Nicotinic Ach Receptors As Therapeutic Targets in CNS Disorders

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Review

Nicotinic ACh receptors as therapeutic

targets in CNS disorders

1 2 3

Kelly T. Dineley , Anshul A. Pandya , and Jerrel L. Yakel

Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch at Galveston

(UTMB), Galveston, TX, USA

Chukchi Campus, Department of Bioscience, College of Rural and Community Development, University of Alaska Fairbanks, P.O.

Box 297, Kotzebue, AK 99752-0297, USA

Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health (NIEHS/NIH),

Department of Health and Human Services (DHHS), F2-08, P.O. Box 12233, 111 T.W. Alexander Drive, Research Triangle Park, NC

27709, USA

The neurotransmitter acetylcholine (ACh) can regulate or those composed of both a and b subunits, including the

neuronal excitability by acting on the cys-loop cation- a4b2* and a3b4* subtypes [12–17]; the * denotes that these

conducting ligand-gated nicotinic ACh receptor (nAChR) nAChRs can contain other a and b subunits as well.

channels. These receptors are widely distributed The a4b2* receptor subtype was initially found to be

throughout the central nervous system (CNS), being the major nAChR subtype in the brain (where it com-

expressed on neurons and non-neuronal cells, where prises 90% of the high afﬁnity nicotine binding sites

they participate in a variety of physiological responses [16,18]), while the a3b4* nAChR is known primarily as

such as anxiety, the central processing of pain, food a ganglionic receptor in the PNS. The a3b4* nAChR is

intake, nicotine seeking behavior, and cognitive func- also expressed in a variety of brain areas, including (but

tions. In the mammalian brain, nine different subunits not limited to) the interpeduncular nucleus and medial

have been found thus far, which assemble into penta- habenula [16,17]. In addition, the a2, a5, a6, and b3

meric complexes with much subunit diversity; however, subunits participate in nAChRs expressed in various

the a7 and a4b2 subtypes predominate in the CNS. brain regions, although they represent a minority popu-

Neuronal nAChR dysfunction is involved in the patho- lation of the total.

physiology of many neurological disorders. Here we will The a7* nAChR subunit is a particularly intriguing

brieﬂy discuss the functional makeup and expression of subunit as these receptors are expressed on a variety of

the nAChRs in mammalian brain, and their role as tar- cell types in the periphery, including immune cells [19–23]

gets in neurodegenerative diseases (in particular Alzhei- and neurons [24], as well as in brain regions that underlie

mer’s disease, AD), neurodevelopmental disorders (in learning and memory [25,26]. Furthermore, these recep-

particular autism and schizophrenia), and neuropathic tors are highly permeable to calcium, implicating them as

pain. signiﬁcant modulators of intracellular signaling and neu-

rotransmitter release from neurons. In the brain, the a7*

Functional role of nAChRs in the brain receptors are expressed on both neurons and non-neuronal

The nAChRs belong to the superfamily of cys-loop receptors cells [20], including (but not limited to) astrocytes, micro-

(Figure 1), which also includes the serotonin 5-HT3, a-amino- glia, oligodendrocyte precursor cells, endothelial cells, and

3-hydroxy-5-methyl-4-isoxazolepropionic acid (GABA)A, chondroitin sulfate proteoglycan NG2-expressing (NG2)

GABAC, and glycine receptors, and participate in a variety cells [21–23,27–30]. Expression of a7* receptors in these

of physiological functions, including the regulation of neuro- non-neuronal cells suggests a possible role in brain innate

nal excitability and neurotransmitter release [1–4]. The immunity, inﬂammation, and neuroprotection [31,32]. Im-

nAChRs are widely distributed throughout the peripheral mune cell expression of a7* receptors has been shown to

nervous system (PMS) and the CNS, as well as the immune modulate inﬂammatory responses by regulating the pro-

system and various peripheral tissues [5–9]. In the mamma- duction of inﬂammatory cytokines and chemokines [33,34].

lian brain, nine different nAChR subunits are known to exist While the a7* nAChR was initially thought to be func-

(a2–7 and b2–4), which combine as either homo- or hetero- tionally expressed as homomeric receptors, it has recently

meric complexes into multiple functionally diverse penta- been shown to be capable of co-assembling with other

meric receptors [3,10,11]. The predominant subtypes subunits, which provides an explanation for the incongru-

functionally expressed in the brain are categorized as a7* ent properties of in situ a7-containing receptors and in

subunit-containing receptors (either homo- or heteromeric), vitro expressed homomeric a7 receptors [35–39]. Initially,

we found that a7 and b2 subunits co-assembled in vitro

Corresponding author: Yakel, J.L. ([email protected]).

[14,15,40]; subsequently it was found that basal forebrain

Keywords: a7 receptor; a4b2 receptor; nAChR; cys-loop receptor.

cholinergic neurons express functional a7b2 receptors with

0165-6147/

an enhanced sensitivity to the amyloid-b (Ab) peptide

Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tips.2014.12.002

associated with AD [41] (see below).

