Article

Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies

Chukchi Campus, Department of Bio-science, College of Rural and Community Development, University of Alaska Fairbanks, P.O. Box-297, Kotzebue, AK. 99752-0297. USA. Electronic address: .
Biochemical pharmacology (Impact Factor: 5.01). 05/2013; 86(8). DOI: 10.1016/j.bcp.2013.05.018
Source: PubMed

ABSTRACT

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation-conducting transmembrane channels from the cys-loop receptor superfamily. The neuronal subtypes of these receptors (e.g. the α7 and α4β2 subtypes) are involved in neurobehavioral processes such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and a number of cognitive functions like learning and memory. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders, and behavioral studies in animals are useful models to assess the effects of compounds that act on these receptors. Allosteric modulators are ligands that bind to the receptors at sites other than the orthosteric site where acetylcholine, the endogenous agonist for the nAChRs, binds. While conventional ligands for the neuronal nAChRs have been studied for their behavioral effects in animals, allosteric modulators for these receptors have only recently gained attention, and research on their behavioral effects is growing rapidly. Here we will discuss the behavioral effects of allosteric modulators of the neuronal nAChRs.

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Available from: Anshul Pandya, Feb 20, 2015
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    • "α7 nAChRs are highly expressed in BLA and play a critical role in neuronal excitability (Almeida-Suhett et al, 2014; Jiang et al, 2008; Klein and Yakel, 2006). Because the α7 subunit is expressed in both glutamatergic and GABAergic neurons in the amygdala and can modulate both excitatory and inhibitory neurons (Pidoplichko et al, 2013), decreasing the activity of this nAChR subtype could have opposite behavioral consequences depending on whether the nucleus is highly active or quiescent (Pandya and Yakel, 2013). It has been suggested that the primary role of α7 nAChRs in basolateral amygdala is to enhance inhibitory synaptic transmission (Pidoplichko et al, 2013), but several studies have demonstrated that signaling through α7 nAChRs can increase excitatory transmission (Barazangi and Role, 2001; Jiang et al, 2008; Klein et al, 2006). "
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    ABSTRACT: Electrophysiological and neurochemical studies implicate cholinergic signaling in the basolateral amygdala in behaviors related to stress. Both animal studies and human clinical trials suggest that drugs that alter nicotinic acetylcholine receptor (nAChR) activity can affect behaviors related to mood and anxiety. Clinical studies also suggest that abnormalities in cholinergic signaling are associated with major depressive disorder, whereas pre-clinical studies have implicated both β2 subunit-containing (β2*) and α7 nAChRs in the effects of nicotine in models of anxiety- and depression-like behaviors. We therefore investigated whether nAChR signaling in the amygdala contributes to stress-mediated behaviors in mice. Local infusion of the non-competitive non-selective nAChR antagonist mecamylamine or viral-mediated down-regulation of the β2 or α7 nAChR subunit into the amygdala all induced robust anxiolytic- and antidepressant-like effects in several mouse behavioral models. Further, whereas α7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only β2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the basolateral amygdala. In contrast, α7, but not β2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through β2* nAChRs is essential for baseline excitability of the basolateral amygdala, and a decrease in signaling through β2 nAChRs alters anxiety- and depression-like behaviors even in unstressed animals. In contrast, stimulation of α7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.Neuropsychopharmacology accepted article preview online, 16 October 2015. doi:10.1038/npp.2015.316.
    Full-text · Article · Oct 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Between two and five orthosteric ACh-binding sites reside at the interface between adjacent α subunits (except α5), depending on the receptor subtype (Papke, 2014). The nAChRs also have an allosteric binding site whose activation can increase (positive allosteric modulation, or 'PAM') or decrease (negative allosteric modulation) receptor activity when there is a ligand binding to the ACh site (Changeux and Edelstein, 2005; Pandya and Yakel, 2013). "
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    ABSTRACT: Most individuals with schizophrenia suffer some cognitive dysfunction: such deficits are predictive of longer-term functioning; and current dopamine-blocking antipsychotics have made little impact on this domain. There is a pressing need to develop novel pharmacological agents to tackle this insidious but most disabling of problems. The acetylcholinergic system is involved in cognitive and attentional processing, and its metabotropic and nicotinic receptors are widespread throughout the brain. Deficits in acetylcholinergic functioning occur in schizophrenia, and high rates of tobacco smoking have been posited to represent a form of self-medication. The nicotinic acetylcholine receptor (nAChR) has emerged as a putative target to improve cognitive deficits in schizophrenia, and this study systematically reviewed the emerging data. Nineteen studies were identified, covering three compound classes: agonists at the α7 and α 4β2 nAChRs, and positive allosteric modulators. Overall data are underwhelming: some studies showed significant improvements in cognition but as many studies had negative findings. It remains unclear if this represents drug limitations or nascent study methodology problems. The literature is particularly hindered by variability in inclusion of smokers, generally small sample sizes, and a lack of consensus on cognitive test batteries. Future work should evaluate longer-term outcomes, and, particularly, the effects of concomitant cognitive training. © The Author(s) 2015.
    Full-text · Article · Jan 2015 · Journal of Psychopharmacology
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    • "To our knowledge, nAChR-mediated desensitization has not been measured in vivo; however, the narrow therapeutic ranges observed with the nAChR agonists have limited their investigation in the clinic. Whereas allosteric modulators have so far received less attention, these molecules are progressively developing and have also shown beneficial outcomes in animal models (for review, see Pandya and Yakel, 2013). As both type I allosteric modulator, such as NS-1738, which is known to increase the a 7 response without affecting the desensitization, as well as type II modulator, such as PNU-120596, display beneficial effects in animal models, these data do not provide further clues about the relevance of the fast desensitization of the a 7 nAChRs. "
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    ABSTRACT: Clinical and pre-clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in attempt to avoid the rapid desensitization properties associated with the α7nAChR following orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on pharmacological characterization of the novel compound RO5126946 (5-Chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide) which allosterically modulates α7nAChR activity. RO5126946 increased ACh-evoked peak current and delayed current decay, but did not affect recovery of α7nAChRs from desensitization. In addition, RO5126946 effects were absent when nicotine-evoked currents were completely blocked by co-application of the α7nAChR-selective antagonist methyllycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. Absence of RO5126946 effects at human α4β2nAChR and 5HT3 receptors, amongst others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable, brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rat. In addition, pro-cognitive effects of RO5126946 were investigated in presence of nicotine to address potential pharmacological interactions on behavior. RO5126946 potentiated nicotine's effects on fear memory when both compounds were administered at sub-threshold doses and did not interfere with pro-cognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive enhancing properties.
    Preview · Article · Jun 2014 · Journal of Pharmacology and Experimental Therapeutics
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