Antidepressant-like effects of the subtype-selective nicotinic acetylcholine receptor agonist, SIB-1508Y, in the learned helplessness rat model of depression

Rationale: Epidemiological studies of smokers suggest that there: is a link between nicotine and depression. Nonetheless, few studies have examined th e potential use of nicotinic ligands in the treatment of depression. Object ives The goal of this study was to evaluate the effects of SIB-1508Y, a nov el subtype-selective ligand for high affinity nicotinic acetylcholine recep tors (nAChRs), in the learned helplessness model of depression in rats. Met hods In this model, exposure to inescapable footshock produces a lasting de ficit in escape responses emitted in a subsequent conditioned avoidance pro cedure (learned helplessness). The effect of SIB-1508Y on learned helplessn ess was compared to the clinically used antidepressants, imipramine and flu oxetine, and the nonselective nAChR ligand, nicotine. Results: Similarly to imipramine and fluoxetine, subchronic treatment (5 days) with SIB-1508Y re versed the escape deficit in the learned helplessness model in a dose depen dent manner. The effect of SIB-1508Y on learned helplessness was still appa rent 1 week following drug administration and was also maintained after 1 w eeks of daily administration. In contrast, while nicotine was able to atten uate the learned helplessness deficit, this trend only reached statistical significance after chronic administration. The non-competitive ion channel blocker mecamylamine increased escape failures when administered alone and blocked the effects: of SIB-1508Y but not imipramine. SIB-1508Y also produc ed an increase in avoidance responding, which suggests an enhancement of le arning. Conclusion: These results not only suggest a role for nAChRs in the development of a depressive-like syndrome, but also that subtype-selective nAChR agonists, such as SIB-1508Y, may offer a novel therapeutic approach to the treatment of depression.