Products containing naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073) are emerging drugs of abuse. Here, the behavioral effects of JWH-018 and JWH-073 were examined in one behavioral assay selective for cannabinoid agonism, rhesus monkeys (n ϭ 4) discriminating ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC; 0.1 mg/kg i.v.), and another assay sensitive to cannabinoid withdrawal, i.e., monkeys (n ϭ 3) discriminating the cannabinoid antagonist rimonabant (1 mg/kg i.v.) during chronic ⌬ 9 -THC (1 mg/kg s.c. 12 h) treatment. ⌬ 9 -THC, JWH-018, and JWH-073 increased drug-lever responding in monkeys discriminating ⌬ 9 -THC; the ED 50 values were 0.044, 0.013, and 0.058 mg/kg, respectively and the duration of action was 4, 2, and 1 h, respectively. Rimonabant (0.32-3.2 mg/kg) produced surmountable antagonism of ⌬ 9 -THC, JWH-018, and JWH-073. Schild analyses and single-dose apparent affinity estimates yielded apparent pA 2 /pK B values of 6.65, 6.68, and 6.79 in the presence of ⌬ 9 -THC, JWH-018, and JWH-073, respectively. In ⌬ 9 -THC-treated monkeys discriminating rimonabant, the training drug increased responding on the rimonabant lever; the ED 50 value of rimonabant was 0.20 mg/kg. ⌬ 9 -THC (1-10 mg/kg), JWH-018 (0.32-3.2 mg/kg), and JWH-073 (3.2-32 mg/kg) dose-dependently attenuated the rimonabantdiscriminative stimulus (i.e., withdrawal). These results suggest that ⌬ 9 -THC, JWH-018, and JWH-073 act through the same receptors to produce ⌬ 9 -THC-like subjective effects and attenuate ⌬ 9 -THC withdrawal. The relatively short duration of action of JWH-018 and JWH-073 might lead to more frequent use, which could strengthen habitual use by increasing the frequency of stimulusoutcome pairings. This coupled with the possible greater efficacy of JWH-018 at cannabinoid 1 receptors could be associated with greater dependence liability than ⌬ 9 -THC.

Rationale Cannabinoid CB1 receptor agonists vary in efficacy in vitro; however, relationships between efficacy and behavioral effects are unclear. Objective This study examined the relationship between apparent CB1 agonist efficacy and in vivo effects. Methods Male C57BL/6J mice responded for food under a fixed ratio 30 schedule; rectal temperature was measured. Sensitivity of the mice to cannabinoid agonists (rank order efficacy in vitro reported to be CP 55940>anandamide>Δ9-tetrahydrocannabinol; Δ9-THC) and a non-cannabinoid (the benzodiazepine midazolam) was determined before, during, and after discontinuation of daily Δ9-THC treatment (32 mg/kg/day, i.p.). Rimonabant was combined with cannabinoids to examine whether CB1 receptors mediated effects on response rate. Results Δ9-THC, CP 55940, anandamide, and midazolam decreased responding at doses smaller than those producing hypothermia. Rimonabant antagonized the rate-decreasing effects of Δ9-THC and CP 55940, but not those of anandamide. Δ9-THC treatment produced tolerance for both rate-decreasing and hypothermic effects. Δ9-THC treatment did not change sensitivity to the rate-decreasing effects of CP 55940, but produced cross-tolerance to CP 55940 for hypothermic effects. Δ9-THC treatment did not modify sensitivity to anandamide and midazolam. Conclusions CB1 receptors mediate the operant rate-decreasing effects of Δ9-THC and CP 55940, but not anandamide, in mice. CB1 agonist efficacy is an important determinant of in vivo effects, especially with regard to the magnitude of tolerance and cross-tolerance resulting from daily Δ9-THC treatment. This applies not only to different cannabinoids when measuring the same effect but also to the same cannabinoid when measuring different effects.

