Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels

Abstract

Cannabidiol (CBD) is a compound of Cannabis sativa with relevant therapeutic potential in several neuropsychiatric disorders including depression. CBD treatment has shown significant antidepressant-like effects in different rodent preclinical models. However, the mechanisms involved in CBD-induced antidepressant effects are still poorly understood. Therefore, this work aimed at investigating the participation of serotonin (5-HT) and/or noradrenaline (NA) in CBD-induced antidepressant-like effects in the forced swimming test (FST) by: 1) testing if CBD co-administration with serotonergic (fluoxetine, FLX) or noradrenergic (desipramine, DES) antidepressants would have synergistic effects; and 2) investigating if 5-HT or NA depletion would impair CBD-induced behavioral effects. Results showed that CBD (10 mg/kg), FLX (10 mg/kg) and DES (5 mg/kg) induced antidepressant-like effects in mice submitted to FST. Ineffective doses of CBD (7 mg/kg), when co-administered with ineffective doses of FLX (5 mg/kg) or DES (2.5 mg/kg) resulted in significant antidepressant-like effects, thus implicating synergistic and/or additive mechanisms. Pretreatment with PCPA (an inhibitor of serotonin synthesis: 150 mg/kg, i.p., once per day for 4 days), but not DSP-4 (a noradrenergic neurotoxin: 1 μg/μl, i.c.v., 24 h before the test), reduced monoamine levels in the brain. However, only PCPA treatment abolished CBD-induced behavioral effects in FST, indicating the participation of serotonergic mechanisms. None of the treatments induced locomotor effects. Our results suggest that the antidepressant-like effect induced by CBD in the FST is dependent on serotonin levels in the central nervous system (CNS).

Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes

“…Histone activity is modulated by their level of acetylation. Interestingly, the histone deacetylases, a family of enzymes that determine histone level of acetylation, have been reported as targets in neuroprotection [46]. In addition, histone post-transcriptional modifications influence gene expression and play a role in the pathophysiology of neurological diseases, suggesting novel therapeutic approaches [47].…”

Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms

“…Finally, there is an association between drug addiction and depression and it could be expected that the improvement of depressive symptoms, such as helplessness and anhedonia, may be accompanied by a reduction of drug use. In experimental rodents, CBD had anti-depressive effects in the forced swim test [131,132,133,134,135], tail suspension test [136,137,138,139], sucrose preference test [75], saccharin preference test [139] and the learned helplessness paradigm [133]. Indirect activation of CB1 receptors in the ventromedial PFC [134], stimulation of serotonin [132] and 5-HT1A receptors [16,75,135,140], enhanced cortical 5-HT/glutamate neurotransmission [75] and increased BDNF- TrkB-mTOR signalling in the amygdala, medial PFC and the hippocampus [133,134,136] have been involved in the antidepressant effects of CBD.…”

Cannabinoid Actions on Neural Stem Cells: Implications for Pathophysiology

“…CBD has also been extensively shown to have potent anxiolytic and antidepressant effects in both humans and rodents, being currently investigated as a possible new avenue for the treatment of these disorders (reviewed in [554,555,556]). As such, acute and chronic CBD administration have been shown to induce anxiolytic- and antidepressant-like changes in animal behavioral tests, with low doses resulting in anxiolytic effects, while higher doses produce no effect on anxiety [499,557,558,559,560,561,562,563]. In addition, CBD-induced anxiolytic effects were shown to be dependent on AHN [220].…”