BACKGROUND AND PURPOSE This study evaluated gene expression differences between two mouse strains, characterized by opposite impulsivity‐like traits and the involvement of the cannabinoid CB₂ receptor in the modulation of impulsivity.

EXPERIMENTAL APPROACH Behavioural tests were conducted to compare motor activity, exploration and novelty seeking, attention and cognitive and motor impulsivity (delayed reinforcement task: session duration 30 min; timeout 30 s) between A/J and DBA/2 mice. Expression of genes for dopamine D₂ receptors, CB₁ and CB₂ receptors were measured in the cingulate cortex (CgCtx), caudate‐putamen (CPu), accumbens (Acc), amygdala (Amy) and hippocampus (Hipp). Involvement of CB₂ receptors in impulsivity was evaluated in DBA/2 mice with a CB₂ receptor agonist (JWH133) and an antagonist (AM630).

KEY RESULTS DBA/2 mice presented higher motor and exploratory activity, pre‐pulse inhibition impairment and higher cognitive and motor impulsivity level than A/J mice. In addition, DBA/2 mice showed lower (CgCtx, Acc, CPu) D₂ receptor, lower (Amy) and higher (CgCtx, Acc, CPu, Hipp) CB₁ receptor and higher (CgCtx, Acc, Amy) and similar (CPu, Hipp) CB₂ receptor gene expressions. Treatment with JWH133 (0.5, 1, 3 mg·kg⁻¹, i.p.) reduced cognitive and motor impulsivity level, accompanied by CB₂ receptor down‐regulation (CgCtx, Acc, Amy) but did not modify other behaviours. In contrast, AM630 (1, 2, 3 mg·kg⁻¹, i.p.) improved pre‐pulse inhibition and reduced novelty seeking behaviour in DBA/2 mice.

CONCLUSIONS AND IMPLICATIONS CB₂ receptors might play an important role in regulating impulsive behaviours and should be considered a promising therapeutic target in the treatment of impulsivity‐related disorders.