Preclinical and clinical studies suggest that neuronal nicotinic acetylcholine receptor (nAChR) antagonists have antidepressant-like properties. The present study examined the effects of lobeline, a nAChR antagonist, in the forced swim test (FST), tail suspension test (TST), and novelty suppressed feeding test (NSFT) of antidepressant efficacy. Lobeline (1 or 4 mg/kg, s.c.) was administered 20 min before the FST and TST in C57BL/6J mice. Pretreatment with lobeline significantly reduced immobility time in the FST but not in the TST. Repeated lobeline (1 or 4 mg/kg, s.c.) treatment for 21 days significantly reduced feeding latency in the NSFT. We also determined the effects of lobeline on forced swim stress (FSS)-induced increased in plasma corticosterone levels using enzyme immunoassay. Pretreatment with lobeline (1 mg/kg, s.c.) significantly attenuated the corticosterone levels. Further, the effects of lobeline on FSS-induced increased in norepinephrine (NE) and serotonin levels in the prefrontal cortex (PFC) and hippocampus were determined using high performance liquid chromatography. Pretreatment with lobeline (1 or 10 mg/kg, s.c.) significantly reduced NE levels in the PFC. Overall, the present study indicates that lobeline produces antidepressant-like effects by targeting brain nAChRs and/or neuroendocrine and brain noradrenergic systems.