Long-lasting behavioral, molecular and functional connectivity alterations after chronic exposure to THC in adolescent mice

Abstract Heavy and daily use of cannabis with high contents of Δ⁹-tetrahydrocannabinol (THC) during adolescence is associated with an increased risk of developing psychotic disorders later in life. Here, we have generated a mouse model of THC exposure during adolescence that exhibits impairments in social interaction and increased vulnerability to develop sensorimotor gating deficiencies comparable to those previously described among heavy cannabis consumers. Importantly, we provide evidence on long-term cortico-striatal dysconnectivity induced by exposure to THC during adolescence and its correlation with impaired social interactions occurring later in adulthood. Moreover, we have observed long-lasting molecular alterations in key elements that regulate the mesolimbic dopaminergic system, namely on the balance between dopamine D₂, adenosine A2A, and cannabinoid CB₁ receptors in the striatum of treated mice. Together, these findings contribute to a better understanding of the neurobiological bases of the deleterious effects associated with cannabis abuse during adolescence and point to the D₂R, A2AR and CB₁R equilibrium as a potential target to reverse or prevent these effects.