Adolescent rats find repeated Delta(9)-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure.

The current study examined whether adolescent rats are more vulnerable than adult rats to the lasting adverse effects of cannabinoid exposure on brain and behavior. Male Wistar rats were repeatedly exposed to Delta-9-tetrahydrocannabinol (Delta(9)-THC, 5 mg/kg i.p.) in a place-conditioning paradigm during either the adolescent (post-natal day 28+) or adult (post-natal day 60+) developmental stages. Adult rats avoided a Delta(9)-THC-paired environment after either four or eight pairings and this avoidance persisted for at least 16 days following the final Delta(9)-THC injection. In contrast, adolescent rats showed no significant place aversion. Adult Delta(9)-THC-treated rats produced more vocalizations than adolescent rats when handled during the intoxicated state, also suggesting greater drug-induced aversion. After a 10-15 day washout, both adult and adolescent Delta(9)-THC pretreated rats showed decreased social interaction, while only Delta(9)-THC pretreated adolescent rats showed significantly impaired object recognition memory. Seventeen days following their last Delta(9)-THC injection, rats were euthanased and hippocampal tissue processed using two-dimensional gel electrophoresis proteomics. There was no evidence of residual Delta(9)-THC being present in blood at this time. Proteomic analysis uncovered 27 proteins, many involved in regulating oxidative stress/mitochondrial functioning and cytoarchitecture, which were differentially expressed in adolescent Delta(9)-THC pretreated rats relative to adolescent controls. In adults, only 10 hippocampal proteins were differentially expressed in Delta(9)-THC compared to vehicle-pretreated controls. Overall these findings suggest that adolescent rats find repeated Delta(9)-THC exposure less aversive than adults, but that cannabinoid exposure causes greater lasting memory deficits and hippocampal alterations in adolescent than adult rats.