Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

恒河猴大麻素戒断的治疗

• 批准号: 8512680
• 负责人: Lance R McMahon
• 金额: $ 34.23万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512680
• 关键词: 2-arachidonylglycerol; Address; Adrenergic Agonists; Adverse effects; Agonist; Analgesics; Antiemetics; Attenuated; Behavioral; Behavioral Assay; Biological Assay; Cannabinoids; Chronic; Clinical; Dependence; Discrimination; Dose; Endocannabinoids; Funding; Human; In Vitro; Individual; Intoxication; Laboratory Study; Macaca mulatta; Marijuana; Marijuana Dependence; Marijuana Smoking; Mediating; Metabolism; Modification; Neuropharmacology; Opioid; Pharmacotherapy; Public Health; Stimulus; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Effect; Withdrawal; abstracting; anandamide; base; cannabinoid receptor; deprivation; drug discrimination; experience; indexing; inhibitor/antagonist; marijuana user; novel; novel therapeutics; receptor; research study; reuptake; rimonabant; uptake

Abstract Marijuana use is a public health concern. Withdrawal that occurs in over one-half of daily marijuana users is responsible, in part, for marijuana smoking. However, cannabinoids in marijuana produce a variety of therapeutic effects (analgesic and anti-emetic effects). While progress has been made toward establishing receptor mechanisms underlying the behavioral effects of cannabinoids, it is not clear whether the clinically useful actions and abuse liability of cannabinoids vary as a function of pharmacologic efficacy at cannabinoid receptors. Moreover, it is not clear whether pharmacologic modulation (e.g. decreased metabolism or cellular uptake) of endogenous cannabinoid agonists (e.g. anandamide) produces therapeutic effects and less of the non-preferred effects associated with direct cannabinoid agonism. This competing continuation of an 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 predictive of marijuana-like effects in humans. Aim 1 uses a drug discrimination assay of rimonabant-induced cannabinoid withdrawal in rhesus monkeys to characterize the neuropharmacology of withdrawal that emerges upon discontinuation of treatment. Aim 2 explores relationships between pharmacologic (agonist) efficacy at cannabinoid receptors and behavioral effects. Tolerance and cross-tolerance among cannabinoids that vary in efficacy will be examined in rhesus monkeys discriminating ¿9-tetrahydrocannabinol (¿9-THC). This aim also establishes a discrimination assay with a high efficacy cannabinoid agonist and examines dependence to a high efficacy cannabinoid agonist, indexed by discriminative stimulus effects and overt signs of withdrawal. The ¿9-THC discrimination assay in rhesus monkeys was highly sensitive to exogenously administered anandamide, and this assay is used in Aim 3 to examine pharmacologic manipulation of endogenous cannabinoids and interactions between endocannabinoids and ¿9-THC. Aim 3 also examines modification of cannabinoid withdrawal by anandamide and inhibitors of its metabolism (URB 597) and uptake (AM 404). This competing continuation addresses a need for understanding the neuropharmacology of cannabinoids in behavioral assays predictive of marijuana-like intoxication and dependence. Collectively, studies in this competing continuation provide a framework for developing novel pharmacotherapies of marijuana withdrawal and cannabinoid-based therapeutics that could produce fewer adverse effects (i.e. abuse and dependence liability) than marijuana.

摘要

项目成果

Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Delta9-tetrahydrocannabinol.

• DOI: 10.1007/s00213-008-1230-8
• 发表时间: 2009-04
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: McMahon LR

JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects.

• DOI: 10.1016/j.ejphar.2014.06.023
• 发表时间: 2014-10-05
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Rodriguez, Jesse S.;McMahon, Lance R.
• 通讯作者: McMahon, Lance R.

Purity of synthetic cannabinoids sold online for recreational use.

在线销售的用于娱乐用途的合成大麻素的纯度。

• DOI: 10.1093/jat/bkr018
• 发表时间: 2012
• 期刊: Journal of analytical toxicology
• 影响因子: 2.5
• 作者: Ginsburg,BrettC;McMahon,LanceR;Sanchez,JesusJ;Javors,MartinA
• 通讯作者: Javors,MartinA

Enhanced discriminative stimulus effects of Δ(9)-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys.

在存在大麻二酚和 8-OH-DPAT 的情况下，在恒河猴中增强 α(9)-THC 的辨别刺激效果。

• DOI: 10.1016/j.drugalcdep.2016.05.016
• 发表时间: 2016
• 期刊: Drug and alcohol dependence
• 影响因子: 4.2
• 作者: McMahon,LanceR

Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice.

• DOI: 10.1016/j.pnpbp.2012.04.011
• 发表时间: 2012-08-07
• 期刊: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
• 影响因子: 5.6
• 作者: Gould, Georgianna G.;Seillier, Alexandre;Weiss, Gabriela;Giuffrida, Andrea;Burke, Teresa F.;Hensler, Julie G.;Rock, Crystal;Tristan, Amanda;McMahon, Lance R.;Salazar, Alexander;O'Connor, Jason C.;Satsangi, Neera;Satsangi, Rajiv K.;Gu, Ting-Ting;Treat, Keenan;Smolik, Corey;Schultz, Stephen T.
• 通讯作者: Schultz, Stephen T.