Efeitos do canabidiol sobre modelos preditivos de depressão em camundongos

Abstract

Depression is a severe psychiatric disorder characterized by emotional, cognitive, and behavioral dysfunctions that significantly impact quality of life. Conventional treatment, based on antidepressants, has limitations such as delayed therapeutic effects, low response rates, and adverse side effects. Cannabidiol (CBD), a compound derived from Cannabis sativa, has emerged as a potential antidepressant agent due to its anxiolytic, neuroprotective, and anti-inflammatory properties. This study investigated the antidepressant effects of CBD in predictive models of depression in Swiss mice, aiming to evaluate its action and the neurochemical mechanisms involved. A total of 103 male Swiss mice (25–30g) were divided into experimental groups. The protocol included three experiments: (i) administration of different doses of CBD (3, 10, and 30 mg/kg, i.p.) and fluoxetine (5 and 10 mg/kg, i.p.), (ii) combination of a subdose of fluoxetine (5 mg/kg) with CBD, and (iii) investigation of the dopaminergic system’s involvement in CBD’s antidepressant effects using the D2 antagonist sulpiride (50 mg/kg, i.p.). The animals underwent behavioral tests, including the Forced Swimming Test (FST), Tail Suspension Test (TST), Open Field Test (OFT), Novel Object Recognition Test (NORT), Hole Board Test (HB), T -Maze Test (TMT), and Y -Maze Test (YMT). After the behavioral assessments, neurochemical analyses were conducted in the hippocampus, striatum, and prefrontal cortex, including lipid peroxidation (TBARS), nitrite/nitrate levels, and reduced glutathione (GSH) quantification. The results showed that CBD significantly reduced immobility time in both the FST and TST, indicating an antidepressant effect. The combination of CBD 10 mg/kg with fluoxetine 5 mg/kg enhanced this response, suggesting a possible synergistic effect between the drugs. Additionally, sulpiride administration reversed CBD’s effects in the TST, reinforcing the involvement of the dopaminergic system in its antidepressant properties. In the OFT, conducted on the last day of the experiment, CBD did not induce significant locomotor changes, supporting the hypothesis that its antidepressant action is not due to nonspecific stimulating effects. The NORT revealed that CBD 10 mg/kg and 30 mg/kg improved recognition memory, suggesting a pro-cognitive effect. In the T -Maze Test, CBD promoted anxiolytic effects, increasing exploration of the open arms, especially when combined with fluoxetine. Neurochemical analyses demonstrated that fluoxetine significantly increased lipid peroxidation (TBARS) levels, while CBD exhibited a neuroprotective effect by reducing oxidative stress in some brain regions. CBD 3 mg/kg significantly modulated nitrite/nitrate levels, suggesting antioxidant and neuroprotective effects. GSH analysis showed that CBD 30 mg/kg significantly increased antioxidant activity in the basal nuclei, while the 3 mg/kg dose showed effects in the prefrontal cortex. These findings reinforce the therapeutic potential of CBD for depression treatment, suggesting that its effects involve modulation of dopaminergic systems, as well as ntioxidant and neuroprotective properties. The combination of CBD with conventional antidepressants may be a promising strategy to optimize depression treatment by reducing drug doses and minimizing adverse effects. Future studies should further investigate the underlying mechanisms and assess the translational potential of CBD in clinical trials.