Effects of training dose and two- versus three-choice testing procedure onnicotine discrimination responding in humans

Rationale: Discrimination of a drug's interoceptive stimulus effects often depends substantially on training and testing conditions. Objectives: We ex amined changes in nicotine discrimination behavior in humans as a function of lowering the training dose and of varying the discrimination testing pro cedure. Methods: Smokers and never-smokers (n=10 each) were initially train ed to discriminate 20 mu g/kg nicotine by nasal spray from placebo (0) and tested on generalization of discrimination responding across a range of dos es from 0 to 20 mu g/kg. Each subsequently learned to reliably discriminate progressively smaller doses of nicotine from placebo until his or her thre shold dose for discrimination was identified (mean=2.7 mu g/kg). A repeat t esting of generalization responding across 0-20 mu g/kg was then conducted, using placebo and the subject's threshold dose as training doses. Generali zation testing involved both two-choice and three-choice (novel response op tion) quantitative procedures. Results: A significant shift to the left was seen in nicotine-appropriate responding in the two-choice procedure when t he nicotine training dose was lowered (i.e. from the first to the second te st of generalization). In the three-choice procedure, however, there was no such leftward shift. Instead, in never-smokers, a flattening of nicotine-a ppropriate responding occurred with a lowering of the training dose, while novel-appropriate responding significantly increased. The subjective effect s of "head rush" and, in never-smokers only, "jittery" also showed a shift to the left in their relationship with nicotine generalization dose when th e training dose was lowered. Conclusions: These results confirm the importa nce of training and testing conditions on discrimination behavior and subje ctive drug responses within subjects and demonstrate the utility of the nov el-response, three-choice procedure for assessing qualitatively different s timulus effects of novel drug doses.