Long-term single housing increases aggressive behavior in mice, a condition named isolation-induced aggression or territorial aggression, which can be attenuated by anxiolytic, antidepressant, and antipsychotic drugs. Preclinical and clinical findings indicate that cannabidiol (CBD), has anxiolytic, antidepressant, and antipsychotic properties. Few studies, however, have investigated the effects of CBD on aggressive behaviors. This study investigated whether CBD (5, 15, 30, and 60 mg/kg; i.p.) could attenuate social isolation-induced aggressive behavior in the resident-intruder test. Male Swiss mice (7–8 weeks) were single-housed for 10 days (resident mice) to induce aggressive behaviors, while conspecific mice of same sex and age (intruder mice) were group-housed. During the test, the intruder was placed into the resident’s home-cage and aggressive behaviors initiated by the resident, including the latency for the first attack, number of attacks, and total duration of aggressive encounters, were recorded. The involvement of 5-HT1A and CB1 receptors (CB1R) in the effects of CBD was also investigated. All tested CBD doses induced anti-aggressive effects, indicated by a decrease in the number of attacks. CBD, at intermediary doses (15 and 30 mg/kg), also increased latency to attack the intruder and decreased the duration of aggressive encounters. No CBD dose interfered with locomotor behavior. CBD anti-aggressive effects were attenuated by the 5-HT1A receptor antagonist WAY100635 (0.3 mg/kg) and the CB1 antagonist AM251 (1 mg/kg), suggesting that CBD decreases social isolation-induced aggressive behaviors through a mechanism associated with the activation of 5-HT1A and CB1 receptors. Also, CBD decreased c-Fos protein expression, a neuronal activity marker, in social-isolated mice exposed to the resident-intruder test, indicating a potential involvement of this brain region in the drug effects. Taken together, their findings suggest that CBD may be therapeutically useful to treat aggressive behaviors that are usually associated with psychiatric disorders.
The result of this study was that CBD produced anti-aggressive effects in socially-isolated mice tested in the resident-intruder paradigm. Even if these results, at least with the dose of 15 mg/kg, were replicated in three independent experiments, they contrast with those described in two studies that have failed to detect anti-aggressive effects of CBD (Ham and De Jong, 1975; van Ree et al., 1984). However, these previous studies differ from the present work by having used different animal species, doses, behavioral tests, and aggression-induction models (Ham and De Jong, 1975; van Ree et al., 1984). CBD anti-aggressive effect was not associated with any locomotor impairment and, at least partially, depended on the activation of 5-HT1A and CB1 receptors.