Cannabis is the most commonly used illicit drug in the United States. Chronic heavy cannabis use can result in impaired cognitive processing as characterized by deficits in attention, memory, decision-making and inhibitory control. Neuroimaging studies in humans have demonstrated that long-term heavy cannabis use produces alterations in the function of the prefrontal (orbitofrontal) cortex, hippocampus and components of the basal ganglia, and it has been proposed that neural dysfunction in these regions contributes to a loss of inhibitory control that propels continued cannabis use. However, the cellular and neurochemical mechanisms that underlie cannabis-induced cognitive dysfunction are not known. The overall goals of this project are to employ rodent behavioral tasks to evaluate the effect of chronic treatment with A9-tetrahydrocannabinol (A9- THC) on cognitive function in adolescent and adult rats and to characterize A9-THC-induced alterations in neurochemical signaling that underlie these behavioral abnormalities. A9-THC doses that produce plasma A9-THC concentrations which bracket those achieved by human cannabis smokers will be administered to periadolescent and adult rats in a repeating cycle of 14-day blocks in which A9-THC is administered 2x per day for 6 days, followed by an 8-day drug-free period in during which behavioral testing is performed. This cycle of A9-THC dosing and behavioral testing will be repeated for up to 6 months, and behavioral testing will continue for up to two months after cessation of A9-THC dosing. In the context of the rat lifespan this will provide a reasonable approximation of long-term cannabis use in humans. The experiments in Specific Aim 1 will evaluate the onset, progression and persistence of cognitive dysfunction during and after this A9-THC dosing regimen. Evaluations of attentional capacity (5-CSRTT), impulsive choice/decision making (delaydiscount task), impulsive action/inhibitory control (DRL testing) and executive function (set-shifting) will be made. The experiments in Specific Aim 2 will employ in vivo brain microdialysis to characterize altered neurochemical function in the frontal cortex and related areas that are associated with A9-THC-induced performance deficits in these behavioral tasks. Task-related alterations in interstitial levels of monoamines, excitatory and inhibitory amino acids, acetylcholine and endogenous cannabinoids will be compared between treatment groups. These rodent experiments will complement the neuropsychological testing and brain imaging to be performed in the periadolescent non-human primate, adolescent human and adult human projects of this Center. The establishment of these four, projects will provide a very strong scientific platform for investigations into the neuropsychological and neurobiological bases of cannabis abuse and dependence.
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