The possible role of the CB 2 receptor (CB 2 r) in psychiatric disorders has been considered. Several animal models use knockout (KO) mice that display schizophrenia-like behaviors and this study evaluated the role of CB 2 r in the regulation of such behaviors. Mice lacking the CB 2 r (CB 2 KO) were challenged in open field, light-dark box, elevated plus-maze, tail suspension, step down inhibitory avoidance, and pre-pulse inhibition tests (PPI). Furthermore, the effects of treatment with cocaine and risperidone were evaluated using the OF and the PPI test. Gene expression of dopamine D 2 (D 2 r), adrenergic-a 2C (a 2C r), serotonergic 5-HT 2A and 5-HT 2C receptors (5-HT 2A r and 5-HT 2C r) were studied by RT-PCR in brain regions related to schizophrenia. Deletion of CB 2 r decreased motor activity in the OF test, but enhanced response to acute cocaine and produced mood-related alterations, PPI deficit, and cognitive impairment. Chronic treatment with risperidone tended to impair PPI in WT mice, whereas it 'normalized' the PPI deficit in CB 2 KO mice. CB 2 KO mice presented increased D 2 r and a 2C r gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT 2C r gene expression in the dorsal raphe (DR), and 5-HT 2A r gene expression in the PFC. Chronic risperidone treatment in WT mice left a 2C r gene expression unchanged, decreased D 2 r gene expression (15 mg/kg), and decreased 5-HT 2C r and 5-HT 2A r in PFC and DR. In CB 2 KO, the gene expression of D 2 r in the PFC, of a 2C r in the LC, and of 5-HT 2C r and 5-HT 2A r in PFC was reduced; 5-HT 2C r and 5-HT 2A r gene expressions in DR were increased after treatment with risperidone. These results suggest that deletion of CB 2 r has a relation with schizophrenia-like behaviors. Pharmacological manipulation of CB 2 r may merit further study as a potential therapeutic target for the treatment of schizophrenia-related disorders.

This study evaluated the effects of cannabidiol (CBD) on ethanol reinforcement, motivation and relapse in C57BL/6 J mice. The effects of CBD (60 mg/kg, i.p.) on blood ethanol concentration, hypothermia and handling-induced convulsions associated to acute ethanol administration were evaluated. The two-bottle choice paradigm was performed to assess the effects of CBD (30, 60 and 120 mg/kg/day, i.p.) on ethanol intake and preference. In addition, an oral ethanol self-administration experiment was carried out to evaluate the effects of CBD [a single s.c. administration of a microparticle formulation providing CBD continuous controlled release (30 mg/kg/day)] on the reinforcement and motivation for ethanol. The effects of CBD (60 and 120 mg/kg/day, i.p.) on ethanol-induced relapse were also evaluated. Gene expression analyses of tyrosine hydroxylase in ventral tegmental area and μ-opioid (Oprm1), cannabinoid (CB 1 r and CB 2 r) and GPR55 receptors in nucleus accumbens (NAcc) were carried out by real-time polymerase chain reaction. Cannabidiol reduced the ethanol-induced hypothermia and handling-induced convulsion but failed to modify blood ethanol concentration. CBD reduced ethanol consumption and preference in the two-bottle choice, significantly decreased ethanol intake and the number of effective responses in the oral ethanol self-administration, and reduced ethanol-induced relapse. Furthermore, the administration of CBD significantly reduced relative gene expression of tyrosine hydroxylase in the ventral tegmental area, Oprm1, CB 1 r and GPR55 in the NAcc and significantly increased CB 2 r in the NAcc. Taken together, these results reveal that the administration of CBD reduced the reinforcing properties, motivation and relapse for ethanol. These findings strongly suggest that CBD may result useful for the treatment of alcohol use disorders.

The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders.

During the last years, an extraordinary effort has been made to identify biomarkers as potential tools for improving prevention, diagnosis, drug response and drug development in psychiatric disorders. Contrary to other diseases, mental illnesses are classified by diagnostic categories with a broad variety list of symptoms. Consequently, patients diagnosed from the same psychiatric illness present a great heterogeneity in their clinical presentation. This fact together with the incomplete knowledge of the neurochemical alterations underlying mental disorders, contribute to the limited efficacy of current pharmacological options. In this respect, the identification of biomarkers in psychiatry is becoming essential to facilitate diagnosis through the developing of markers that allow to stratify groups within the syndrome, which in turn may lead to more focused treatment options. In order to shed light on this issue, this review summarizes the concept and types of biomarkers including an operational definition for therapeutic development. Besides, the advances in this field were summarized and sorted into five categories, which include genetics, transcriptomics, proteomics, metabolomics, and epigenetics. While promising results were achieved, there is a lack of biomarker investigations especially related to treatment response to psychiatric conditions. This review includes a final conclusion remarking the future challenges required to reach the goal of developing valid, reliable and broadly-usable biomarkers for psychiatric disorders and their treatment. The identification of factors predicting treatment response will reduce trial-and-error switches of medications facilitating the discovery of new effective treatments, being a crucial step towards the establishment of greater personalized medicine.