AbstractAlthough lobeline and nicotine are both potent ligands at neuronal nicotinic cholinergic receptors, chronic lobeline does not produce the upregulation of nicotinic receptors found with chronic nicotine or the less potent agonist anabasine. Since agonist‐induced receptor upregulation is believed to result from receptor desensitization during chronic treatment, this suggests that lobeline may not desensitize neuronal nicotinic receptors. We addressed this question by comparing lobeline‐ and nicotine‐induced desensitization of the actions of nicotine, using body temperature and locomotor activity as dependent variables. Nicotine pretreatment reduced the hypothermia and locomotor suppression produced by a subsequent nicotine challenge, whereas lobeline pretreatment did not. When tested alone, both nicotine and lobeline reduced locomotor activity and body temperature to a similar degree, but lobeline was significantly less potent. The reductions in activity and temperature produced by nicotine were significantly attenuated in chlorisondamine‐treated mice, whereas treatment with this long‐lasting nicotinic cholinergic antagonist did not alter the effects of lobeline. Thus, nicotine and lobeline appear to differ in their ability to produce desensitization. Furthermore, the effects of these two compounds on locomotor activity and body temperature may be mediated via different mechanisma. © 1994 Wiley