Both major depression and depressive symptoms are associated with a high rate of nicotine dependence, and a history of major depression has an adverse impact on smoking cessation. The main objective of this study was to investigate whether continuous ingestion of nicotine affects indices of depressive behavior in the rat. We compared cholinergic- and serotonergic-hypersensitive Flinders Sensitive Line rats (FSL), a genetic animal model of depression, with their control counterparts, Flinders Resistant Line rats (FRL). Female rats of both lines were allowed access to a solution of nicotine bitartrate (100 microg/mL) in tap water for 14 days. Subsequent behavioral testing revealed striking effects of continuous ingestion of nicotine on depressive-like behavior of both lines. FSL and FRL rats that ingested nicotine for 14 days displayed less immobility in the 10-min forced-swim test (an index of depressive-like behavior) relative to the animals of both lines that were not exposed to nicotine or exposed to nicotine for shorter periods of time. This finding indicates that ingested nicotine has antidepressant properties that are independent of the genetic difference between FSL and FRL female rats. Animal studies on nicotine ingestion and withdrawal may become an important source of insights into the comorbidity of depression and nicotine self-administration.