Subtype-selective nicotinic acetylcholine receptor agonists can improve cognitive flexibility in an attentional set shifting task

Wood, C.; Kohli, Shivali; Malcolm, Emma; Allison, Claire; Shoaib, Mohammed

doi:10.1016/j.neuropharm.2016.01.006

Cited by 21 publications

(27 citation statements)

References 54 publications

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“…Our previous study demonstrated that TC-2403 facilitated ED set-shifting in rats and that this effect was blocked by DHβE [25]. The improvement in rats' ED performance was also demonstrated after the administration of 5IA-85380, a β2-nAChR-selective agonist [31]. The current results corroborate these findings by demonstrating the potential of an α4β2-nAChR PAM to facilitate cognitive flexibility in an α4β2-nAChR-dependent manner.…”

Section: Discussionsupporting

confidence: 86%

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

et al. 2020

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Rationale The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4β2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of α4β2-nAChR positive allosteric modulators (PAMs) have not been extensively characterized. Objectives The aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4β2-nAChR PAM. Methods Cognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats. Results The results demonstrate that dFBr attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. The beneficial effects of dFBr were inhibited by dihydro-β-erythroidine, a relatively selective α4β2-nAChR antagonist, indicating the involvement of α4β2-nAChRs in cognitive processes. The tested α4β2-PAM was also effective against ketamine-and scopolamine-induced deficits of object recognition memory. Moreover, procognitive effects were also observed after combined treatment with inactive doses of dFBr and TC-2403, a selective α4β2-nAChR agonist. Conclusions These findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4β2-nAChR potentiation as a plausible therapy for cognitive impairment.

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Section: Discussionsupporting

confidence: 86%

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

et al. 2020

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“…We conjectured that such a combined learning and attention paradigm is needed to clarify open questions about subreceptor specific functions. In particular, an exhaustive literature survey of attention effects of fourteen studies applying systemically α7 agonists (Table S1) (Briggs CA et al 1997;Hahn B et al 2003;Buccafusco JJ et al 2007;Buccafusco JJ and AV Terry, Jr. 2009;Rezvani AH et al 2009; Wallace TL, PM Callahan, et al 2011;McLean SL et al 2012;Gould RW et al 2013;Yang Y et al 2013;Young JW et al 2013;Jones KM et al 2014;Kolisnyk B et al 2015;Wood C et al Nicotinic sub-receptor specific modulation of learning and attention 2016;Wadenberg MG et al 2017), and thirteen studies using α4β2 agonists (Table S2) (Buccafusco JJ et al 1995;Decker MW et al 1997;Schneider JS et al 1999;Schneider JS et al 2003;Decamp E and JS Schneider 2006;Buccafusco JJ et al 2007;Howe WM et al 2010;Gould RW et al 2013;Paolone G et al 2013;Kolisnyk B et al 2015;Terry AV, Jr. et al 2016;Wood C et al 2016) failed to reveal sub-receptor specific contributions to working memory and distractor filtering functions in the NHP animal model.…”

Section: Nicotinic Sub-receptor Specific Modulation Of Learning and Amentioning

confidence: 99%

Double Dissociation of Nicotinic α7 and α4/β2 Sub-receptor Agonists for Enhancing Learning and Attentional Filtering of Distraction

Azimi

Oemisch

Womelsdorf

2018

Preprint

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Nicotinic acetylcholine receptors (nAChR) modulate attention, memory, and higher executive functioning, but it has remained unclear whether nAChR sub-receptors tap into different neural mechanisms of these functions. We therefore set out to contrast the contributions of selective alpha-7 nAChR and alpha-4/beta-2 nAChR agonists in mediating value learning and attentional filtering of distractors in the nonhuman primate. We found that the alpha-7 nAChR agonist PHA-543613 selectively enhanced the learning speed of feature values but did not modulate how salient distracting information was filtered from ongoing choice processes. In contrast, the selective alpha-4/beta-2 nAChR agonist ABT-089 did not affect learning speed but reduced distractibility. This double dissociation was dose-dependent and evident in the absence of systematic changes in overall performance, reward intake, motivation to perform the task, perseveration tendencies, or reaction times. These results suggest nicotinic sub-receptor-specific mechanisms consistent with (1) alpha-4/beta-2 nAChR specific amplification of cholinergic transients in prefrontal cortex linked to enhanced cue detection in light of interferences, and (2) alpha-7 nAChR specific activation prolonging cholinergic transients, which could facilitate subjects to follow-through with newly established attentional strategies when outcome contingencies change. These insights will be critical for developing function-specific drugs alleviating attention and learning deficits in neuro-psychiatric diseases.

