Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice

Julie Vignisse, Harry W. M. Steinbusch, Vladimir Grigoriev, Alexei Bolkunov, Alexey Proshin, Lucien Bettendorff, Sergey Bachurin*, Tatyana Strekalova

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Web of Science)

Abstract

Bifunctional drug therapy targeting distinct receptor signalling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blacker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6 J at 1 or 5 mg/kg, ip) with new derivatives of isothiourea (0.5-1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/kg and exhibited the lowest IC50 values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 replicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance.
Original languageEnglish
Pages (from-to)309-320
JournalEuropean Neuropsychopharmacology
Volume24
Issue number2
DOIs
Publication statusPublished - Feb 2014

Keywords

  • Low-affinity NMDA receptor blockade
  • Positive modulation of AMPA receptor
  • Multi-target mechanism
  • Mouse

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