Background and purpose: Cannabidiol (CBD) is a non‐psychotomimetic compound fromCannabis sativawhich induces anxiolytic‐ and antipsychotic‐like effects in rodents. These effects could be mediated by facilitation of the endocannabinoid system or by the activation of 5‐HT_1Areceptors. As either of these mechanisms could promote adaptation to inescapable stress, the aim of the present work was to test the hypothesis that CBD would attenuate the autonomic and behavioural consequences of restraint stress (RS). We also investigated if the responses to CBD depended on activation of 5‐HT_1Areceptors.Experimental approach: Male Wistar rats received i.p. injections of vehicle or CBD (1, 10 or 20 mg kg⁻¹) and 30 min later were submitted to 60 min of restraint where their cardiovascular responses were recorded. The protocol of the second experiment was similar to the first one except that animals received i.p. injections of the 5‐HT_1Areceptor antagonist WAY100635 (0.1 mg kg⁻¹) before CBD treatment and exposure to restraint. 24 h later they were also tested in the elevated plus‐maze (EPM), an animal model of anxiety.Key results: Exposure to RS increased blood pressure and heart rate and induced an anxiogenic response in the EPM 24 h later. These effects were attenuated by CBD. WAY100635 by itself did not change the cardiovascular and anxiogenic response to RS, but blocked the effects of CBD.Conclusion and implications: The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5‐HT_1Areceptor‐mediated neurotransmission.

Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here.

BACKGROUND AND PURPOSE Epigenetic modifications are thought to play an important role in the neurobiology of depression. Antidepressant treatment induces histone acetylation in the hippocampus, which is associated with transcriptional activation, whereas stress increases DNA methylation, which is associated with transcriptional repression. Because the specific involvement of DNA methylation in the regulation of depressive‐like behaviours is not yet known, we have investigated the effects induced by systemic or intra‐hippocampal administration of inhibitors of DNA methyltransferase (DNMT) in rats submitted to a range of behavioural tests.EXPERIMENTAL APPROACH Rats received i.p. injections of 5‐aza‐2‐deoxycytidine (5‐azaD, 0.1–0.8 mg·kg⁻¹), 5‐azacytidine (5‐azaC, 0.4–3.2 mg·kg⁻¹), imipramine (15 mg·kg⁻¹) or vehicle and were submitted to the forced swimming test (FST) or open field test (OFT). Other groups of rats received intra‐hippocampal injection of DNMT inhibitors.KEY RESULTS Systemic administration of DNMT inhibitors induced a dose‐dependent antidepressant‐like effect, which was followed by decreased DNA methylation and increased brain‐derived neurotrophic factor (BDNF) levels in the hippocampus. Hippocampal inhibition of DNA methylation induced similar behavioural effects. No treatment induced any locomotor effects in the OFT. Antidepressant‐like effects of 5‐azaD were confirmed in mice submitted to the FST or the tail suspension test.CONCLUSIONS AND IMPLICATIONS Systemic, as well as hippocampal, inhibition of DNA methylation induced antidepressant‐like effects. These effects could be associated with increased hippocampal expression of BDNF. Our data give further support to the hypothesis that DNA methylation is an important epigenetic mechanism involved in the development of depressive‐like behaviours.