Cognitive Enhancer Effects of Low Memantine Doses Are Facilitated by an Alpha7 Nicotinic Acetylcholine Receptor Agonist in Scopolamine-Induced Amnesia in Rats

Abstract

Alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in learning and memory and are promising targets for pharmacological cognitive enhancement. Memantine, an approved substance for Alzheimer’s disease treatment, is an antagonist of the N-Methyl-D-aspartate receptor (NMDAR) and also acts as an alpha7 nAChR antagonist. Here, we tested the interaction between an alpha7 nAChR agonist (PHA-543613) and memantine. Efficacy of memantine, PHA-543613, and their co-administration were investigated on the spatial working memory of rats using the spontaneous alternation paradigm in T-maze. Scopolamine-induced transient amnesia was used to model cognitive impairment. First, the dose-response relationship was assessed for memantine, and its lowest effective dose was found to be 0.1 mg/kg. Then, co-administration treatments with subeffective doses of the alpha7 nAChR agonist PHA-543613 and different doses of memantine were tested. The co-administration of subeffective drug doses significantly improved memory performance of the rats and reversed scopolamine-induced deficits. Interestingly, a higher than effective (0.3 mg/kg) dose of memantine did not increase performance in monotreatment, only in co-administration with PHA-543613. However, the co-administration of PHA-543613 did not further increase the efficacy of the previously effective monotreatment doses of memantine. Thus, the efficacy of memantine monotreatment and its co-administration with PHA-543613 converged to create a common ceiling effect, with an additive interaction found in the behavioral effects. These results suggest that memantine and PHA-543613 may exert their cognitive enhancer effects on the same target, possibly on the alpha7 nAChRs. Results also suggest possible benefits of a combination therapy with memantine and alpha7 nAChR agonists.

Potentiation of cognitive enhancer effects of Alzheimer’s disease medication memantine by alpha7 nicotinic acetylcholine receptor agonist PHA-543613 in the Morris water maze task

“…In agreement with these results, in a more recent study from the same laboratory, the authors confirmed that alpha7 nAChR PAMs increase pro-cognitive effects of memantine in an object recognition memory task (Potasiewicz et al 2020). In addition, in our previous study we also reported the improvement of spatial working memory of rats by the co-administration of memantine and the alpha7 nAChR agonist PHA-543613 in the spontaneous alternation (spatial working memory) task (Bali et al 2019a). The above findings convergently suggest that the observed combination effects may well involve alpha7 nAChRs as common targets of memantine and PHA-543613.…”

“…In a previous study from our laboratory, we tested whether pharmacological interaction between a selective alpha7 nAChR agonist PHA-543613 and memantine may have beneficial effects on working memory performance of rats in the spontaneous alternation task over their monotreatments (Bali et al 2019a). Our previous results indicate a clear additive interaction in the behavioral effects of the two compounds suggesting a potential novel preclinical experimental approach for the treatment of AD.…”

Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

“…Nicotinic (Dwyer, McQuown, & Leslie, 2009) and NMDA receptors (Ben‐Ari, Khazipov, Leinekugel, Caillard, & Gaiarsa, 1997) are critically involved in neurodevelopment. There is considerable evidence on the interactive effects of α7nACh and NMDA receptors (Askew and Metherate, 2016; Bali et al, 2017, 2019a, 2019b; Elnagar et al, 2018; Hamilton et al, 2018; Jerusalinsky, Kornisiuk, & Izquierdo, 1997; Koola, 2020; Koukouli & Maskos, 2015; Levy & Aoki, 2002; Lin et al, 2010, 2014a, 2014b; Li, Nai, Lipina, Roder, & Liu, 2013; Lozada et al, 2012; Parikh, Ji, Decker, & Sarter, 2010; Phenis et al, 2020; Moriguchi, Marszalec, Zhao, Yeh, & Narahashi, 2004; Schilström, Ivanov, Wiker, & Svensson, 2007; Tang et al, 2018; Timofeeva & Levin, 2011; H. L. Wang et al, 2006; Y. Wang et al, 2015; Zhang, Li, Li, & Liu, 2016; Zhao et al, 2006). α7nAChR may protect against glutamate neurotoxicity and prevent cell death (J. P. Lopes, Tarozzo, Reggiani, Piomelli, & Cavalli., 2013; Shimohama et al, 1998, 2018).…”

Combination of memantine and alpha7 nicotinic acetylcholine receptor ligands exerts superior efficacy over monotreatments to improve cognitive performance of aged rats

“…These findings are further supported by two recent studies from our laboratory, in which the combined effect of memantine and the selective α7 nAChR agonist PHA-543613 was tested on different cognitive functions in a scopolamine-induced transient amnesia model. First, we reported, that rats receiving memantine-PHA-543613 treatment showed better working memory performance in the spontaneous alternation task compared to rats receiving monotreatments (Bali et al 2019a). Furthermore, our most recent findings indicate that the same treatment combination improved both short-term memory and recall of long-term memory of rats in the Morris water maze test (Bruszt et al 2021).…”