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Modulation of specific nicotinic acetylcholine receptors (nAChRs) and estrogen receptors (ERs) have been implicated in regulating mood and depressive behavior. In this study we sought to determine whether cytisine and diarylpropionitrile (DPN) reduce depressive characteristics of female rats. Cytisine is a α4β2 nAChR partial agonist and α7 nAChR agonist. DPN is an ERβ agonist. Ovariectomized adult female Sprague Dawley rats (n=8/group) received subcutaneous injections of DPN (0.1 mg/kg) 60 minutes before the forced swim test (FST), cytisine (0.5 mg/kg) 30 minutes before the FST, or the combination. Doses and latencies for drug administration were chosen based on preliminary studies. Controls received corn oil and saline. Locomotor activity was also assessed. Compared to control, acute administration of cytisine or DPN reduced immobility in the FST by 44% and 57%, respectively. The combination of cytisine and DPN reduced immobility compared to control by 82%. No significant differences in locomotor activity were detected. Acute administration of cytisine and DPN significantly decreased immobility in the FST, suggesting an antidepressant‐like effect. Furthermore, the combination of cytisine and DPN produced a greater reduction than either agent administered alone, indicating an additive effect. Supported by Mercer University College of Pharmacy and Health Sciences