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 Delta(9)-THC. Employing a two-lever choice drug discrimination procedure, rats were trained to discriminate between 1.8, 3.0, or 5.6 mg/kg Delta(9)-tetrahydrocannabinol (Delta(9)-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% Delta(9)-THC responses in the two lower Delta(9)-THC training dose conditions. However, only around 60% Delta(9)-THC responses occurred in the 5.6 mg/kg Delta(9)-THC training dose condition in tests with 18 mg/kg (R)-methanandamide; a higher dose (30 mg/kg) produced even fewer Delta(9)-THC-appropriate responses in this group. Morphine did not substitute for Delta(9)-THC. In conclusion, the data with Delta(9)-THC 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.