Discriminative stimulus properties of delta 9-tetrahydrocannabinol: mechanistic studies

delta 9-Tetrahydrocannabinol (THC) produces a multiplicity of pharmacologic effects including analgesic, antiinflammatory, anticonvulsant, antidiarrheal, antiglaucoma, antihypertensive, and sedative effects. Efforts to elucidate the neurochemical systems mediating the THC effects have used these and related endpoints. However, animal models useful for evaluating the mechanisms by which THC produces its unique subjective effects have only recently been established. The use of drugs as discriminative stimuli provides a means for studying such mechanisms, since generalization data from this test closely correlate with subjective properties observed in clinical studies. The present study examined the ability of various drugs to mimic or block the cue produced by THC in rats. In animals trained to discriminate 3.2 mg/kg THC from vehicle, generalization occurred consistently with cannabinoids such as 11-OH-THC, HHC, and nabilone. Stereoselective generalization was also obtained with isomers of a potent analgesic, nantradol; potencies were consistent with results from other endpoints. In contrast, THC cueing was not produced by agents acting on adrenergic, cholinergic, serotonergic, GABAergic, or opiate systems. Similarly, a number of drugs previously reported to antagonize various nonunique effects of THC uniformly failed to block its subjective properties. These results indicate that the subjective properties of THC are mediated through as yet unidentified neurochemical systems.