Time matters: CB2 receptor, developmental stress sensitivity and affective vulnerability

Early-life experiences are among the strongest predictors of vulnerability to emotional disorders, including depression in adulthood. Despite this association, the neurodevelopmental mechanisms underlying this link remain poorly understood. In this context, the endocannabinoid system—a neuromodulatory lipid signaling system in the brain—has garnered attention for its role in regulating stress responses and emotional behavior during development. Initially, most studies focused on the cannabinoid receptor type 1, but in recent years, an increasing number of studies have examined the role of cannabinoid receptor type 2 (CB2r) as a potential key modulator of brain response to environmental challenges during developmental states. This review aims to summarize current evidence on how adverse experiences during early life and adolescence influence CB2r in the brain, explore the connection between CB2r and the neuroimmune and behavioral alterations induced by these experiences, and evaluate how pharmacological and genetic studies support a role for CB2r in modulating brain responses to early adversity. Evidence from models of early-life stress, prenatal or perinatal drug exposure, adolescent stress, and recreational drug use indicates that CB2r expression is dynamically regulated by developmental stage, brain region, and biological sex. Moreover, pharmacological and genetic approaches have begun to provide functional evidence that modulation of CB2r may influence the neuroimmune and behavioral consequences of these developmental insults. Although further studies are needed to fully understand the complex role of CB2r, evidence to date suggests a potential involvement of this cannabinoid receptor in the affective and neuropsychiatric consequences of developmental adversity.