Vet World   Vol.18   September-2025  Article - 22 

Cannabidiol reverses depression-like behaviors by enhancing hippocampal synaptic plasticity in rats with chronic restraint stress

Background and Aim: Major depressive disorder is a prevalent psychiatric condition associated with impaired neuroplas­ticity, particularly in the hippocampus. Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed, their delayed onset and adverse effects highlight the need for alternative therapies. Cannabidiol (CBD), a non-psychotomi­metic cannabinoid, has shown antidepressant-like properties, but its mechanistic link to hippocampal synaptic plasticity remains unclear. This study aimed to evaluate the effects of CBD on depression-like behaviors and hippocampal neuroplas­ticity in rats subjected to chronic restraint stress (CRS).

Materials and Methods: Sixty male Wistar rats were randomly divided into six groups: Non-stressed vehicle (NV), CRS vehi­cle (SV), escitalopram-treated CRS (SE, 10 mg/kg), and CBD-treated CRS at 10, 30, or 100 mg/kg (SC10, SC30, and SC100). Rats were subjected to CRS for 28 days and treated daily through intraperitoneal injection. Depression-like behaviors were assessed using the forced swim test (FST) and sucrose preference test (SPT). Locomotor activity was evaluated through the open-field test (OFT). Hippocampal dendritic spine density (Golgi–Cox staining) and long-term potentiation (LTP, electro­physiology) were measured on day 28.

Results: CRS induced behavioral despair (↑ immobility in FST) and anhedonia (↓ sucrose preference in SPT), accompanied by reduced hippocampal spine density. At all doses, CBD significantly reduced immobility, comparable to escitalopram. Notably, only CBD at 100 mg/kg and escitalopram reversed anhedonia. All CBD-treated groups showed an increase in den­dritic spine density, with SC10 producing the greatest enhancement. Moreover, CBD at 100 mg/kg markedly improved hippocampal LTP at 1 h and 2 h post-stimulation, an effect not observed with escitalopram. Locomotor activity remained unaffected.

Conclusion: CBD demonstrated potent antidepressant-like effects in a CRS rat model, alleviating behavioral despair and anhedonia while enhancing hippocampal dendritic spine density and synaptic strength. These findings suggest CBD as a promising candidate for stress-related mood disorders, with mechanistic actions distinct from conventional SSRIs and potential utility in patients unresponsive to current therapies.

Keywords: cannabidiol, chronic stress, depression, hippocampus, long-term potentiation, synaptic plasticity.

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How to cite this article: Ruanpang J, Thongta N, Vattarakorn A, Ngampramuan S, Pariwatcharakul P, Tapechum S, Care C, and Pakaprot N (2025) Cannabidiol reverses depression-like behaviors by enhancing hippocampal synaptic plasticity in rats with chronic restraint stress, Veterinary World, 18(9): 2823-2838.

Received: 29-04-2025   Accepted: 18-08-2025   Published online: 23-09-2025

Corresponding author: Narawut Pakaprot    E-mail: narawut.pak@mahidol.ac.th

DOI: 10.14202/vetworld.2025.2823-2838

Copyright: Ruanpang, et al. This article is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.