(R)-methanandamide, but not anandamide, substitutes for Delta(9)-THC in a drug-discrimination procedure

Fourteen male rats were trained to discriminate between injections of 2 mg/kg delta-9-tetrahydrocannabinol (Delta(9)-THC) and vehicle in a 2-lever operant drug-discrimination paradigm. Following training, substitution tests using a cumulative dosing procedure revealed that anandamide (0.5-16 mg/kg ip), the putative endogenous cannabinoid receptor ligand, failed to generalize to the discriminative stimulus properties of the training dose of Delta(9)-THC. However, dose-dependent generalization to the Delta(9)-THC cue was observed following administration of both CP-55,940 (0.05-0.8 mg/kg ip), a synthetic cannabinoid, and (R)-methanandamide (0.5-8 mg/kg ip), a metabolically stable analog of anandamide. Collectively, these results demonstrate a cannabinoid-specific in vivo effect of an anandamide compound and suggest that the naturally occurring form of anandamide may be metabolized too rapidly to produce a cannabimimetic interoceptive state when administered peripherally.