Effects of central and peripheral nicotinic blockade on human nicotine discrimination

Nicotine produces interoceptive stimulus effects in humans, which may be cr itical in understanding tobacco use. It has not yet clearly been demonstrat ed that discrimination of nicotine. or any drug, in humans is due to its ce ntral effects. We compared effects of mecamylamine (10 mg PO), a central an d peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10-40 mu g/kg per min IV). a peripheral nicotine antagonist o nly, and placebo. Smokers (n = 6) were first trained to reliably discrimina te 0 versus 20 mu g/kg nicotine by nasal spray and then tested on generaliz ation of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 mu g/kg) following antagonist/placebo pretreatment. Nicotine self-admin istration was also assessed after generalization testing by having particip ants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the high est dose of nicotine was significantly attenuated following mecamylamine bu t not trimethaphan. Similar results were observed for some subjective respo nses to nicotine, Mecamylamine also tended to increase nicotine self-admini stration. Consistent with previous animal studies, these results suggest th at discriminative stimulus effects of nicotine in humans are mediated at le ast in part by its central effects.