SR 141716A differentially attenuates the behavioral effects of Δ⁹-THC in rhesus monkeys

The prototypic cannabinoid CB₁ antagonist SR 141716A is one important pharmacologic tool for examining CB₁ receptors that mediate the behavioral and physiologic effects of Δ⁹- tetrahydrocannabinol (Δ⁹-THC). This study examined the effects of SR141716A on the rate-decreasing, hypothermic and discriminative stimulus effects of Δ⁹-THC in rhesus monkeys. In monkeys (n=4) responding under a multiple fixed ratio (FR-10:FR-10) schedule of food presentation and stimulus-shock termination, the potency of i.m. Δ⁹-THC to decrease responding in the food component (ED ₅₀=0.64 mg/kg) was threefold greater than its potency in the stimulus-shock termination component (ED₅₀=2.14 mg/kg). In the same monkeys, hypothermia was induced by Δ⁹-THC at a dose (e.g. 0.32 mg/kg) that did not alter responding in either schedule component; the maximum decrease was 2.1°C at a dose of 3.2 mg/kg. A dose of 0.32 mg/kg of SR 141716A, significantly attenuated Δ⁹-THC-induced hypothermia without attenuating the rate-decreasing effects of Δ⁹-THC in either component of the multiple schedule. The largest dose of i.m. SR 141716A that was studied, 1.0 mg/kg, significantly decreased rectal temperature and responding in the food component but did not significantly decrease responding in the stimulus-shock termination component of the multiple schedule. In a separate group of monkeys (n=3) that discriminated i.v. Δ⁹-THC (0.1 mg/kg) while responding under an FR-5 schedule of stimulus-shock termination, SR 141716A (0.32 and 1 mg/kg) significantly increased the ED ₅₀ of the Δ⁹-THC by 2.3- and 3.7-fold, respectively. Collectively, these results demonstrate that the behavioral effects of Δ⁹-THC are not equally attenuated by SR 141716A.