Kumar, A., Verma, A., & Singh, N. (2023). New insights into the role of berberine against 3-nitropropionic-acid–induced striatal neurotoxicity: Possible involvement of BDNF-TrkB-PI3K/Akt and NF-κB signaling. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2023.109568 DOI: https://doi.org/10.1016/j.neuropharm.2023.109568
Lepicard, E. M., Venault, P., Negroni, J., Perez-Diaz, F., Joubert, C., Nosten-Bertrand, M., Berthoz, A., & Chapouthier, G. (2003). Posture and balance responses to a sensory challenge are related to anxiety in mice. Psychiatry Research, 118(3), 273–284. https://doi.org/10.1016/S0165-1781(03)00069-6 DOI: https://doi.org/10.1016/S0165-1781(03)00069-6
Li, M., Chen, Y., & Wang, J. (2025). The potential value of berberine in depression: A systematic review and meta-analysis of preclinical studies. Frontiers in Pharmacology, 16, 1664784. https://doi.org/10.3389/fphar.2025.1664784 DOI: https://doi.org/10.3389/fphar.2025.1664784
Liu, Y. M., Niu, L., Wang, L. L., Bai, L., Fang, X. Y., Li, Y. C., & Yi, L. T. (2017). Berberine attenuates depressive-like behaviors by suppressing neuro-inflammation in stressed mice. Brain Research Bulletin, 134, 220–227. https://doi.org/10.1016/j.brainresbull.2017.08.008 DOI: https://doi.org/10.1016/j.brainresbull.2017.08.008
Mayo-Smith, M. F., Beecher, L. H., Fischer, T. L., Gorelick, D. A., Guillaume, J. L., Hill, A., Jara, G., Kasser, C., & Melbourne, J. (2004a). Management of alcohol withdrawal delirium: An evidence-based practice guideline. Archives of Internal Medicine, 164(13), 1405–1412. https://doi.org/10.1001/ARCHINTE.164.13.1405, DOI: https://doi.org/10.1001/archinte.164.13.1405
Meyer, L., & Caston, J. (2005). Repeated stress alters caffeine action on motor coordination in C57Bl6/J male mice. Brain Research, 1039(1–2), 171–176. https://doi.org/10.1016/j.brainres.2005.01.053 DOI: https://doi.org/10.1016/j.brainres.2005.01.053
Morisot, N., & Ron, D. (2017). Alcohol-dependent molecular adaptations of the NMDA receptor system. Genes, Brain and Behavior, 16(1), 139–148. https://doi.org/10.1111/GBB.12363, DOI: https://doi.org/10.1111/gbb.12363
Ngui, H. H. L., Kow, A. S. F., Lai, S., Tham, C. L., Ho, Y. C., & Lee, M. T. (2022). Alcohol Withdrawal and the Associated Mood Disorders—A Review. International Journal of Molecular Sciences 2022, Vol. 23, Page 14912, 23(23), 14912. https://doi.org/10.3390/IJMS232314912 DOI: https://doi.org/10.3390/ijms232314912
Njung’e, K., & Handley, S. L. (1991). Evaluation of marble-burying behavior as a model of anxiety. Pharmacology Biochemistry and Behavior, 38(1), 63–67. https://doi.org/10.1016/0091-3057(91)90590-X DOI: https://doi.org/10.1016/0091-3057(91)90590-X
Olsen, R. W., & Liang, J. (2017). Role of GABAA receptors in alcohol use disorders suggested by chronic intermittent ethanol (CIE) rodent model. Molecular Brain 2017 10:1, 10(1), 1–20. https://doi.org/10.1186/S13041-017-0325-8 DOI: https://doi.org/10.1186/s13041-017-0325-8
Pellow, S., Chopin, P., File, S. E., & Briley, M. (1985). Validation of open : closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods, 14(3), 149–167. https://doi.org/10.1016/0165-0270(85)90031-7, DOI: https://doi.org/10.1016/0165-0270(85)90031-7
Peng, W. H., Lo, K. L., Lee, Y. H., Hung, T. H., & Lin, Y. C. (2007). Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice. Life Sciences, 81(11), 933–938. https://doi.org/10.1016/j.lfs.2007.08.003 DOI: https://doi.org/10.1016/j.lfs.2007.08.003
