Rimonabant-induced Delta9-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 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.

Fig. 1.

Discriminative stimulus effects of rimonabant (1 mg/kg) in rhesus monkeys receiving chronic Δ⁹-THC (1 mg/kg/12 h). Abscissae: vehicle (V) or dose in mg/kg body weight (A and C) and time (Min) after administration of the training dose (1 mg/kg) of rimonabant (B and D). Ordinates: mean (± S.E.M.) percentage of responding on the rimonabant lever (A and B) and mean (± S.E.M.) response rate expressed as a percentage of control (V training days) rate [rate (% control)] (C and D). *, p < 0.05 versus V.

Fig. 2.

Head shaking and heart rate produced by rimonabant in combination with chronic Δ⁹-THC treatment (Chronic Δ⁹-THC; ○) and without Δ⁹-THC (No chronic Δ⁹-THC; ●). Abscissae: vehicle (V) or dose in mg/kg body weight (A and C) and time (Min) after administration of 1 mg/kg rimonabant (B and D). Ordinates: mean (± S.E.M.) frequency of head shaking (A and B) and mean (± S.E.M.) change in heart rate (beats per min) from the nondrug control (C and D). *, p < 0.05 versus V, Chronic Δ⁹-THC. #, p < 0.05 versus V, No chronic Δ⁹-THC.

Fig. 3.

Discriminative and other behavioral effects resulting from abrupt discontinuation of chronic Δ⁹-THC (1 mg/kg/12 h) treatment. Abscissae: Consecutive days before (leftmost THC), during (Deprivation), and after (rightmost THC) temporary discontinuation of 1 mg/kg/12 h Δ⁹-THC. Ordinates: percentage of responding on the rimonabant lever (A), mean (± S.E.M.) response rate expressed as a percentage of control (vehicle training days) rate [rate (% control)] (B), mean (± S.E.M.) frequency of head shaking (C), and cumulative home cage activity during the night (D). *, p < 0.05 versus rightmost Δ⁹-THC point (i.e., predeprivation control).

Fig. 4.

Discriminative stimulus effects and head shaking after cannabinoid agonists, alone and in combination with rimonabant. Abscissae: dose in mg/kg body weight of cannabinoid agonist in combination with vehicle (V) (A–C) or rimonabant (1 mg/kg; R) (D–F). Ordinates: mean (± S.E.M.) percentage of responding on the rimonabant lever (A and D), mean (± S.E.M.) response rate expressed as a percentage of control (V alone) rate [rate (% control)] (B and E), and mean (± S.E.M.) head shaking expressed as a percentage of control (R alone) (C and F). *, p < 0.05 versus V or R in corresponding panels.

Fig. 5.

Discriminative stimulus effects and head shaking after noncannabinoids, alone and in combination with rimonabant. Abscissae: dose in mg/kg body weight of clonidine, cocaine, or diazepam in combination with vehicle (V) (A–C) or rimonabant (1 mg/kg; R) (D–F). Ordinates: mean (± S.E.M.) percentage of responding on the rimonabant lever (A and D), mean (± S.E.M.) response rate expressed as a percentage of control (V alone) rate [rate (% control)] (B and E), and mean (± S.E.M.) head shaking expressed as a percentage of control (R alone) (C and F). *, p < 0.05 versus V or R in corresponding panels.