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

Jarbe et al. (1998a) trained rats to discriminate between (-)-Delta(9)-tetr ahydrocannabinol (Delta(9)-THC) and vehicle, using different training doses in order to create assays with different efficacy demands, to examine whet her (R)-methanandamide, an analog of the endogenous ligand anandamide, had lower efficacy than Delta(9)-THC. Rats were initially trained with 3 mg/kg Delta(9)-THC, then tested with (R)-methanandamide and Delta(9)-THC. Thereaf ter, the rats were split into two groups and retrained with either 1.8 or 5 .6 mg/kg Delta(9)-THC, followed by additional tests with the two agonists. The current study systematically replicated this study in two groups of rat s, trained from the outset to discriminate between vehicle and either 1.8 o r 5.6 mg/kg Delta(9)-THC, respectively. Two-lever operant drug discriminati on procedures were used. The outcomes in the two studies were similar. In t ests with (R)-methanandamide, full substitution occurred in the low-dose De lta(9)-THC training group, whereas substitution was partial in the high-dos e Delta(9)-THC training group. (R)-Methanandamide in higher doses exerted m arked suppression of lever pressing. In tests with Delta(9)-THC, full subst itution occurred in both Delta(9)-THC-trained groups, and rates of respondi ng 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 th eir behavioral actions through multiple mechanisms, or both. Prevailing tra ining-dose condition rather than prior training-dose history is the major d eterminant for the substitution pattern. (C) 2000 Lippincott Williams and W ilkins.