Work

Repeated treatment with JWH-018 progressively increases motor activity and aggressiveness in male mice: involvement of CB1 cannabinoid and D1/D2 dopaminergic receptors

Year: 2025

Type: article

Abstract: To date, the exposure to Synthetic Cannabinoids (SCs) has been linked to unanticipated psychiatric symptoms such as agitation, psychosis, and aggressive behavior. In line with this, preclinical studies have shown that acute and long-term exposure to these compounds can result in psychostimulant effects that may be related to CB 1 -mediated and dopamine-dependent mechanisms. This study focuses on the progressive effects induced by repeated injection of 1-pentyl-3-(1-naphthoyl)indole JWH-018 (6 mg/kg, i.p.) on the locomotor activity and aggressive behavior in adult male ICR-CD1® mice. Thus, the interaction with the cannabinoid CB 1 receptor-preferring antagonist/inverse agonist AM-251 (6 mg/kg, i.p.), the dopamine D 1/5 receptor antagonist SCH23390 (0.1 mg/kg, i.p.), and the dopamine D 2/3 receptor antagonist haloperidol (0.05 mg/kg, i.p.) have been evaluated. Expression and distribution of D 1 and D 2 receptors and tyrosine hydroxylase (TH) have been also investigated by immunohistochemistry on brain and cerebellar samples to explore potential neuroplastic events. The repeated treatment with JWH-018 lead to the exacerbation of unanticipated psychomotor agitation, progressively increasing spontaneous locomotion and aggressiveness. Pre-treatment with AM-251 prevents the effects induced by the SC first, third and seventh injection. SCH23390 and haloperidol significantly attenuate and fully prevent the effects induced by JWH-018 seventh injection when pre-administered, respectively, alone and in combination. Behavioral changes observed in JWH-018-treated mice are accompanied by alterations in cortical, hippocampal, striatal and cerebellar D 1 , D 2 and TH gene expression levels. The present results demonstrated that repeated treatment with high dosage of JWH-018 induces psycho-stimulants effects via both CB 1 receptor-mediated and dopamine-dependent mechanisms. • Repeated injection of JWH-018 in male mice exacerbates psychomotor agitation. • JWH-018 causes psycho-stimulant effects via CB 1 - and dopamine-dependent mechanisms. • Dopaminergic mechanisms underlie the JWH-018 induced psycho-stimulant effects.

Source: European Journal of Pharmacology

DOI: 10.1016/j.ejphar.2025.177633