Age- and sex-dependent participation of the endocannabinoid system in locomotion and risk assessment of an ADHD rat model

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting individuals across age groups. Impairments in executive function characterize ADHD and are often associated with elevated levels of risk-taking behaviors. The endocannabinoid system plays a crucial role in modulating prefrontal cortex circuits. Here, we assessed the effects of acute pharmacological manipulation of cannabinoid CB1 and CB2 receptors on locomotion and risk assessment/anxiety-like behaviors in an ADHD animal model during adolescence and adulthood. Further, we investigated the protein levels and gene expression of endocannabinoid system components (CB1, CB2, FAAH, MAGL) in the prefrontal cortex at both ages. During adolescence, activation of cannabinoid receptors aggravated the hyperactivity and risky behaviors of the ADHD model. These behavioral traits were more evident in female rats. In adulthood, manipulation of cannabinoid receptors did not alter hyperactivity but worsened risk assessment. Overall, gene expression levels of receptors and enzymes of the endocannabinoid system were increased in the ADHD model. Our findings suggest that the endocannabinoid system may operate differently in ADHD, and manipulating this system, especially in adolescents, could exacerbate deficits in inhibitory control.