Delta9-THC training dose as a determinant for (R)-methanandamide generalization in rats: a systematic replication.

Järbe et al. (1998a) trained rats to discriminate between (-)-delta9-tetrahydrocannabinol (delta9-THC) and vehicle, using different training doses in order to create assays with different efficacy demands, to examine whether (R)-methanandamide, an analog of the endogenous ligand anandamide, had lower efficacy than delta9-THC. Rats were initially trained with 3 mg/kg delta9-THC, then tested with (R)-methanandamide and delta9-THC. Thereafter, the rats were split into two groups and retrained with either 1.8 or 5.6 mg/kg delta9-THC, followed by additional tests with the two agonists. The current study systematically replicated this study in two groups of rats, trained from the outset to discriminate between vehicle and either 1.8 or 5.6 mg/kg delta9-THC, respectively. Two-lever operant drug discrimination procedures were used. The outcomes in the two studies were similar. In tests with (R)-methanandamide, full substitution occurred in the low-dose delta9-THC training group, whereas substitution was partial in the high-dose delta9-THC training group. (R)-Methanandamide in higher doses exerted marked suppression of lever pressing. In tests with delta9-THC, full substitution occurred in both delta9-THC-trained groups, and rates of responding were comparable to those observed during regular drug training sessions. In conclusion, both sets of data indicate that cannabinoid agonists either can have varying degrees of efficacy at a receptor site, or may produce their behavioral actions through multiple mechanisms, or both. Prevailing training-dose condition rather than prior training-dose history is the major determinant for the substitution pattern.