ReviewEffects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies
Graphical abstract
Introduction
Nicotinic acetylcholine receptors (nAChRs) are cation-conducting pentameric transmembrane proteins that are activated by the endogenous neurotransmitter acetylcholine (ACh), and are located at the neuromuscular junction and in the central and peripheral nervous systems [1], [2], [3]. For the neuronal nAChRs, 12 genes have been identified thus far (nine α (α2–α10) and three β (β2–β4) subunits) that are widely expressed in the nervous system, on both neuronal and non-neuronal cells [1], [3], [4], [5], [6], [7], [8], [9].
The different neuronal nAChR subunits combine in various permutations to form functional receptors [1], [3]. Of the many possible subtypes of nAChRs that have previously been described, the α7 and the α4β2 receptors are the two main subtypes widely expressed in the brain, in particular in the hippocampus [10], [11], [12], [13], [14], [15], [16]. While the α7 subunits can form functional homopentameric receptors [1], [3], there is evidence that in both heterologous expression systems and in the brain, the α7 subunit can also form functional receptors in combination with the β2 subunit [16], [17], [18]. The α7 receptors are characterized by relatively high calcium permeability and rapid desensitization upon exposure to agonists [19], [20], [21]. The heteromeric α4β2 receptors (composed of both the α4 and β2 subunits) are expressed in at least two different stoichiometries; the (α4)2(β2)3 stoichiometry which binds to ACh and nicotine with higher affinity, and the (α4)3(β2)2 stoichiometry which binds with lower affinity [22], [23], [24], [25], [26]. The α7 and α4β2 nAChRs are found at pre- and postsynaptic sites, as well as non-synaptic sites in various regions of the brain [27], [28], [29], [30], [31], [32], [33]. Due to the widespread distribution of nAChRs in the central nervous system, it is not surprising that they are involved in the pathophysiology of many neurological diseases and conditions [1], [3], [34], including (but not limited to) nicotine addiction [35], [36], [37], Alzheimer's disease [33], [38], [39], human epilepsy syndrome [40], [41], [42], [43], schizophrenia [44], [45], [46] and autism [47], [48], [49]. Experimental evidence also suggests that nAChRs are involved in cognitive processes like attention [50], [51], [52], [53] and learning and memory [54], [55], in the central processing of pain [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], and in psychological behaviors such as anxiety [54], [66], [67], [68], [69] and depression [68], [70], [71].
The neuronal nAChRs behave as allosteric proteins with multiple, inter-convertible conformations [72], [73], [74], [75], [76], [77]. Many different pharmacological ligands preferentially bind to and stabilize the nAChR in a specific confirmation [12], [77], [78]. While agonists bind to the orthosteric site, there are many ligands which are known to bind to the receptor at sites separate and distinct from the orthosteric site; these are referred to as allosteric sites [12], [77], [78], [79], [80], [81], [82], [83], [84], and the ligands that bind to the nAChRs at these sites are referred to as allosteric modulators [12], [78], [85]. These allosteric modulators can be classified as positive (PAMs) or negative allosteric modulators (NAMs) [12], [78], [85], [86]; PAMs are compounds that increase the receptor response induced by an agonist [12], [78], while NAMs on the other hand are compounds which decrease the receptor response [12], [83]. PAMs do not have any agonist activity on their own, but they change the ability of the orthosteric ligand (agonist) to affect channel opening [12], [78], [85]. Therefore, allosteric modulators provide an alternative approach to manipulate nAChR function [39], [87], [88], [89]. For example, PAMs can potentially increase the effectiveness of endogenous ACh that is released into the synapse, and strengthen the cholinergic tone without directly activating nAChRs [12], [85]. It is known that partial and full agonists cause desensitization of nAChRs and an upregulation of receptor expression levels [90], [91], [92], [93]. Since the PAMs do not activate the nAChRs directly, they do not induce either desensitization or upregulation. In the presence of PAMs, the nAChR-driven cholinergic synapse will remain under the control of the released endogenous ACh, and only the magnitude of the nAChR response will increase due to the PAM. Thus the nAChR PAMs provide a distinct advantage over agonists. Since the α7 and α4β2 nAChRs are widely distributed in the brain and are involved in the pathophysiology of a variety of neurological diseases and conditions, allosteric modulators for these receptors hold immense therapeutic potential.
