Research Article | 23 Sep 2025

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

Jutamas Ruanpang1 , Namphung Thongta1 , Anchalee Vattarakorn1 , Sukonthar Ngampramuan2 , Pornjira Pariwatcharakul3 , Sompol Tapechum1 , Chit Care1 , and Narawut Pakaprot1 Show more
VETERINARY WORLD | pg no. 2823-2838 | Vol. 18, Issue 9 | DOI: 10.14202/vetworld.2025.2823-2838
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Abstract

          
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.