A comprehensive review of the multifaceted role of cannabinoid receptor type 2 in neurodegenerative and neuropsychiatric disorders.

Research carried out during the last 30 years since the first identification of CB2r in 1993 has changed the landscape of this receptor's role and therapeutic utility. Initially, studies focused on elucidating the role of CB2r at the periphery since it was first characterized in spleen and lymphocytes. Later, CB2r was found in the brain not only under pathological conditions but also under basal conditions. It is now known that this receptor is expressed in different brain regions and different cell types, including neurons and microglia. Experimental studies have provided robust evidence that CB2r is involved in the modulation of the immune system, neuroinflammation, oxidative stress and neuroprotection. Besides, CB2r mediated the response to stress, anxiety, and depression. Also, CB2r plays a relevant role in modulating the reinforcing properties of different drugs of abuse, including alcohol, nicotine and cocaine. In this review, we summarize the cumulative knowledge regarding the immunomodulatory, anti-inflammatory, antioxidant, and neuroprotective properties of CB2r against the development of neurodegenerative diseases. Indeed, we cover the anxiolytic and antidepressant potential of CB2r, which raises the therapeutic interest of this receptor in different psychiatric diseases associated with anxiety and depression. Finally, we discuss the involvement of CB2r in the regulation of drug addiction. A better understanding of the properties of CB2r is essential for the pharmacological development of this receptor in different neurodegenerative, psychiatric, and addictive disorders.