Investigation of varenicline and tropisetron in latent inhibition and novel object recognition in mice

There is currently no treatment for cognitive-impairment associated with schizophrenia (CIAS). Animal and human studies suggest that nicotinic cholinergic agonists and 5-HT3 antagonists have potential therapeutic benefits. We investigated whether co-administration of varenicline, an alpha4beta2 nAChR partial agonist and alpha7 nicotinic receptor agonist, and tropisetron, a 5-HT3 antagonist and alpha7 nicotinic receptor agonist is pro-cognitive in male c57/Bl6 mice. We first assessed Latent inhibition (LI) an associative learning process of learning to ignore irrelevant stimuli. We report no effect of tropisetron on LI (0.01, 0.04, 0.4 mg/kg s.c.). Varenicline at 0.5 mg/kg s.c. potentiated LI. Co-administration of tropisetron 0.4 mg/kg s.c. and 0.5 mg/kg s.c. varenicline abolished varenicline’s potentiation of LI. In 24 h retention of novel object recognition (NOR) where memory performance (discrimination-index) is poor in controls there was no effect of varenicline or tropisetron. When varenicline (0.5 mg/kg) and tropisetron (0.01, 0.1, 1.0 mg/kg) were co-administered NOR discrimination-index was higher compared to controls. These data indicate that varenicline enhances LI when low in controls, demonstrate an interaction between varenicline and tropisetron in LI and suggest synergistic interaction between tropisetron and varenicline to potentiate NOR memory merits further investigation. These findings have implications for treatment of CIAS and disorders with cognitive impairment.