Repeated doses of the synthetic cannabinoid JWH-018 progressively increased hyperactivity and aggression in mice

Repeated JWH-018 (6 mg/kg) treatment progressively increased spontaneous locomotion and aggressiveness in mice. The CB1 antagonist AM-251 prevented effects across all injections. Dopamine D1 antagonist SCH23390 and D2 antagonist haloperidol attenuated and prevented seventh-injection effects, respectively, especially in combination. Behavioral changes were accompanied by alterations in cortical, hippocampal, striatal, and cerebellar dopamine receptor and tyrosine hydroxylase gene expression.

Adult male ICR-CD1 mice received repeated JWH-018 injections (6 mg/kg, i.p.) with pharmacological challenges using CB1 antagonist AM-251, D1 antagonist SCH23390, and D2 antagonist haloperidol. Behavior was assessed by locomotor activity and aggression. Brain immunohistochemistry examined D1, D2 receptor and tyrosine hydroxylase expression.

Synthetic cannabinoids are linked to unpredictable psychiatric symptoms including agitation and aggression. This study identifies specific neurobiological mechanisms through which repeated exposure may produce escalating behavioral effects.

The dual CB1 and dopamine mechanism identified here helps explain why synthetic cannabinoid users sometimes present with symptoms resembling stimulant psychosis rather than typical cannabis intoxication.

Animal study using a single high dose that may not reflect human use patterns. Only male mice were studied. JWH-018 is one of many synthetic cannabinoids with varying pharmacology. Behavioral tests in mice have limited translational value for human aggression.