Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice

Abstract

Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction.Electronic supplementary materialThe online version of this article (10.1007/s00213-017-4792-5) contains supplementary material, which is available to authorized users.

Mesoscopic Mapping of Stimulus-Selective Response Plasticity in the Visual Pathways Modulated by the Cholinergic System

“…Mice were injected subcutaneously behind the neck with 0.1 mL/10 g (mouse weight) of sterile saline (Sham and CS, n = 5 per group) or with 0.3 mg/kg DPZ (Bontempi et al, 2003 ; Bretin et al, 2018 ) diluted in 0.1 mL/10 g (mouse weight) of sterile saline (CS/DPZ; n = 5) 15 min prior to the visual conditioning session in order to reach the maximal cortical effect of the drug (Geerts et al, 2005 ).…”

“…Mice were injected subcutaneously behind the neck with 0.1 mL/10 g (mouse weight) of sterile saline (Sham and CS, n = 5 per group) or with 0.3 mg/kg DPZ (Bontempi et al, 2003;Bretin et al, 2018) diluted in 0.1 mL/10 g (mouse weight) of sterile saline (CS/DPZ; n = 5) 15 min prior to the visual conditioning FIGURE 2 | Cortical activation maps of adult Thy1-GCaMP6s mice. (A) Color-coded maps show the effect of a sham-conditioning (Sham) visual conditioning coupled with saline (CS) or cholinergic potentiation (CS/DPZ) on the cortical response in superficial layers.…”

“…The goal of the study was to evaluate whether the cholinergic system would change the correlation of neural activity between areas to enhance efficiency and automation of the processing of the trained stimulus. The cholinergic system was potentiated through systemic administration of 0.3 mg/kg DPZ (Bontempi et al, 2003 ; Geerts et al, 2005 ; Bretin et al, 2018 ). A monocular conditioning to an oblique pattern was performed daily for a week.…”

The 4‐Hole‐Board Test for Assessment of Long‐Term Spatial Memory in Mice

“…A rewarded variant of the hole‐board test has also been devised, in which one quarter of the holes are baited with food and the others are not: 4 on 16 in the 16‐hole‐board (Castilla‐Ortega et al., 2010; Oades, 1981; Oades & Isaacson, 1978; Sampedro‐Piquero et al., 2018; van der Staay, van Nies, & Raaijmakers, 1990; Van der Zee, Compaan, de Boer, & Luiten, 1992) and 1 on 4 in the 4‐hole‐board (Béracochéa, Philippin, Meunier, Morain, & Bernard, 2007; Bretin et al., 2018; Brosnan‐Watters, Wozniak, Nardi, & Olney, 1996; Célérier, Piérard, Rachbauer, Sarrieau, & Béracochéa, 2004; Chauveau et al., 2009; Chauveau et al., 2019; Micheau, Destrade, & Jaffard, 1985; Pierard, Krazem, Henkous, Decorte, & Béracochéa, 2015; Venault, Beracochea, Valleau, Joubert, & Chapouthier, 2006). But the rewarded version requires food restriction before exposure to the hole‐board.…”