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 D 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 anandamidemediated 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, PPARg receptors agonism, intracellular (Ca 2þ ) increase, etc.), on CBD behavioural effects.

The bed nucleus of the stria terminalis (BNST) is a heterogeneous and complex limbic forebrain structure, which plays an important role in controlling autonomic, neuroendocrine and behavioral responses. The BNST is thought to serve as a key relay connecting limbic forebrain structures to hypothalamic and brainstem regions associated with autonomic and neuroendocrine functions. Its control of physiological and behavioral activity is mediated by local action of numerous neurotransmitters. In the present review we discuss the role of the BNST in control of both autonomic and neuroendocrine function. A description of BNST control of cardiovascular and hypothalamus-pituitary-adrenal axisactivity at rest and during physiological challenges (stress and physical exercise) is presented. Moreover, evidence for modulation of hypothalamic magnocellular neurons activity is also discussed. We attempt to focus on the discussion of BNST neurochemical mechanisms. Therefore, the source and targets of neurochemical inputs to BNST subregions and their role in control of autonomic and neuroendocrine function is discussed in details.

Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hippocampal parvalbumin interneurons, we tested whether alleviating stress early in life can effectively circumvent transition to schizophrenia-like states. Administering diazepam prepubertally at an antianxiety dose in MAM rats was effective at preventing the emergence of the hyperdopaminergic state in the adult. Moreover, multiple stressors applied to normal rats at the same time point resulted in pathology similar to the MAM rat. These data suggest that a genetic predisposition leading to stress hyper-responsivity, or exposure to substantial stressors, could be a primary factor leading to the emergence of schizophrenia later in life, and furthermore treating stress at a critical period may be effective in circumventing this transition.

Cannabidiol (CBD) is a major non-psychotomimetic component of Cannabis sativa that has been shown to have an anxiolytic effect in human and animal models. Earlier studies suggest that these effects involve facilitation of serotonin, a neurotransmitter that has also been related to obsessive-compulsive disorder. On the basis of this evidence, this study investigated the effects of CBD in C57BL/6J mice submitted to the marble-burying test (MBT), an animal model proposed to reflect compulsive behaviour. CBD (15, 30 and 60 mg/kg) induced a significant decrease in the number of buried marbles compared with controls (34, 41 and 48%, respectively). A similar, although larger, decrease was also found after the serotonin selective reuptake inhibitor paroxetine (10 mg/kg, 77% decrease) and the benzodiazepine diazepam (2.5 mg/kg, 84% decrease). The effect of CBD (30 mg/kg) was still significant after 7 days of daily repeated administration, whereas the effect of diazepam disappeared. Pretreatment with WAY100635 (3 mg/kg), a 5HT1A receptor antagonist, prevented the effects of paroxetine but failed to alter those of CBD. These latter effects, however, were prevented by pretreatment with the CB1 receptor antagonist AM251 (1 mg/kg). These results indicated that CBD and paroxetine decrease the number of buried marbles in the MBT through distinct pharmacological mechanisms. They also suggest a potential role of drugs acting on the cannabinoid system in modulating compulsive behaviour.