Rationale Δ9-tetrahydrocannabinol (Δ9-THC) modifies dopamine efflux. However, the extent to which cannabinoid and dopamine drugs modify each other’s behavioral effects has not been fully established. Objectives This study examined dopamine releasers and/or transport inhibitors alone and in combination with cannabinoids in two drug discrimination assays. Methods Experimentally and pharmacologically experienced rhesus monkeys (n=5) discriminated Δ9-THC (0.1 mg/kg i.v.) from vehicle while responding under a fixed ratio 5 schedule of stimulus-shock termination. A separate group (n=6) of monkeys responded under the same schedule, received daily Δ9-THC (1 mg/kg/12 h s.c.), and discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.), i.e. cannabinoid withdrawal, from vehicle. A sign of withdrawal sign (head shaking) was examined in monkeys receiving Δ9-THC daily. Results Rimonabant antagonized the Δ9-THC discriminative stimulus and a dose of Δ9-THC greater than the daily treatment attenuated the rimonabant discriminative stimulus. In monkeys discriminating Δ9-THC, the dopamine transporter ligands cocaine, amphetamine, bupropion, RTI 113, and RTI 177 produced a maximum of 2% responding on the drug lever and blocked the discriminative stimulus effects of Δ9-THC. In Δ9-THC treated monkeys discriminating rimonabant, the dopamine transporter ligands partially substituted for and increased the potency of rimonabant to produce discriminative stimulus effects. The dopamine antagonist haloperidol enhanced the Δ9-THC discriminative stimulus without significantly modifying the rimonabant discriminative stimulus. Imipramine and desipramine, which have low affinity for dopamine transporters, were less effective in modifying either the Δ9-THC or rimonabant discriminations. The dopamine transporter ligands and haloperidol attenuated head shaking, whereas imipramine and desipramine did not. Conclusions Dopamine release and/or inhibition of dopamine transport blocks detection of Δ9-THC and is potentially the mechanism by which some therapeutics (e.g. bupropion) reduce the subjective effects of marijuana and enhance the subjective effects of marijuana withdrawal.

Cannabis withdrawal upon discontinuation of long-term, heavy Cannabis use is reported in humans; however, methods to establish the nature and intensity of cannabinoid withdrawal, especially directly observable signs, have not been widely established. This study quantified activity in the home cage of rhesus monkeys and examined the extent to which activity can be used to quantify tolerance to and dependence on Δ9-tetrahydrocannabinol (Δ9-THC). Home-cage activity was measured in one group that received Δ9-THC (1 mg/kg s.c.) every 12 h (i.e., chronic Δ9-THC), and a second group that received Δ9-THC (0.1 mg/kg i.v.) once every 3 days (i.e., intermittent Δ9-THC). Treatment was temporarily discontinued in the chronic Δ9-THC group and the effects of rimonabant and Δ9-THC were examined in both groups. Activity counts were highest during the day (lights on 0600–2000 h) and were lower at night. Rimonabant (0.1–3.2 mg/kg i.v.) dose-dependently increased activity (maximum 20-fold) in the chronic Δ9-THC group but did not significantly alter activity in the intermittent Δ9-THC group. Δ9-THC (0.32–3.2 mg/kg i.v.) dose-dependently decreased activity counts (maximum 4-fold) in both groups but was somewhat more potent in the intermittent as compared with the Δ9-THC group. Discontinuation of Δ9-THC treatment resulted in an immediate (i.e., within 24 h) and time-related increase in activity. The time-related increase in home-cage activity upon abrupt discontinuation of chronic Δ9-THC treatment, as well as the effects of rimonabant to increase activity in monkeys receiving chronic, but not intermittent, Δ9-THC treatment, are consistent with signs of physical dependence on Δ9-THC in primates.

Cannabis withdrawal upon discontinuation of long-term, heavy Cannabis use is reported in humans; however, methods to establish the nature and intensity of cannabinoid withdrawal, especially directly observable signs, have not been widely established. This study quantified activity in the home cage of rhesus monkeys, and examined the extent to which activity can be used to quantify tolerance to and dependence on  9 -tetrahydrocannabinol ( 9 -THC). Home-cage activity was measured in one group that received  9 -THC (1 mg/kg s.c.) every 12 h (i.e., chronic  9 -THC), and a second group that received  9 -THC (0.1 mg/kg i.v.) once every 3 days (i.e., intermittent  9 -THC). Treatment was temporarily discontinued in the chronic  9 -THC group and the effects of rimonabant and  9 -THC were examined in both groups. Activity counts were highest during the day (lights on 0600-2000 h) and were lower at night. Rimonabant (0.1-3.2 mg/kg i.v.) dose-dependently increased activity (maximum 20-fold) in the chronic  9 -THC group, but did not significantly alter activity in the intermittent  9 -THC group.  9 -THC (0.32-3.2 mg/kg i.v.) dose-dependently decreased activity counts (maximum 4-fold) in both groups, but was somewhat more potent in the intermittent as compared with the  9 -THC group.Discontinuation of  9 -THC treatment resulted in an immediate (i.e., within 24 h) and timerelated increase in activity. Resumption of  9 -THC treatment (1 mg/kg/12 h) produced hypoactivity that was no longer evident within 9 days of treatment. The time-related increase in home-cage activity upon abrupt discontinuation of chronic  9 -THC treatment, as well as the effects of rimonabant to increase activity in monkeys receiving chronic, but not intermittent,  9 -THC treatment, are consistent with signs of physical dependence on  9 -THC in primates.