CONSEQUENCES OF CHRONIC EXPOSURE TO DELTA9-THC IN MONKEYS

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The objective of Project #3 "Consequences of chronic exposure to A9-tetrahydrocannabinol in monkeys" is to further the goals of the P20 center by establishing a model of adolescent cannabis exposure in nonhuman primates. The studies propose to examine the neurobehavioral and neurochemical sequelae of chronic exposure to A9-tetrahydrocannabinol (THC) in peri-adolescent rhesus monkeys. The model offers a unique translational bridge across the Center Projects because monkeys will be studied across the adolescent (Proj #2) to young adult (Proj #1) developmental stages, will be examined on tasks identical in many cases to the human tasks and can be exposed to specific drug models informed by Proj #4 rodent results. The first Aim is to determine the effects of chronic THC exposure on neuropsychological test battery measures (CANTAB) long established in the laboratory. The acquisition and performance of tasks which measure attentional shift, spatial memory, recognition memory, decision making motor function and motivation will be compared between animals chronically exposed to THC for 2 years and vehicle-exposed monkeys. Since CANTAB measures will also be employed in Proj #1 and #2, and analogous tasks used in the rodent Proj #4, the results from the monkeys will be used to refine the specificity of the behavioral measures for all projects. Periodic cerebrospinal fluid sampling will be employed throughout chronic dosing to monitor neurochemical sequelae of chronic exposure. The second Aim is to determine the effects of withdrawal from chronic THC exposure on behavior, neurochemistry and physiology; antagonist challenge (SR141716A) and spontaneous (28 day) withdrawal approaches will be examined. The fourth Aim is to determine the effects of chronic THC exposure on brain activation using functional Magnetic Resonance Imaging. This f MRI approach is developmental in nature and will be informed by ongoing results from Proj #1 and #2. In total, the studies proposed will address questions regarding the impact of chronic exposure to the primary psychoactive constituent of cannabis and the behavioral specificity, neurochemical and neurovascular sequelae of chronic THC in monkeys will be determined. These studies will also establish a peri-adolescent model of cannabis exposure with tremendous potential for further translational studies in an eventual full Center.