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 beta 2-subunit (beta 2* nAChRs) results in antidepressant-like effects. In this study, we tested three novel compounds with different affinity and functional efficacy at alpha 4 beta 2* 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. Behavioural Pharmacology 22: 291-299 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.