Discriminative stimulus functions of AM-1346, a CB1R selective anandamide analog in rats trained with Δ⁹-THC or (R)-methanandamide (AM-356)

Objective: To characterize in vivo the high-affinity cannabinoid CB1 receptor (CB1R) selective anandamide analog AM-1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination procedures. d-Amphetamine and also morphine in the (R)-methanandamide-trained group (see below) were examined to assess pharmacological specificity. Methods: Three groups of rats were trained to discriminate between vehicle and (1) 1.8 mg/kg Δ⁹- tetrahydrocannabinol (Δ⁹-THC); (2) 5.6 mg/kg Δ⁹-THC; and (3) 10 mg/kg (R)-methanandamide (AM-356; a metabolically stable analog of anandamide). Δ⁹-THC was given i.p. 30 min and (R)-methanandamide 15 min before training. Results: AM-1346 generalized to all three training conditions, both at 15 and 30 min after administration. The rank order potency was: Δ⁹-THC > AM-1346 > (R)-methanandamide. AM-1346 appeared slightly more potent 30 min compared to 15 min postadministration. In the presence of 0.3 mg/kg of the CB1R antagonist/inverse agonist SR-141716A, the dose generalization curves of Δ⁹-THC and AM-1346 resulted in parallel shifts to the right in the 1.8 mg/kg Δ⁹-THC-trained group. A long duration of action for AM-1346 (relative to AM-356) was indicated in tests where AM-1346 was examined in the 5.6 mg/kg Δ⁹-THC-trained group. Neither d-amphetamine, nor morphine generalized in either of the groups, suggesting pharmacological specificity. Conclusion; Unlike (R)-methanandamide, the surmountable antagonism between SR-141716A and AM-1346 shows that the structural features of anandamide can be modified in ways that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB1R agonists derived from an anandamide template.