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

Nick P. van Goethem, Dean Paes, Daniela Puzzo, Ernesto Fedele, Claudia Rebosio, Walter Gulisano, Agostino Palmeri, Lawrence P. Wennogle, Youyi Peng, Daniel Bertrand, Jos Prickaerts

Research output: Contribution to journalArticlepeer-review

Abstract

α7 nicotinic acetylcholine receptors (α7nAChRs) have been targeted to improve cognition in different neurological and psychiatric disorders. Nevertheless, no α7nAChR activating ligand has been clinically approved. Here, we investigated the effects of antagonizing α7nAChRs using the selective antagonist methyllycaconitine (MLA) on receptor activity in vitro and cognitive functioning in vivo. Picomolar concentrations of MLA significantly potentiated receptor responses in electrophysiological experiments mimicking the in vivo situation. Furthermore, microdialysis studies showed that MLA administration substantially increased hippocampal glutamate efflux which is related to memory processes. Accordingly, pre-tetanus administration of low MLA concentrations produced longer lasting potentiation (long-term potentiation, LTP) in studies examining hippocampal plasticity. Moreover, low doses of MLA improved acquisition, but not consolidation memory processes in rats. While the focus to enhance cognition by modulating α7nAChRs lies on agonists and positive modulators, antagonists at low doses should provide a novel approach to improve cognition in neurological and psychiatric disorders.

Original languageEnglish
Article number109338
JournalCellular Signalling
Volume62
DOIs
Publication statusPublished - Oct 1 2019

Keywords

  • Antagonist
  • Ligand-gated ion channel
  • Long-term potentiation
  • Memory acquisition
  • Receptor activity
  • α7 nicotinic acetylcholine receptors

ASJC Scopus subject areas

  • Cell Biology

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