Neural and Behavioral Consequences of Chronic THC Exposure During Adolescence

Abstract Studies in humans suggest that frequent cannabis use during adolescence can alter brain structure and function and impair motivational and cognitive processes. However, the extent to which such neural changes and neurocognitive deficits persist into adulthood remains poorly understood, hampering the assessment of long- term health risks. Consequently, there is a pressing need for prospective research to investigate the potential long-term impact of adolescent cannabis exposure on brain development and dynamic behavioral processes. In ongoing work under R01-DA047575 to address this need, we have conducted longitudinal studies in nonhuman primates to examine the long-term impact of chronic exposure during adolescence to Δ9-THC, the most prominent cannabinoid in cannabis products. In male and female squirrel monkeys, neuroimaging data show that moderate and high levels of Δ9-THC exposure for 6 months during late adolescence interfered with normal age-related changes in functional connectivity and produced changes in brain structure and function that persisted into adulthood. Exposure to Δ9-THC during adolescence also had persisting effects on motivation, assessed with an economic demand analysis of both reward processing and the reinforcing strength of a highly palatable food, and on reward-based learning and cognitive flexibility, assessed with a stimulus discrimination/reversal task. Moreover, brain regions implicated in motivated behavior and cognitive function were among those in which resting state functional connectivity was altered. In conjunction, our findings thus far are striking. To further advance our understanding of the long-term consequences of chronic exposure to Δ9- THC during adolescence, we plan to continue our studies along three lines of investigation. First, to assess the unique vulnerability of adolescence to the effects of daily exposure to Δ9-THC, we will conduct longitudinal studies in adult monkeys identical to those already conducted in adolescent monkeys. This will permit direct comparison of long-lasting neural and behavioral effects of adolescent and adult Δ9-THC exposure. Second, to explore the generality of the reward devaluation revealed in economic demand studies of food reinforcement, neuroimaging (BOLD) data and exponential demand functions from studies of drug (cocaine, fentanyl) reinforcement during awake 9.4T scan sessions will be collected and analyzed. Third, we plan to further examine the disruption of reward-based learning mechanisms by adolescent Δ9-THC exposure. In these studies, we will investigate the effects of such exposure on the dynamics of Pavlovian conditioning of neutral stimuli with appetitive or aversive events (acquisition and extinction of conditioned stimulus properties) and on associated patterns of neural activity revealed with BOLD imaging during awake 9.4T scan sessions. Overall, these studies will significantly extend our understanding of selectivity and persistence of neural and behavioral abnormalities following chronic Δ9-THC exposure during adolescence. The overall impact of this research will lie in increasing awareness of long-term health risks that can follow exposure to Δ9-THC-containing cannabis products.