Rimonabant-Induced Δ9-Tetrahydrocannabinol Withdrawal in Rhesus Monkeys: Discriminative Stimulus Effects and Other Withdrawal Signs

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 Δ⁹-tetrahydrocannabinol (Δ⁹-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 Δ⁹-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 (ED₅₀ = 0.25 mg/kg) and accompanied by head shaking. In the absence of chronic Δ⁹-THC treatment (i.e., in nondependent monkeys), a larger dose (3.2 mg/kg) of rimonabant produced head shaking and tachycardia. Temporary discontinuation of Δ⁹-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 Δ⁹-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 [(<i>R</i>)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and the α₂-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 Δ⁹-THC-treated monkeys are a more pharmacologically selective measure of cannabinoid withdrawal than rimonabant-induced head shaking. These results suggest that cannabinoid and noncannabinoid (α₂-adrenergic) agonists are potentially useful therapeutics for marijuana dependence inasmuch as they attenuate the subjective experience of Δ⁹-THC withdrawal.