Agonists for nAChRs have been under investigation for a variety of neurological disorders for some time [94], [95], [96]. Animal behavioral studies, including animal models with nAChR gene knockouts, provide a suitable and useful tool to assess the effects of pharmacological agents that target these receptors [96], [97], [98], [99]. Behavioral studies with nAChR agonists have primarily focused on animal models of cognition, depression and neuropathic pain [50], [51], [52], [53], [54], [55], [59], [60], [61], [68], [70], [71]. However to date, there are few studies that identify the effects of nAChR PAMs in different paradigms of animal behavior, with little to no published clinical data. Here we will discuss what has been reported thus far on the behavioral studies using different allosteric modulators for the neuronal nAChRs.
Section snippets
Behavioral studies with allosteric modulators of the α7 receptors
Behavioral studies with allosteric modulators of the α7 receptors have mostly focused on PAMs since there is evidence that increasing (rather than decreasing) cholinergic output through these receptors causes an enhancement of cognitive performance and alleviation of pain [78], [100]. Table 1 provides a summary of the effects of α7 receptor PAMs in different animal behavioral studies. Many PAMs for α7 receptors have been discovered, and they are divided into two categories: (a) type I PAMs
Behavioral studies with allosteric modulators of the α4β2 receptors
Many ligands are known to act as allosteric modulators for the α4β2 subtype of nAChRs; these include 17-β-estradiol [79], NS-9283 [62], [63], [64], desformylflustrabromine [80], [81], and LY-2087101 (a (2-amino-5-keto) thiazole compound) [117] which act as PAMS, and KAB-18 [83], UCI-30002 [118] and progesterone [119] which act as NAMs. To date, most of the behavioral research in animals with allosteric modulators for α4β2 receptors has focused on PAMs, similar to that seen with the α7
Pharmacokinetic/pharmacodynamic (PK/PD) relationship of nAChR PAMs
The PAMs for the α7 (PNU-120596 and NS-1738) and α4β2 (NS-9283) receptors have been tested for their effects on cognition and nociception, and it has been observed that the dose of these compounds needed to induce a positive effect may be different; for example the dose required to induce a beneficial effect in pain models is different from the dose required to induce pro-cognitive effects [54], [56], [59], [60], [61], [111]. This indicates the importance of considering pharmacokinetic
PAMs with dual actions
In addition to the PAMs for α4β2 and α7 receptors already discussed here, other PAMs like galantamine and physostigmine have also been studied in different behavioral paradigms in animals [121], [122]. However in addition to being PAMs for nAChRs, galantamine and physostigmine are also acetylcholinesterase inhibitors [39]. While the beneficial effects of these two compounds in restoring cholinergic tone in the synapse is expected to be enhanced by these dual actions [12], [39], it can be
PAMs for other nAChR subtypes
In functional studies, the anthelmintic compounds levamisole [123] and morantel [124] have been identified as PAMs for human α3β2 and α3β4 nAChR subtypes, however no behavioral studies with either of these compounds have been reported thus far. Hypothalamic α3β4 receptors have been identified as the nAChR subtype that is involved in the regulation of food intake in mice [125], therefore nAChR PAMs for subtypes other than the α4β2 and α7 receptors may have important clinical applications.
Conclusion
The recent focus on the discovery and characterization of nAChR PAMs has created new opportunities for targeting these receptors and developing drug treatments in diseases and conditions where they may be involved. It is known that nAChRs are involved in neuropsychological process in the brain like cognition, central processing of pain, anxiety and depression [4], [33], [34], [38], [39], [47], [59], [60], [61], [126]. Allosteric modulation provides an alternative mechanism of nAChR
Acknowledgements
We would like to thank and acknowledge the contributions of Drs. Christian Erxleben and Serena Dudek for their help in the review of the manuscript. Participants in this research review are supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH.
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