α4β2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties

Previous studies have suggested that treatment with antagonists or partial agonists of nicotinic acetylcholine receptors containing the β2-subunit (β2 nAChRs) results in antidepressant-like effects. In this study, we tested three novel compounds with different affinity and functional efficacy at α4β2 nAChRs, which were synthesized as part of nAChR discovery projects at Pfizer, in the tail-suspension, forced-swim, and novelty-suppressed feeding tests of antidepressant efficacy. All compounds tested reduced immobility in the forced-swim test and one of the compounds also reduced immobility in the tail-suspension test. All the compounds appeared to affect food intake on their own, with two compounds reducing feeding significantly in the home cage, precluding a clear interpretation of the results in the novelty-suppressed feeding test. None of the compounds altered locomotor activity at the doses and time points used here. Therefore, a subset of these compounds has pharmacological and behavioral properties that demonstrate the potential of nicotinic compounds as a treatment of mood disorders. Further development of nicotinic-based antidepressants should focus on increasing nAChR subtype selectivity to obtain consistent antidepressant properties with an acceptable side-effect profile.