Spontaneous motor activity in a Y-maze was measured in DBA/2Ibg and C57BL/6Ibg mice which had received nicotine or saline injections three times a day for two, four or seven days. Both genotype and sex influenced the development of tolerance to nocotine's effects on spontaneous motor activity, with DBA males requiring the longest exposure to nicotine and C57 males requiring the shortest drug exposure for tolerance development. DBA and C57 females developed behavioral tolerance equally after two days of pretreatment, but the C57 females showed a greater degree of tolerance after seven days of injections than did the DBA females. The development of behavioral tolerance in DBA males after four days of nicotine pretreatment was associated with the development of behavioral tolerance in DBA males after four days of nicotine pretreatment was associated with the development of drug dispositional tolerance, with minimal evidence for a change in nervous system sensitivity. Drug dispositional tolerance in DBA females, C57 males and C57 females, however, did not seem to affect spontaneous motor activity.