JWH-018 in rhesus monkeys: Differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED₅₀=0.01 mg/kg) and decreased response rate (ED₅₀=0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940=JWH-018>Δ⁹-THC=WIN-55212-2=JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and Δ⁹-THC decreased rectal temperature by 2.2 and 2.8 °C, respectively; the doses decreasing temperature by 2 °C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and Δ⁹-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ⁹-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ⁹-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ⁹-THC act at the same receptors to produce several of their shared psychopharmacological effects.