Adolescent self-administration of the synthetic cannabinoid receptor agonist JWH-018 induces neurobiological and behavioral alterations in adult male mice.

Rationale The use of synthetic cannabinoid receptor agonists (SCRAs) is growing among adolescents, posing major medicaland psychiatric risks. JWH-018 represents the reference compound of SCRA-containing products.Objectives This study was performed to evaluate the enduring consequences of adolescent voluntary consumption ofJWH-018.Methods The reinforcing properties of JWH-018 were characterized in male CD1 adolescent mice by intravenous selfadministration(IVSA). Afterwards, behavioral, neurochemical, and molecular evaluations were performed at adulthood.Results Adolescent mice acquired operant behavior (lever pressing, Fixed Ratio 1-3; 7.5 ?g/kg/inf); this behavior wasspecifically directed at obtaining JWH-018 since it increased under Progressive Ratio schedule of reinforcement, and wasabsent in vehicle mice. JWH-018 IVSA was reduced by pretreatment of the CB1-antagonist/inverse agonist AM251. Adolescentexposure to JWH-018 by IVSA increased, at adulthood, both nestlet shredding and marble burying phenotypes, suggestinglong-lasting repetitive/compulsive-like behavioral effects. JWH-018 did not affect risk proclivity in the wire-beambridge task. In adult brains, there was an increase of ionized calcium binding adaptor molecule 1 (IBA-1) positive cells inthe caudate-putamen (CPu) and nucleus accumbens (NAc), along with a decrease of glial fibrillary acidic protein (GFAP)immunoreactivity in the CPu. These glial alterations in adult brains were coupled with an increase of the chemokine RANTESand a decrease of the cytokines IL2 and IL13 in the cortex, and an increase of the chemokine MPC1 in the striatum.Conclusions This study suggests for the first time that male mice self-administer the prototypical SCRA JWH-018 duringadolescence. The adolescent voluntary consumption of JWH-018 leads to long-lasting behavioral and neurochemical aberrationsalong with glia-mediated inflammatory responses in adult brains.