Cannabidiol prevents social avoidance, potentiation of cocaine reward and gene expression alterations induced by exposure to intermittent social defeat in mice

Exposure to intermittent social defeat (ISD), a model of social stress, increased anxiety- and depression-like behaviors and enhanced sensitivity of mice to the rewarding effects of cocaine. In this study, we evaluated the role of cannabidiol on these behavioral effects of ISD and ISD-induced alterations in targets of the serotonin, endocannabinoid and hypothalamus-pituitary-adrenal (HPA) systems. Male mice were treated with cannabidiol (30 or 60 mg/kg) and exposed to four episodes of social defeat on PND 47, 50, 53 and 56. Control mice were not exposed to stress. In experiment 1, on PND 57-58, mice were tested in several behavioral tests and, three weeks later, underwent a cocaine-induced conditioned place preference. In experiment 2, the gene expression of the serotonin transporter in the dorsal raphe, corticotrophin-releasing factor in the paraventricular nucleus, proopiomelanocortin in the arcuate nucleus and the glucocorticoid and cannabinoid receptors in the hippocampus were evaluated after the last episode of defeat. CBD reversed the social interaction deficit and the potentiation of cocaine preference, but not anxiety-like effects induced by ISD. In addition, except for the glucocorticoid receptor, ISD reduced gene expression, and this effect was reversed by cannabidiol. Our results indicated the involvement of serotonin, HPA and endocannabinoid systems in the effects of social stress. They showed that CBD is a promising therapeutic agent to prevent social avoidance, enhanced vulnerability to cocaine and gene expression alterations in stress-exposed individuals.