Antagonizing α7 nicotinic receptors with methyllycaconitine (MLA) potentiates receptor activity and memory acquisition

α7 nicotinic acetylcholine receptors (α7nAChRs) have been targeted to improve cognition in different neuro-logical and psychiatric disorders. Nevertheless, noα7nAChR activating ligand has been clinically approved.Here, we investigated the effects of antagonizingα7nAChRs using the selective antagonist methyllycaconitine(MLA) on receptor activity in vitro and cognitive functioning in vivo. Picomolar concentrations of MLA sig-nificantly potentiated receptor responses in electrophysiological experiments mimicking the in vivo situation.Furthermore, microdialysis studies showed that MLA administration substantially increased hippocampal glu-tamate efflux which is related to memory processes. Accordingly, pre-tetanus administration of low MLA con-centrations produced longer lasting potentiation (long-term potentiation, LTP) in studies examining hippo-campal plasticity. Moreover, low doses of MLA improved acquisition, but not consolidation memory processes inrats. While the focus to enhance cognition by modulatingα7nAChRs lies on agonists and positive modulators,antagonists at low doses should provide a novel approach to improve cognition in neurological and psychiatricdisorders.