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.