Δ⁹-THC training dose as a determinant for (R)-methanandamide generalization in rats

The objective of this study was to examine if (R)-methanandamide, a metabolically stable chiral analog of the endogenous ligand anandamide, is a cannabimimetic with a lower efficacy than Δ⁹-THC. Employing a two-lever choice drug discrimination procedure, rats were trained to discriminate between 1.8, 3.0, or 5.6 mg/kg Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and vehicle. Different training doses were used in order to create assays with different efficacy demands. Generalization tests with 18 mg/kg (R)- methanandamide yielded around 90% Δ⁹THC responses in the two lower Δ⁹- THC training dose conditions. However, only around 60% Δ⁹-THC responses occurred in the 5.6 mg/kg Δ⁹-THC training dose condition in tests with 18 mg/kg (R)-methanandamide; a higher dose (30 mg/kg) produced even fewer Δ⁹- THC-appropriate responses in this group. Morphine did not substitute for Δ⁹-THC. In conclusion, the data with Δ⁹THC and (R)-methanandamide indicate that cannabinoid agonists can have varying degrees of intrinsic activity at a receptor site, or may produce their behavioral actions through multiple mechanisms, or both.