Antidepressive-like effect induced by Cannabidiol is dependent on brain serotonine levels, A.J. Sales et al., 2018

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

A.J. Sales, C. C. Crestani, F. S. Guimaraes, S. R.L. Joca,
Progress in Neuropsychopharmacology & Biological Psychiatry, 2018 Aug 30; 86: 255-261.

Doi: 10.1016/j.pnpbp.2018.06.002

PMID : 29885468


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).

KEYWORDS : Antidepressant; Cannabidiol; Desipramine; Fluoxetine; Noradrenaline; Serotonin



Cannabidiol (CBD) is a major component of Cannabis sativa with a broad spectrum of beneficial pharmacological actions in psychiatric disorders, including anxiolytic, antipsychotic, neuroprotective and antidepressant properties (Campos et al., 2016; Ligresti et al., 2016). Accordingly, preclinical studies have demonstrated that administration of CBD induces antidepressant-like effects in several animal models (Zanelati et al., 2010; El-Alfy et al., 2010; Réus et al., 2011; Shoval et al., 2016; Linge et al., 2016; Sartim et al., 2016; Schiavon et al., 2016). However, the pharmacological mechanisms responsible for CBD effects remain unclear.

In the central nervous system (CNS), noradrenaline (NA) and serotonin (5-HT) systems play an important role in emotional regulation, stress response and depression neurobiology (Ressler and Nemeroff, 2000). Currently available antidepressant treatments, such as selective serotonin reuptake inhibitors (SSRI) and tricyclic drugs, have their therapeutic effect related to the increase in monoaminergic neurotransmission in limbic brain regions (Ressler and Nemeroff, 2000). Accordingly, the antidepressant action of CBD seems to be mediated by serotonin 5HT1A receptors, since systemic administration of WAY100635, a 5-HT1A receptor antagonist, prevented the antidepressant-like effects induced by CBD in both forced swimming test (FST; Zanelati et al., 2010) and olfactory bulbectomy mouse model of depression (OBX, Linge et al., 2016).

Important brain structures involved in depression and antidepressant response, such as the prefrontal cortex (PFC) and hippocampus (HPC), have been associated with the effects induced by CBD. In rats, CBD administration into the ventral medial prefrontal cortex (vmPFC) produces antidepressant-like effects in the forced swimming test (FST), an effect blocked by systemic pretreatment with the 5-HT1A receptor antagonist WAY100635 (Sartim et al., 2016). A similar antidepressant-like effect was observed after intra-vmPFC injection of 8-OH-DPAT, a 5-HT1A receptor agonist (Sartim et al., 2016). However, it is not clear if 5-HT1A participation in CBD effects is a consequence of increased serotonin availability or direct receptor activation/facilitation by CBD itself. Therefore, it becomes relevant to investigate CBD effects under conditions of decreased serotonin availability in the CNS.

Additionally, several studies have shown important interactions between cannabinoids and the noradrenergic system (Oropeza et al., 2005, 2007; Page et al., 2007; Fox et al., 2009), but there is no study evaluating the participation of NA in CBD-induced antidepressant-like effects.

The present study, therefore, tested the hypothesis that the antidepressant-like effects induced by CBD involve the facilitation of noradrenergic and/or serotonergic neurotransmitter systems in the brain. To this aim, we investigated if: 1. the co-administration of CBD with serotonergic (fluoxetine, FLX) or noradrenergic (desipramine, DES) reuptake blockers would promote significant antidepressant-like effects in the FST; 2. the depletion of serotonin or noradrenaline levels in the brain would abrogate CBD effects.



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