Pinto Brod, L. M., Fronza, M. G., Vargas, J. P., Lüdtke, D. S., Luchese, C., Wilhelm, E. A., & Savegnago, L. (2016). Involvement of monoaminergic system in the antidepressant-like effect of (octylseleno)-xylofuranoside in the mouse tail suspension test. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 65, 201–207. https://doi.org/10.1016/J.PNPBP.2015.10.008 DOI: https://doi.org/10.1016/j.pnpbp.2015.10.008
Pisula, W., Modlinska, K., Goncikowska, K., & Chrzanowska, A. (2021). Can the Hole–Board Test Predict a Rat’s Exploratory Behavior in a Free-Exploration Test? Animals 2021, Vol. 11, Page 1068, 11(4), 1068. https://doi.org/10.3390/ANI11041068 DOI: https://doi.org/10.3390/ani11041068
Porsolt, R. D., Bertin, A., & Jalfre, M. (1977). Behavioral despair in mice: a primary screening test for antidepressants. Archives Internationales de Pharmacodynamie et de Therapie, 229(2), 327–336. https://europepmc.org/article/med/596982
Poudel, A., Gurung, B., & Khanal, G. P. (2020). Perceived social support and psychological wellbeing among Nepalese adolescents: The mediating role of self-esteem. BMC Psychology, 8(1), 1–8. https://doi.org/10.1186/S40359-020-00409-1 DOI: https://doi.org/10.1186/s40359-020-00409-1
Qin, Z., Shi, D.-D., Li, W., Cheng, D., Zhang, Y.-D., Zhang, S., & Zhang-Jin, Z. (2023). Berberine ameliorates depression-like behaviors via inhibiting NLRP3 inflammasome–mediated neuroinflammation and preventing neuroplasticity disruption. Journal of Neuroinflammation, 20(1), 54. https://doi.org/10.1186/s12974-023-02744-7 DOI: https://doi.org/10.1186/s12974-023-02744-7
Takeda, H., Tsuji, M., & Matsumiya, T. (1998). Changes in head-dipping behavior in the hole-board test reflect the anxiogenic and/or anxiolytic state in mice. European Journal of Pharmacology, 350(1), 21–29. https://doi.org/10.1016/S0014-2999(98)00223-4 DOI: https://doi.org/10.1016/S0014-2999(98)00223-4
Tang, Y., Su, H., Nie, K., Wang, H., Gao, Y., Chen, S., Lu, F., & Dong, H. (2024). Berberine exerts antidepressant effects in vivo and in vitro through the PI3K/AKT/CREB/BDNF signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 170, 116012. https://doi.org/10.1016/j.biopha.2023.116012 DOI: https://doi.org/10.1016/j.biopha.2023.116012
Võikar, V., & Stanford, S. C. (2023). The Open Field Test. Neuromethods, 190, 9–29. https://doi.org/10.1007/978-1-0716-2748-8_2 DOI: https://doi.org/10.1007/978-1-0716-2748-8_2
Walsh, R. N., & Cummins, R. A. (1976). The open-field test: A critical review. Psychological Bulletin, 83(3), 482–504. https://doi.org/10.1037/0033-2909.83.3.482 DOI: https://doi.org/10.1037//0033-2909.83.3.482
Witkin, J. M., & Smith, J. L. (2023). Marble Burying in Mice. Neuromethods, 190, 71–88. https://doi.org/10.1007/978-1-0716-2748-8_5 DOI: https://doi.org/10.1007/978-1-0716-2748-8_5
Zhu, W. Q., Wu, H. Y., Sun, Z. H., Guo, Y., Ge, T. T., Li, B. J., Li, X., & Cui, R. J. (2022). Current Evidence and Future Directions of Berberine Intervention in Depression. Frontiers in Pharmacology, 13, 824420. https://doi.org/10.3389/FPHAR.2022.824420 DOI: https://doi.org/10.3389/fphar.2022.824420
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Copyright (c) 2025 Jayesh Bagul, Manojkumar Mahajan, Aman Upaganlawar, Chandrashekhar Upasani (Author)

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