Clinical and preclinical evidence suggest a role of nicotinic acetylcholine receptors in major depression. In humans, both nicotine and the nonselective nicotinic acetylcholine receptor antagonist mecamylamine ameliorate depressive symptoms. Similarly, both drugs produce antidepressant-like effects in rodents. In rats, the most consistent finding is antidepressant-like effects of nicotine, but not mecamylamine. Conversely, in mice, several studies show antidepressant-like effects of mecamylamine, whereas nicotine has shown modest or no effects. These contradictory results might be because of genetic differences. Here, we compared the effects of nicotine and mecamylamine in females and males of NMRI, C57BL/6J and BALB/c mice using the mouse forced swim (mFST) and tail suspension tests (mTST). In the mFST, mecamylamine, but not nicotine, increased swim distance in NMRI mice. In contrast, nicotine, but not mecamylamine, increased swim distance in C57BL/6J mice. Both drugs increased swim distance in BALB/c mice. Effects in the mFST were independent of sex. In the mTST, mecamylamine decreased immobility in NMRI mice only, independent of sex. Nicotine was devoid of effects in the mTST, except in female C57BL/6J mice, where it increased immobility. We hypothesize that nicotine and mecamylamine produce antidepressant-like effects through partially different mechanisms.