Δ9‐Tetrahydrocannabinol‐induced anti‐inflammatory responses in adolescent mice switch to proinflammatory in adulthood

Marijuana abuse is prominent among adolescents. Although 9 -THC, one of its main components, has been demonstrated to modulate immunity in adults, little is known about its impact during adolescence on the immune system and the long-lasting effects in adulthood. We demonstrate that 10 days of 9 -THC treatment induced a similar alteration of macrophage and splenocyte cytokines in adolescent and adult mice. Immediately at the end of chronic 9 -THC, a decrease of proinflammatory cytokines IL- 1 and TNF- and an increase of antiinflammatory cytokine IL-10 production by macrophages were present as protein and mRNA in adolescent and adult mice. In splenocytes, 9 -THC modulated Th1/Th2 cytokines skewing toward Th2: IFN- was reduced, and IL-4 and IL-10 increased. These effects were lost in adult animals, 47 days after the last administration. In contrast, in adult animals treated as adolescents, a perturbation of immune responses, although in an opposite direction, was present. In adults treated as adolescents, a proinflammatory macrophage phenotype was observed (IL-1 and TNF- were elevated; IL-10 decreased), and the production of Th cytokines was blunted. IgM titers were also reduced. Corticosterone concentrations indicate a longlasting dysregulation of HPA in adolescent mice. We measured blood concentrations of 9 -THC and its metabolites, showing that 9 -THC plasma levels in our mice are in the order of those achieved in human heavy smokers. Our data demonstrate that 9 -THC in adolescent