The effects of nicotinic receptor agonists on the elevated plus-maze test of anxiety were investigated in CD1 mice after intraperitoneal injections. Nicotine and lobeline, but not cytisine, exhibited a significant increase in the time spent by the mice in the open arms, a measure of anxiolytic activity. Nicotine also increased the total number of arm entries, a measure of general activity, but this effect was secondary to its anxiolytic-like properties. Nicotinic receptor antagonists on their own did not modify the behavior of mice in the maze. The effect of nicotine was mediated by central nicotinic receptors as it was blocked by the centrally-acting nicotinic antagonists mecamylamine and chlorisondamine, but not by hexamethonium (a peripherally acting blocker). Cotinine, the major metabolite of nicotine, was evaluated at different times after systemic injections and had no effect in the plus-maze. The anxiolytic-like profile induced by nicotinic receptor stimulation was not associated with potentiation of alcohol effects, a liability associated with the benzodiazepine therapy. This study demonstrates the anxiolytic-like properties of nicotine and lobeline in mice, and suggests that central nicotinic receptors are involved in the expression of emotional behavior.