Activation of alpha7 nicotinic and NMDA receptors is necessary for performance in a working memory task

Abstract

Rationale-Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA's effects may reflect interference with the function of both the a7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor. Objectives-The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP). Methods-DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Clkynurenic acid). Attenuation of KYN-or 4-Cl-KYN-induced deficits was assessed by coadministration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of a7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site. Results-Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were

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

“…Wang et al, 2013) systems should be concurrently targeted for the synergistic effect. Finally, this hypothesis has been corroborated by recent animal (Nikiforuk et al, 2016;Phenis et al, 2020) and human (Matsuzono et al, 2015;Vasenina, Gankina, & Levin, 2018) studies.…”

“…Thus, nicotinic‐cholinergic (Levy & Aoki, 2002; X. Wang, Lippi, Carlson, & Berg, 2013) and glutamate/NMDA/α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) (Levy & Aoki, 2002; X. Wang et al, 2013) systems should be concurrently targeted for the synergistic effect. Finally, this hypothesis has been corroborated by recent animal (Nikiforuk et al, 2016; Phenis et al, 2020) and human (Matsuzono et al, 2015; Vasenina, Gankina, & Levin, 2018) studies.…”

“…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).…”

Inflammation control and improvement of cognitive function in COVID-19 infections: is there a role for kynurenine 3-monooxygenase inhibition?

“…KYNA also protects cells from oxidative stress by acting as a free radical scavenger [7] . However, high concentrations of KYNA can be detrimental because they can cause excessive inhibition of NMDARs, resulting in cognitive impairment 8 , 9 . By contrast, QUIN is a NMDAR agonist that, at high concentrations, induces excitotoxicity [10] and can cause oxidative cell death by promoting the generation of free radicals [11] .…”

Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

“…Though other molecular targets may be of relevance as well, the neurobiological effects of endogenous KYNA are mediated primarily through its actions as an antagonist of both the NMDA and the α7nAChR function, i.e. two receptors that are critically involved in cognitive processes (Moroni et al, 2012;Stone et al, 2013;Phenis et al, 2020). Consequently, as shown consistently in experimental animals, elevated brain KYNA levels are associated with a number of cognitive deficits, such as impairments in contextual learning and memory and abnormal visuospatial working memory (Schwarcz et al, 2012;Muneer, 2020).…”