A role for neuronal nicotinic receptor (NNR) activation in animal models of depression has been established. In order to determine the mechanism by which NNR ligands exert their antidepressant effects, experiments using different NNR receptor antagonists in both the mouse and the rat forced swim test (RFST) were performed. In the mouse forced swim test (MFST), A-85380 (0.62 μmol/kg=0.14 mg/kg, i.p.), an NNR agonist, increased swim distance when administered 15 min prior to test. This effect was blocked by pre-treatment with mecamylamine (1.5 μmol/kg=0.3 mg/kg, i.p.), suggesting that an NNR mechanism is involved. Further, chlorisondamine at a non-central nervous system (CNS) penetrating dose (1.6 μmol/kg=1 mg/kg, i.p.) did not antagonize A-85380 in this model, thus implicating central rather than peripheral nicotinic receptors. Dihydro-β-erythroidine (DHβE, 0.3 μmol/kg=0.1 mg/kg, i.p.) pre-treatment also blocked this effect, indicating that the α 4 β 2 receptor subtype may be involved in A-85380-induced antidepressant effects. Finally, methiothepin (0.33 μmol/kg=0.14 mg/kg, i.p.) pre-treatment antagonized this effect, suggesting serotonergic involvement. In the rat modified forced swim test, sub-acute administration of A-85380 (0.62 μmol/kg, i.p.) increased swimming behavior and decreased immobility. Climbing behavior was unaffected. In contrast, desipramine treatment (33 μmol/kg=10 mg/kg, i.p.) resulted in an increase in climbing behavior with no effect on swimming. This behavioral profile has been shown to be more typical of serotonergic rather than noradrenergic antidepressants, suggesting that A-85380 exerts its effects via NNR activation of serotonergic systems.