Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors

Author(s)

Hartmann, Alice ^{[1, 2]} ; Lisboa, Sabrina Francesca ^{[1, 2]} ; Sonego, Andreza Buzolin ^{[1, 2]} ; Coutinho, Debora ^[2] ; Gomes, Felipe Villela ^{[1, 2]} ; Guimaraes, Francisco Silveira ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo - Brazil

^[2] Univ Sao Paulo, FMRP, Med Sch Ribeirao Preto, Dept Pharmacol, 3900 Bandeirantes Ave, BR-14049900 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY; v. 94, AUG 30 2019.
• Web of Science Citations: 0

Abstract

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), a non-psychotomimetic compound from Cannabis sativa, has anxiolytic, antidepressant, and antipsychotic properties. Few studies, however, have investigated the effects of CBD on aggressive behaviors. Here, we 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 the lateral periaqueductal gray (lPAG) in social-isolated mice exposed to the resident-intruder test, indicating a potential involvement of this brain region in the drug effects. Taken together, our findings suggest that CBD may be therapeutically useful to treat aggressive behaviors that are usually associated with psychiatric disorders. (AU)

• FAPESP's process: 16/14282-6 - Evaluation of the Cannabidiol effects under neuroimmunoendocrine and behavioral alterations induced by stress in mice
• Grantee: Alice Hartmann dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/17343-0 - Evaluation of CBD effects on the molecular and behavioral changes induced by repeated treatment with MK-801
• Grantee: Felipe Villela Gomes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/24304-0 - New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders
• Grantee: Francisco Silveira Guimaraes
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/22523-0 - Possible neuroinflammatory mechanisms involved in the extinction deficits of conditioning fear following exposing rats to a predator: the role of endocannabinoid system
• Grantee: Sabrina Francesca de Souza Lisboa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/19731-6 - Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat the posttraumatic stress disorder (PTSD)
• Grantee: Sabrina Francesca de Souza Lisboa
• Support Opportunities: Research Grants - Young Investigators Grants