96 Trends in Pharmacological Sciences, February 2015, Vol. 36, No. 2

Review Trends in Pharmacological Sciences February 2015, Vol. 36, No. 2 (A) (B)

Ligand-binding domain

Transmembrane domain

Intracellular Ligand-binding domain pocket

(C)

α7 α4β2

1 s 1 s Acvaon Fast Slow

Desensizaon Fast Slow Ca2+ High Low permeability α β -BTX, DH E MLA Selecve block

TRENDS in Pharmacological Sciences

Figure 1. The nicotinic acetylcholine receptor (nAChR) channel – basic structure and functional properties. A molecular model of the rat a7 nAChR: (A) a side view showing

the ligand-binding, transmembrane, and intracellular domains, and (B) a top-down view showing the pentameric nature of the receptor with the ligand-binding pocket at

the interface between two subunits. (C) The basic functional and pharmacological properties of the a7 and a4b2 nAChR subtypes. Abbreviations: BTX, bungarotoxin; DHbE,

dihydro-b-erythroidine; MLA, methyllycaconitine.

In the brain, the nAChRs are expressed and function at direct postsynaptic contacts, they are able to release ACh.

the synapse (both pre- and postsynaptically) as well as However, the precise role that extrasynaptic nAChRs play

extrasynaptically [13,16,42,43,12], and participate in in brain circuit excitability and plasticity remains to be

nAChR-mediated postsynaptic responses [44]. While a7* determined.

nAChR-mediated synaptic responses have previously been Several layers of complexity contribute to the challenge

observed in hippocampal interneurons utilizing of deciphering the role of nAChRs in brain circuit excit-

electrophysiological techniques [45,46], optogenetic stimu- ability and plasticity, as well as in disorders and diseases of

lation of direct cholinergic inputs to the hippocampus the brain. Subunit composition directly contributes to

revealed new evidence for a4b2* nAChR-mediated post- nAChR channel permeability and kinetics, whereas sub-

synaptic responses from interneurons [47] and pyramidal cellular localization within the neural network determines

cells [44]. Various subtypes of nAChRs have been shown to the precise contribution of a given nAChR population in a

modulate synaptic transmission in other areas of the brain, spatial- and time-dependent manner. The unique anatom-

including (but not limited to) the visual cortex, cortical ical distribution of each nAChR subtype within the brain

interneurons, supraoptic nuclei, and thalamic nuclei [48– implicates particular ones in brain disease (Table 1). As

51]. In addition to presynaptic and postsynaptic locations such, the a7* and non-a7 nAChR subtypes are active

in which they function to promote neurotransmitter re- targets for therapeutic development in neurodegenerative

lease and excitability, nAChRs are also functionally disease, neurodevelopmental disorders, and chronic pain.

expressed extrasynaptically where they participate in Below we will discuss these receptors as they are under-

non-synaptic communication [4,52]. Although most cholin- stood in the etiology and treatment of AD, autism, schizo-

ergic presynaptic neurotransmitter terminals do not make phrenia, and neuropathic pain.

Review Trends in Pharmacological Sciences February 2015, Vol. 36, No. 2

Table 1. Summary of nAChRs used as targets in CNS diseases – categorized by the CNS diseases discussed in the present review,

brain regions implicated in each disease, and the nAChR subunits implicated in each disease, as well as potential pharmacological

interventions currently identiﬁed using preclinical and clinical trial design

CNS disease Brain regions implicated nAChR subunits implicated Potential pharmacological strategies

Alzheimer’s Basal forebrain cholinergic a7, a4, b2 Agonists, partial agonists, and PAMs

disease nuclei, hippocampus, cerebral for a7* nAChRs, a4b2* agonists

cortex

Autism, autism Cerebral cortex, hippocampus, a3, a4, b2 Agonists or PAMs for a4b2* nAChRs spectrum amygdala, basal ganglia,

disorder cerebellum

Schizophrenia Hippocampus, cortex a7, a4b2 Agonists, partial agonists, or PAMs for

a7* nAChRs or partial agonists for a4b2*

nAChRs

Pain Dorsal root ganglia, brainstem a3, a4, a5, a7, Agonists or PAMs for a4b2* nAChRs or

rostral, ventromedial medulla, a9, a10, b2 type II or PAMs for a7* nAChRs

midbrain periaqueductal gray,

spinal cord dorsal horn

AD (memory loss, confusion, and problems with thinking and

Neuronal nAChR dysfunction is involved in the pathophys- reasoning) of early AD that are thought to be due in part to

iology of various neurodegenerative diseases, including AD the cholinergic deﬁcit, and they remain the ﬁrst line of

and Parkinson’s disease (PD). Here we will focus solely on therapy today.

