Chronic Δ9-tetrahydrocannabinol exposure in adolescent nonhuman primates: persistent abnormalities in economic demand and brain functional connectivity.

Abstract

Although chronic cannabis use during adolescence can alter brain function and impair complex behavioral processes, it is unclear whether such deficits persist into adulthood. Using a coordinated awake neuroimaging and behavioral approach in nonhuman primates, we addressed this issue by examining the impact of chronic adolescent exposure to Δ⁹-tetrahydrocannabinol (THC) on brain functional connectivity and motivational processes during early adulthood. Female and male squirrel monkeys (n = 23) were treated daily for 6 months during adolescence with vehicle or either a low (0.32 mg/kg) or high dose (3.2 mg/kg) of THC. Regional homogeneity and seed-to-whole-brain functional connectivity were analyzed prior to, during, and following discontinuation of chronic treatment to examine changes in regions implicated in reward processing. Subsequently, motivation and reward sensitivity in these subjects, now young adults, were evaluated in economic demand studies by determining the relationship between escalating response requirements and consumption of differing magnitudes of a palatable food reinforcer. Results show that adolescent THC exposure led to persistent alterations in mOFC, caudate, and ventral striatum whole-brain connectivity. Moreover, subjects treated with vehicle during adolescence displayed an orderly and expected inverse relationship between reward magnitude and demand elasticity, whereas THC-treated subjects exhibited dosage-dependent disorder in reward sensitivity and motivational deficits. Changes in neural circuitry (local connectivity in ventral striatum and whole brain connectivity in mOFC) and economic demand were correlated with indices of reward sensitivity in vehicle- but not THC-treated subjects. Taken together, these data indicate that chronic adolescent THC exposure produced long-lasting neurocognitive abnormalities in reward processing.