In addition to S(-)-nicotine, several minor tobacco alkaloids ((+/-)-nornicotine, anabaseine, S(-)-anabasine, and S(-)-N-methylanabasine) are present in tobacco smoke. This study demonstrates that these alkaloids increase fractional H-3 release in a concentration-dependent manner from rat striatal slices preloaded with [H-3]dopamine, with desensitization of this response. The rank order of EC(50) values was S(-)-nicotine (3.0 +/- 2.2 mu M) > (+/-)-nornicotine (6.7 +/ -2.1 mu M) > anabaseine (15.4 +/- 6.1 mu M) = S(-)-N-methylanabasine (16.3 +/- 4.7 mu M) = S(-)-anabasine (19.3 +/- 3.2 mu M). The alkaloids did not modulate fractional H-3 release evoked by electrical-field depolarization. Thus, minor tobacco alkaloids may contribute to the apparent neuroprotective effects of smoking in neurodegenerative diseases.