Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ ⁹ -tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca ²⁺ ) increase, etc.), on CBD behavioural effects.

Several findings relate the hippocampal formation to the behavioural consequences of stress. It contains a high concentration of corticoid receptors and undergoes plastic modifications, including decreased neurogenesis and cellular remodelling, following stress exposure. Various major neurotransmitter systems in the hippocampus are involved in these effects. Serotonin (5-HT) seems to exert a protective role in the hippocampus and attenuates the behavioural consequences of stress by activating 5-HT_1A receptors in this structure. These effects may mediate the therapeutic actions of several antidepressants. The role of noradrenaline is less clear and possibly depends on the specific hippocampal region (dorsal vs. ventral). The deleterious modifications induced in the hippocampus by stress might involve a decrease in neurotrophic factors such as brain derived neurotrophic factor (BDNF) following glutamate N-methyl-d-aspartate (NMDA) receptor activation. In addition to glutamate, nitric oxide (NO) could also be related to these effects. Systemic and intra-hippocampal administration of nitric oxide synthase (NOS) inhibitors attenuates stress-induced behavioural consequences. The challenge for the future will be to integrate results related to these different neurotransmitter systems in a unifying theory about the role of the hippocampus in mood regulation, depressive disorder and antidepressant effects.