Antidepressant-like Effects of Cannabidiol and Tetrahydrocannabinol in a Reserpine-induced Mouse Model of Parkinson’s Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, characterised by the progressive degeneration of dopaminergic neurons in the substantia nigra. Beyond its well-recognised motor manifestations, PD is associated with a broad spectrum of non-motor symptoms including constipation, pain, cognitive impairment, and depressive symptoms. The aim of this study was to investigate the antidepressant-like effects of cannabidiol (CBD) and tetrahydrocannabinol (THC) in a reserpine-induced Parkinson's disease mouse model. Forty-two adult mice were randomly allocated into seven groups of six animals each. Group I received distilled water (10 ml/kg) and served as the normal control; Group II received reserpine (0.5 mg/kg) only; Groups III and IV received reserpine plus CBD at 30 mg/kg and 60 mg/kg respectively; Groups V and VI received reserpine plus THC at 4 mg/kg and 6 mg/kg respectively; and Group VII received reserpine combined with CBD (60 mg/kg) and THC (6 mg/kg). The primary outcome measures were immobility time assessed using the forced swim test (FST) as a behavioural index of depression, and brain dopamine concentration measured by enzyme-linked immunosorbent assay (ELISA). Treatment with CBD and THC, both individually and in combination, significantly reduced immobility time (P < 0.05) compared to the reserpine-only group, with the combination treatment producing the most pronounced effect. Mice treated with THC (4 mg/kg) and the combination of CBD (60 mg/kg) and THC (6 mg/kg) demonstrated significantly elevated brain dopamine concentrations relative to the reserpine-only group. These findings suggest that CBD and THC may exhibit antidepressant-like properties in a preclinical model of Parkinson's disease, with effects potentially mediated through modulation of dopaminergic neurotransmission. Further studies are warranted to evaluate the long-term safety, dose optimisation, and translational relevance of these findings before clinical applications can be considered.