Cannabis is the most widely self-administered psychoactive substance among adolescents in the U.S., and its use shows no signs of abatement. Studies in humans suggest that heavy cannabis use during this critical period of development can alter brain structure and function and impair cognitive and behavioral processes. However, the extent to which neural changes and neuropsychological deficits produced by cannabis use during adolescence persist into adulthood remains poorly understood, hampering the assessment of long-term health risks. Consequently, there continues to be a pressing need for carefully controlled research on the potential long-term impact of adolescent cannabis exposure on brain development, cognitive competency and addiction. The present research addresses this need with longitudinal studies in nonhuman primates to examine the long-term impact of chronic exposure to the cannabinoid ?9-THC during adolescence. In this research, groups of adolescent male and female squirrel monkeys will be treated daily with a low active dose or a high active dose of ?9-THC or with vehicle. Daily treatment will continue throughout adolescence for 6 months, during which time observational and activity data will be collected to assess behavioral status and the any tolerance to the effects of drug treatment. Neuroimaging data will be collected before, during, and after daily treatment to evaluate changes in neural structure or function that may be associated with chronic exposure to ?9-THC. After the chronic regimens are discontinued, subjects will remain drug-free for 6 weeks to allow for the elimination of the lipophilic cannabinoid. Next, using touchscreen-based tasks, subjects will be studied to determine whether prior exposure to ?9-THC may have persisting effects on motivation or different types of cognitive function. First, using a behavioral economic demand analysis, motivation will be assessed by comparing the reinforcing strength of sweetened condensed milk, a highly palatable reinforcer, in the different treatment groups. Subsequently, two tasks (stimulus discrimination/reversal and delayed matching to position) will be used to compare learning, response inhibition, and spatial short-term memory across treatment groups. Neuroimaging information will be collected prior to and following the above testing. Finally, the acquisition of ?9-THC self-administration will be studied to determine whether adolescent exposure to ?9- THC may have enhanced its reinforcing effects. Lastly, the study will conclude with a final neuroimaging scan. Overall, these longitudinal studies will provide information regarding the persistence of neural abnormalities that may be produced by ?9-THC exposure during adolescence, their association with cognitive impairments or changes in sensitivity to abuse-related effects of ?9-THC, and whether such sequelae and associations can be related to the chronic dosage ?9-THC or differ in males and females.

Public Health Relevance

There is increasing concern that cannabis use during adolescence may dramatically influence brain maturation and lead to both long-term cognitive deficits and increased vulnerability to drug abuse. However, there has been limited relevant research in laboratory animals and, consequently, there is a strong need for translational research in nonhuman primates to address this issue. In our proposed research, we plan to systematically address this ?knowledge gap? with a systematic program of neuroimaging (DTI and fMRI) and behavioral testing in monkeys to determine whether chronic exposure during adolescence to ?9-THC, the most prominent psychoactive cannabinoid in cannabis products, can be associated with post-adolescent changes in neural and cognitive endpoints, and/or increased susceptibility to the reinforcing effects of ?9-THC. Data from these studies will provide presently unavailable information for a scientifically-based understanding of the relationship between the likely effects of cannabis use during adolescence and the neural and its behavioral consequences later in life.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Wenzel, Jennifer Millicent
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Mclean Hospital
United States
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