Delta(9)-THC training dose as a determinant for (R)-methanandamide generalization in rats

The objective of this study was to examine if (R)-methanandamide, a metabol ically stable chiral analog of the endogenous ligand anandamide, is a canna bimimetic with a lower efficacy than Delta(9)-THC. Employing a two-lever ch oice drug discrimination procedure, rats were trained to discriminate betwe en 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)-methanan damide yielded around 90% Delta(9)-THC responses in the two lower Delta(9)- THC training dose conditions. However, only around 60% Delta(9)-THC respons es 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 fe wer Delta(9)-THC-appropriate responses in this group. Morphine did not subs titute 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 a ctions through multiple mechanisms, or both.