Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors

Abstract

Background and purpose: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT(1A) receptors. As 5-HT(1A) receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT(1A) receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF).

Experimental approach: Male Swiss mice were given (i.p.) CBD (3, 10, 30, 100 mg*kg(-1)), imipramine (30 mg*kg(-1)) or vehicle and were submitted to the forced swimming test or to an open field arena, 30 min later. An additional group received WAY100635 (0.1 mg*kg(-1), i.p.), a 5-HT(1A) receptor antagonist, before CBD (30 mg*kg(-1)) and assessment by the forced swimming test. BDNF protein levels were measured in the hippocampus of another group of mice treated with CBD (30 mg*kg(-1)) and submitted to the forced swimming test.

Key results: CBD (30 mg*kg(-1)) treatment reduced immobility time in the forced swimming test, as did the prototype antidepressant imipramine, without changing exploratory behaviour in the open field arena. WAY100635 pretreatment blocked CBD-induced effect in the forced swimming test. CBD (30 mg*kg(-1)) treatment did not change hippocampal BDNF levels.

Conclusion and implications: CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT(1A) receptors.

Figure 1

Cannabidiol (CBD, 30 mg·kg⁻¹) and imipramine (IMP, 15 mg·kg⁻¹) reduced immobility time in the forced swimming test. Mice (8–12/group) received i.p. injections of CBD (3–100 mg·kg⁻¹) or imipramine (IMP) and 30 min later were submitted to the forced swim. Data represent the mean ± SEM. * indicates P < 0.05 compared with vehicle group (anova followed by Duncan).

Figure 2

Cannabidiol (CBD, 3–100 mg·kg⁻¹) did not induce any significant change in the exploratory activity. Mice (8 per group) received i.p. injections of CBD and 30 min later the distance moved in an open arena was analysed over 6 min. Data represent the mean ± SEM.

Figure 3

Pretreatment with WAY100635 (Way, 0.1 mg·kg⁻¹) prevented cannabidiol (CBD, 30 mg·kg⁻¹) effects in the forced swimming test. Mice (8–17 per group) received a first i.p. injection of WAY100635 or saline followed, 30 min later, by a second injection of CBD or vehicle (Vehic). The animals were submitted to the forced swim 30 min after the second injection. Data represents mean ± SEM. * indicates P < 0.05 compared with saline + vehicle group (anova followed by Duncan).

Figure 4

Cannabidiol-induced antidepressant-like effects were not associated with alterations in hippocampal BDNF levels. Mice (7–8 per group) received i.p. injection of cannabidiol (CBD, 30 mg·kg⁻¹) or imipramine (IMP, 30 mg·kg⁻¹) and 30 min later were submitted to the forced swim test (left graph). Immediately after, the animals were killed, their hippocampi removed and processed for BDNF measurements (right graph). Data represent the mean ± SEM. * indicates P < 0.05 compared with vehicle group (anova followed by Duncan).