Discriminative‐stimulus effects of the novel CB1 agonist AM 4054 in squirel monkeys

Abstract

Discriminative‐stimulus (Sd) properties of cannabinergic (CB) ligands other than the CB‐1 partial agonist Δ9–THC have not been studied in nonhuman primates. The present studies were conducted to systematically examine the Sd effects of the novel CB‐1 full agonist AM 4054 in squirrel monkeys (n=4) trained under a two‐lever procedure to discriminate i.m. injections of saline from 0.01 mg/kg AM 4054. Results show that the AM 4054 Sd was acquired with varying speed among monkeys. Following acquisition, ≤ 5% and ≥ 97% drug‐lever responding occurred following injection with, respectively, saline and AM 4054. Under test conditions, AM 4054 produced dose‐related (0.001–0.01 mg/kg) increases in drug‐lever responding, with little or no effect on response rate and >90% substitution following 0.0056 mg/kg AM 4054. The Sd effects of 0.01 mg/kg AM 4054 were fully evident 1 hr after injection and dissipated gradually over 12 hr. Dose‐related substitution for AM 4054 also occurred with the CB‐1 agonists Δ9–THC (0.03–3 mg/kg) and methanandamide (0.3–10 mg/kg). In antagonism experiments, SR 141716A dose‐dependently reduced the Sd effects of 0.01 mg/kg AM 4054, with full attenuation after 1.0 mg/kg of the CB‐1 antagonist. Together, these data demonstrate that the discriminative stimulus effects of AM 4054 are CB‐1‐mediated and overlap those of the CB1 agonists Δ9–THC and AM 356 (supported by NIH/NIDA DA19205 and DA7252).