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“…The ␣4␤2 nicotinic receptor (␣4␤2-nAChR) is of interest given its high affinity for nicotine and its relationship to cigarette smoking (Picciotto and Kenny, 2013;McClure-Begley et al, 2016), its widespread distribution in brain (Han et al, 2000), and its links to cognitive processing. For example, genetic alterations in the ␣4 subunit in humans have been associated with altered cognitive and attentional abilities (Reinvang et al, 2009;Espeseth et al, 2010;Mobascher et al, 2016) and possibly to greater incidence of attention deficit hyperactivity disorder (ADHD) (Kent et al, 2001;Winterer et al, 2007;Wallis et al, 2009). Similarly, genetic knockdown or blockade of nicotinic ␣4 and/or ␤2 nicotinic subunits impairs, whereas stimulation improves, attentional processing in rodent models (Guillem et al, 2011;Bloem et al, 2014;Wood et al, 2016) and stimulation of the cholinergic basal forebrain can enhance visual processing in the visual cortex through muscarinic receptors (Goard and Dan, 2009).…”

Section: Significance Statementmentioning

confidence: 99%

“…For example, genetic alterations in the ␣4 subunit in humans have been associated with altered cognitive and attentional abilities (Reinvang et al, 2009;Espeseth et al, 2010;Mobascher et al, 2016) and possibly to greater incidence of attention deficit hyperactivity disorder (ADHD) (Kent et al, 2001;Winterer et al, 2007;Wallis et al, 2009). Similarly, genetic knockdown or blockade of nicotinic ␣4 and/or ␤2 nicotinic subunits impairs, whereas stimulation improves, attentional processing in rodent models (Guillem et al, 2011;Bloem et al, 2014;Wood et al, 2016) and stimulation of the cholinergic basal forebrain can enhance visual processing in the visual cortex through muscarinic receptors (Goard and Dan, 2009). Research in monkeys has also shown prominent muscarinic effects on attentional enhancement of visual processing in V1 (Herrero et al, 2008), but only limited influences of nicotinic receptor stimulation (Disney et al, 2007).…”

Section: Significance Statementmentioning

confidence: 99%

“…Similarly, the genotype for the noradrenergic synthetic enzyme dopamine ␤ hydroxylase interacts with the ␣4 genotype in relationship to working memory abilities with varying attentional load (Greenwood et al, 2009). The ␣4 genotype has also been related to activity of the anterior cingulate and posterior parietal cortex during an oddball task (Winterer et al, 2007) and to alterations in posterior attentional circuits in tasks that require the reorienting of attention (Giessing et al, 2012;Greenwood et al, 2012). Because ␣4␤2-nAChR expression is widespread in the brain, these relationships likely involve receptors in multiple brain circuits.…”

Section: Importance Of ␣4␤2-nachr Mechanisms To Cognitive Circuitsmentioning

confidence: 99%

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Nicotinic α4β2 Cholinergic Receptor Influences on Dorsolateral Prefrontal Cortical Neuronal Firing during a Working Memory Task

et al. 2017

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The primate dorsolateral prefrontal cortex (dlPFC) subserves top-down regulation of attention and working memory abilities. Depletion studies show that the neuromodulator acetylcholine (ACh) is essential to dlPFC working memory functions, but the receptor and cellular bases for cholinergic actions are just beginning to be understood. The current study found that nicotinic receptors comprised of α4 and β2 subunits (α4β2-nAChR) enhance the task-related firing of delay and fixation cells in the dlPFC of monkeys performing a working memory task. Iontophoresis of α4β2-nAChR agonists increased the neuronal firing and enhanced the spatial tuning of delay cells, neurons that represent visual space in the absence of sensory stimulation. These enhancing effects were reversed by coapplication of a α4β2-nAChR antagonist, consistent with actions at α4β2-nAChR. Delay cell firing was reduced when distractors were presented during the delay epoch, whereas stimulation of α4β2-nAChR protected delay cells from these deleterious effects. Iontophoresis of α4β2-nAChR agonists also enhanced the firing of fixation cells, neurons that increase firing when the monkey initiates a trial, and maintain firing until the trial is completed. These neurons are thought to contribute to sustained attention and top-down motor control and have never before been the subject of pharmacological inquiry. These findings begin to build a picture of the cellular actions underlying the beneficial effects of ACh on attention and working memory. The data may also help to explain why genetic insults to α4 subunits are associated with working memory and attentional deficits and why α4β2-nAChR agonists may have therapeutic potential. The acetylcholine (ACh) arousal system in the brain is needed for robust attention and working memory functions, but the receptor and cellular bases for its beneficial effects are poorly understood in the newly evolved primate brain. The current study found that ACh stimulation of nicotinic receptors comprised of α4 and β2 subunits (α4β2-nAChR) enhanced the firing of neurons in the primate prefrontal cortex that subserve top-down attentional control and working memory. α4β2-nAChR stimulation also protected neuronal responding from the detrimental effects of distracters presented during the delay epoch, when information is held in working memory. These results illuminate how ACh strengthens higher cognition and help to explain why genetic insults to the α4 subunit weaken cognitive and attentional abilities.

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Subtype-selective nicotinic acetylcholine receptor agonists can improve cognitive flexibility in an attentional set shifting task

Cited by 21 publications

References 54 publications

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

Double Dissociation of Nicotinic α7 and α4/β2 Sub-receptor Agonists for Enhancing Learning and Attentional Filtering of Distraction

Nicotinic α4β2 Cholinergic Receptor Influences on Dorsolateral Prefrontal Cortical Neuronal Firing during a Working Memory Task

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