Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

AbstractMarijuana use is a public health concern. Withdrawal that occurs in over one-half of dailymarijuana users is responsible, in part, for marijuana smoking. However, cannabinoids inmarijuana produce a variety of therapeutic effects (analgesic and anti-emetic effects). Whileprogress has been made toward establishing receptor mechanisms underlying the behavioraleffects of cannabinoids, it is not clear whether the clinically useful actions and abuse liability ofcannabinoids vary as a function of pharmacologic efficacy at cannabinoid receptors. Moreover, itis not clear whether pharmacologic modulation (e.g. decreased metabolism or cellular uptake) ofendogenous cannabinoid agonists (e.g. anandamide) produces therapeutic effects and less of thenon-preferred effects associated with direct cannabinoid agonism. This competing continuation ofan R01 examines cannabinoid and non-cannabinoid approaches for treating marijuana withdrawal.This application further examines relationships between behavioral effects, pharmacologic(agonist) efficacy, and pharmacologic manipulation of endocannabinoid levels in assays predictiveof marijuana-like effects in humans. Aim 1 uses a drug discrimination assay of rimonabant-inducedcannabinoid withdrawal in rhesus monkeys to characterize the neuropharmacology of withdrawalthat emerges upon discontinuation of treatment. Aim 2 explores relationships betweenpharmacologic (agonist) efficacy at cannabinoid receptors and behavioral effects. Tolerance andcross-tolerance among cannabinoids that vary in efficacy will be examined in rhesus monkeysdiscriminating ø9-tetrahydrocannabinol (ø9-THC). This aim also establishes a discrimination assaywith a high efficacy cannabinoid agonist and examines dependence to a high efficacy cannabinoidagonist, indexed by discriminative stimulus effects and overt signs of withdrawal. The ø9-THCdiscrimination assay in rhesus monkeys was highly sensitive to exogenously administeredanandamide, and this assay is used in Aim 3 to examine pharmacologic manipulation ofendogenous cannabinoids and interactions between endocannabinoids and ø9-THC. Aim 3 alsoexamines modification of cannabinoid withdrawal by anandamide and inhibitors of its metabolism(URB 597) and uptake (AM 404). This competing continuation addresses a need forunderstanding the neuropharmacology of cannabinoids in behavioral assays predictive ofmarijuana-like intoxication and dependence. Collectively, studies in this competing continuationprovide a framework for developing novel pharmacotherapies of marijuana withdrawal andcannabinoid-based therapeutics that could produce fewer adverse effects (i.e. abuse anddependence liability) than marijuana. PUBLIC HEALTH RELEVANCE: Relevance Marijuana use continues to be a public health concern. However, cannabinoids in marijuana produce a variety of therapeutic effects (analgesic and anti-emetic effects). This competing continuation addresses a need to understand mechanisms at cannabinoid receptors that mediate the dependence liability of marijuana and the potential therapeutic utility of the cannabinoids.