Rimonabant-induced Delta9-tetrahydrocannabinol withdrawal in rhesus monkeys: discriminative stimulus effects and other withdrawal signs.
Jennifer L. Stewart, Lance R Mcmahon
Journal of Pharmacology and Experimental Therapeutics July 2010 DOI: 10.1124/jpet.110.168435 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical drug discrimination and observational study in nonhuman primates Peer reviewed |
|---|---|
| Population | Rhesus monkeys receiving chronic Delta(9)-THC or nondependent monkeys |
| Interventions | Rimonabant Delta(9)-tetrahydrocannabinol (Delta(9)-THC) CP 55940 WIN 55212-2 clonidine diazepam cocaine |
| Dose | Delta(9)-THC 1 mg/kg/12 h s.c.; rimonabant 1 mg/kg i.v. (discrimination) and 3.2 mg/kg in nondependent monkeys |
| Topics | Cannabis |
| Key findings | Rimonabant produced dose-dependent discriminative stimulus effects (ED50 = 0.25 mg/kg) in Delta(9)-THC-treated monkeys, and these effects were fully blocked by Delta(9)-THC and CP 55940, partially by WIN 55212-2 and clonidine, and not by diazepam or cocaine. The authors argue this discriminative stimulus is a more pharmacologically selective measure of cannabinoid withdrawal than head shaking and suggest cannabinoid and alpha(2)-adrenergic agonists may be useful therapeutics for marijuana dependence. |
Abstract
Marijuana-dependent individuals report using marijuana to alleviate withdrawal, suggesting that pharmacotherapy of marijuana withdrawal could promote abstinence. To identify potential pharmacotherapies for marijuana withdrawal, this study first characterized rimonabant-induced Delta(9)-tetrahydrocannabinol (Delta(9)-THC) withdrawal in rhesus monkeys by using drug discrimination and directly observable signs. Second, drugs were examined for their capacity to modify cannabinoid withdrawal. Monkeys receiving chronic Delta(9)-THC (1 mg/kg/12 h s.c.) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) under a fixed ratio schedule of stimulus-shock termination. The discriminative stimulus effects of rimonabant were dose-dependent (ED(50) = 0.25 mg/kg) and accompanied by head shaking. In the absence of chronic Delta(9)-THC treatment (i.e., in nondependent monkeys), a larger dose (3.2 mg/kg) of rimonabant produced head shaking and tachycardia. Temporary discontinuation of Delta(9)-THC treatment resulted in increased responding on the rimonabant lever, head shaking, and activity during the dark cycle. The rimonabant discriminative stimulus was attenuated fully by Delta(9)-THC (at doses larger than mg/kg/12 h) and the cannabinoid agonist CP 55940 [5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and partially by the cannabinoid agonist WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and the alpha(2)-adrenergic agonist clonidine. In contrast, a benzodiazepine (diazepam) and monoamine agonist (cocaine) did not attenuate the rimonabant discriminative stimulus. Head shaking was attenuated by all test compounds. These results show that the discriminative stimulus effects of rimonabant in Delta(9)-THC-treated monkeys are a more pharmacologically selective measure of cannabinoid withdrawal than rimonabant-induced head shaking. These results suggest that cannabinoid and noncannabinoid (alpha(2)-adrenergic) agonists are potentially useful therapeutics for marijuana dependence inasmuch as they attenuate the subjective experience of Delta(9)-THC withdrawal.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 11
- Discriminative stimulus properties of 3-substituent rimonabant analogs VCU Scholars Compass 2011
- Chronic exposure to inhaled vaporized cannabis high in Δ9-THC suppresses Adderall-induced brain activity. Frontiers in Pharmacology 2024
- Chronic Δ9-THC in Rhesus Monkeys: Effects on Cognitive Performance and Dopamine D2/D3 Receptor Availability. Journal of Pharmacology and Experimental Therapeutics February 2018
- Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids. Current Topics in Behavioral Neurosciences 2018
- Enhanced discriminative stimulus effects of Δ(9)-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys. Drug and Alcohol Dependence August 1, 2016
and 6 more in the library
Cites 3
- Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Delta9-tetrahydrocannabinol. Psychopharmacology April 2009
- Abstinence symptoms following oral THC administration to humans. Psychopharmacology February 1, 1999
- Mesolimbic dopaminergic decline after cannabinoid withdrawal. Proceedings of the National Academy of Sciences August 18, 1998