The Novel α7 Nicotinic Acetylcholine Receptor AgonistN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide Improves Working and Recognition Memory in Rodents

Abstract

The relative contribution of ␣4␤2, ␣7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the ␣7 nAChR agonist. ABBF bound to ␣7 nAChR in rat brain membranes (K i ϭ 62 nM) and to recombinant human 5-hydroxytryptamine (5-HT) 3 receptors (K i ϭ 60 nM). ABBF was a potent agonist at the recombinant rat and human ␣7 nAChR expressed in Xenopus oocytes, but it did not show agonist activity at other nAChR subtypes. ABBF acted as an antagonist of the 5-HT 3 receptor and ␣3␤4, ␣4␤2, and muscle nAChRs (at higher concentrations). ABBF improved social recognition memory in rats (0.3-1 mg/kg p.o.). This improvement was blocked by intracerebroventricular administration of the ␣7 nAChR antagonist methyllycaconitine at 10 g, indicating that it is mediated by ␣7 nAChR agonism. In addition, ABBF improved working memory of aged rats in a water maze repeated acquisition paradigm (1 mg/kg p.o.) and object recognition memory in mice (0.3-1 mg/kg p.o.). Rats trained to discriminate nicotine (0.4 mg/kg s.c.) from vehicle did not generalize to ABBF (0.3-30 mg/kg p.o.), suggesting that the nicotine cue is not mediated by the ␣7 nAChR and that selective ␣7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that ␣7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.Nicotine enhances cognitive functions, such as attention, learning, consolidation, and retention, in both animals and humans, through activation of brain nicotinic acetylcholine receptors (nAChRs) (Levin et al., 1999(Levin et al., , 2006. These ligandgated ion channels are homopentamers formed by five identical subunits (␣7 nAChR) or heteropentamers of multiple ␣ and ␤ subunits. Various isoforms of these subunits have been identified (␣2-␣10; ␤2-␤4; for reviews, see Paterson and Nordberg, 2000;Gotti et al., 2006). The most common nAChRs found in the brain are the ␣7 subtype with a low affinity for nicotine and the ␣4␤2 subtype with a high affinity for nicotine. Evidence from neuroanatomical, electrophysiological, and behavioral studies support a role for both of these receptor subtypes in processes of learning and memory.

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

“…Moreover, these mutants exhibited performance deficits under baseline conditions in the odor span task, delayed non-match to sample task, win-shift task and attention set-shifting task (Fernandes et al, 2006; Levin et al, 2009; Young et al, 2007; 2011) indicating that perturbations in α7 nAChR signaling influence a wide range of executive processes. Administration of α7 nAChR full/partial agonists or positive allosteric modulators (PAMs) exerted beneficial effects on attention, working and recognition memory, and cognitive flexibility in normal rodents and aged non-human primates (Boess et al, 2007; Bitner et al, 2007; Callahan et al, 2013; Levin et al, 1999; Nikiforuk et al, 2016; Rezvani et al, 2009; Tietje et al, 2008). On the other hand, systemic or intracranial infusions of α7 nAChR antagonist produced impairments in attention and working memory in normal rats (Chan et al, 2007; Hahn et al, 2011; Levin et al, 2002).…”

Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats

“…Systemic α7 agonist treatment has been found to improve cognitive function in a variety of ways. Studies have shown them to attenuate symptoms of schizophrenia (Hauser et al, 2009; Pichat et al, 2007), as well as improve memory (Boess et al, 2007; Prickaerts et al, 2012; Tietje et al, 2008; Van Kampen et al, 2004). The α7 agonist AR-R17779 has been shown to improve learning and memory in rats (Levin et al, 1999).…”

NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

“…The α7 subtype of nicotinic acetylcholine receptor (nAChR) has long been considered a potential therapeutic target for treating cogni-tive disorders, and α7-selective drugs have been shown to be effective at improving baseline or compromised behavior in animal models of learning and memory [5,13,27,45,51,53,55]. Drugs targeting α7 have also been identified as effective at reducing inflammation and asso-ciated pain [43,47].…”