SR 141716A differentially attenuates the behavioral effects of ??9-THC in rhesus monkeys

Abstract

The prototypic cannabinoid CB1 antagonist SR 141716A is one important pharmacologic tool for examining CB1 receptors that mediate the behavioral and physiologic effects of delta9-tetrahydrocannabinol (delta9-THC). This study examined the effects of SR 141716A on the rate-decreasing, hypothermic and discriminative stimulus effects of delta9-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. delta9-THC to decrease responding in the food component (ED50=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 delta9-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 degrees C at a dose of 3.2 mg/kg. A dose of 0.32 mg/kg of SR 141716A, significantly attenuated delta9-THC-induced hypothermia without attenuating the rate-decreasing effects of delta9-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. delta9-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 ED50 of the delta9-THC by 2.3- and 3.7-fold, respectively. Collectively, these results demonstrate that the behavioral effects of delta9-THC are not equally attenuated by SR 141716A.

Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice

“…These limitations notwithstanding, differences in the relative potency of SR 141716A and AM 251 suggest that, in addition to a common mechanism of action at cannabinoid CB 1 receptors, there is another mechanism that differentially contributes to the hypothermic and cataleptic effects of cannabinoid agonists in C57BL/6J mice. SR 141716A was shown in previous studies to be limited in its capacity to antagonize the effects of cannabinoids on rates of operant responding and locomotor activity (Järbe et al, 2002;De Vry and Jentzsch, 2004;McMahon et al, 2005), and the current study shows similar limitations in C57BL/6J mice insofar as SR 141716A did not fully attenuate cannabinoid-induced hypoactivity. AM 251 also did not fully attenuate agonist-induced hypoactivity and this incomplete antagonism was not limited to a single cannabinoid agonist (i.e.…”

“…Studies with the cannabinoid CB 1 receptor-selective antagonist SR 141716A (rimonabant) support this view insofar as the hypothermic, cataleptic, antinociceptive, and discriminative stimulus effects of Δ 9 -THC are antagonized by SR 141716A (Wiley et al, 1995b;Compton et al, 1996;McMahon et al, 2005;Beardsley and Thomas, 2005 for review;McMahon, 2006). Although an effective antagonist of several in vivo effects of cannabinoid agonists, SR 141716A does not consistently block cannabinoid-induced decreases in locomotor activity or operant responding; instead, SR 141716A tends to mimic the effects of agonists under these conditions (Järbe et al, 2002;De Vry and Jentzsch, 2004;McMahon et al, 2005; however, see Winsauer et al, 1999).…”

Unconditioned Behavioral Effects of the Powerful κ-Opioid Hallucinogen Salvinorin A in Nonhuman Primates: Fast Onset and Entry into Cerebrospinal Fluid

“…or vehicle. This rimonabant dose has produced antagonism of CB1 receptor-mediated effects in this species in prior studies (McMahon et al, 2005).…”

Endocannabinoid system involvement in brain reward processes related to drug abuse

“…A protocol that we and others have used to characterize the abuse-related effects of cannabinoids is the two-lever choice drug discrimination procedure with THC or other cannabinoid CB1 agonists as the training drug (78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88). Rats or monkeys readily learn to discriminate even relatively low doses of THC from vehicle, although the development of stable discrimination performance usually requires 30 sessions or more.…”