“Modulatory role of baseline impulsivity on the acute and persistent effects of CB₁ agonism on impulsive choice”

Background: Impulsivity may be defined as a heterogeneous construct characterized by difficulties in inhibiting actions and premature decision-making. Although a high level of impulsivity is recognized as a risk factor for cannabis use disorder, the effects of cannabinoids on impulsive choices have been less explored. Aims: This study aimed to determine the acute and persistent effects of CB_1/2 agonism on impulsive choice in rats using a delay-discounting task (DDT). Methods: Trained adult male Sprague-Dawley rats were injected with either vehicle or increasing doses (0.1, 1, and 5 mg/kg) of the CB_1/2 agonist WIN 55212-2 and tested in the DDT. Results: Our results showed that the effect of WIN55212-2 correlated with baseline impulsivity and reduced impulsivity in rats classified as high impulsive, while no effect was observed in rats classified as low impulsivity. Two weeks after the last WIN55212-2 injection, the rats were injected with vehicle and re-exposed to DDT. Rats classified as high impulsive maintained a significantly high AUC_log value, suggesting a long-lasting effect of WIN 55212-2. Finally, the CB₁ receptor antagonist rimonabant (1 mg/kg) reversed the effect of repeated treatment with WIN55212-2 on impulsivity in the high-impulsive population, suggesting an active role of the CB_1/2 receptor in the persistent effect of WIN55212-2. Conclusions: Our results suggest a potential benefit of CB_1/2 agonism in vulnerable subpopulations with high levels of impulsivity. To maximize therapeutic benefits and minimize potential iatrogenic effects, assessing choice impulsivity and other variables is essential, aligning with personalized medicine principles to effectively tailor interventions.