AD since there are excellent recent reviews discussing the Brain regions associated with attention, spatial, and

complexity between nAChR distribution within the nigro- episodic memory lose cholinergic innervation in early AD;

striatal pathway, how nAChR function contribute to this thus, cholinergic hypofunction is most evident in the neo-

network, and PD pathophysiology [53]. cortex and temporal lobes inclusive of the hippocampus

[57]. The current model for the cholinergic deﬁcit in AD

Prevalence and causes posits that the septo-hippocampal pathway preferentially

AD is a neurodegenerative disease characterized by mem- accumulates misfolded Ab and tau, which leads to loss of

ory and cognitive loss, and represents the leading cause of the cholinergic phenotype, for example, loss of cholinergic

dementia in people aged >60 years [54]. Sporadic, or non- markers (ChAT, VAChT) and eventually cholinergic neu-

inherited, forms of AD comprise the majority of diagnosed rons from the basal forebrain nuclei through altered

cases of the disease. However, identiﬁcation of the genetic nAChR function and disruption of the nerve growth factor

mutations that underlie the familial, or inherited, forms of (NGF) trophic support system [58]. A compelling overlap

AD have provided enormous insight into fundamental exists between NGF-mediated signaling and the a7*

mechanisms, namely that the trigger for synaptic and nAChR subtype as a7 nAChR activation also promotes

neural network dysfunction is the aberrant accumulation the cholinergic phenotype [31]; thus, loss of a7* nAChR

of misfolded amyloid-b (Ab) (Table 2). function in particular likely contributes to early AD cho-

Ab is formed through proteolytic cleavage of its precur- linergic hypofunction and cognitive deﬁcits.

sor protein, a type 1 membrane protein called amyloid As brieﬂy discussed above, nAChRs (primarily a4b2*

precursor protein (APP). Ab peptide length can vary from and a7* subtypes) are expressed within the cholinergic

38 to 43 amino acids in length depending on the g-secretase forebrain nuclei, as well as at pre- and postsynaptic loca-

C-terminal cleavage site and N-terminal post-translation- tions within their projection areas. For example, in the

al truncation events (Figure 2A). hippocampus, a4b2- and a7-containing nAChRs have been

The nAChRs are integral to early AD cholinergic hypo- localized presynaptically and somato-dendritically on glu-

function. In addition to the complex biochemical processes tamatergic principal cells that drive synaptic plasticity;

involved in neuronal degeneration due to misfolded Ab however, these nAChRs are also enriched on GABAergic

accumulation and development of neuroﬁbrillary tangles interneurons that play a signiﬁcant role in modulating

comprised of misfolded tau, the cholinergic deﬁcit due to principal cell activity [59]. Furthermore, nAChR subtypes

the loss of basal forebrain cholinergic neurons and produc- within the basal forebrain are important players in modu-

tion of ACh signiﬁcantly contributes to early AD dementia lating synaptic transmission, plasticity, learning, and

[55]. The cholinergic deﬁcit is evident by reduced choline memory [44,60].

acetyltransferase (ChAT) protein and activity, and vesicular Distinct nAChR subtypes are differentially affected in

ACh transporter (vAChT) protein. In presynaptic nerve AD. The observation that Ab preferentially accumulates in

terminals, ChAT synthesizes ACh, and the vAChT is respon- brain regions that are also enriched for a4b2* and a7*

sible for the transport of ACh into synaptic vesicles for nAChRs may provide an important clue for the selective

storage until exocytotic release into the synapse [56]. Acet- vulnerability of the hippocampus and neocortex to Ab

ylcholinesterases (AChEs), residentwithin the synaptic cleft, toxicity given the high afﬁnity interaction between Ab

hydrolyze ACh to rapidly terminate the availability of neu- and these nAChRs [61,62]. Importantly, a7* nAChRs ex-

rotransmitter and nAChR activation. Acetylcholinesterase hibit an exceptionally high Ab afﬁnity (picomolar range)

inhibitors (Aricept, Exelon, Razadyne, Cognex) were the ﬁrst [63], suggesting a physiological interaction that may inﬂu-

FDA-approved therapies to treat the cognitive symptoms ence synaptic transmission and plasticity [64–66], as well

Review Trends in Pharmacological Sciences February 2015, Vol. 36, No. 2

Table 2. In situ and heterologous expression studies have revealed varied nAChR responses to Ab – they appear to depend upon

the species of receptor and the subunit composition. Both receptor activation and receptor inhibition has been shown for the a7

nAChR subtype

nAChR subtype Experimental preparation Type of interaction Downstream consequences Refs

Human a7* Human brain: control Colocalization and N/A Wang et al. [63]

and AD co-immunoprecipitation

Human a7* Human and rat cell lines High-afﬁnity binding Competitive binding: BTX Wang et al. [191]

versus Ab

Rat a7 Xenopus oocytes Receptor activation Ca inﬂux, ERK activation Dineley et al. [66,87]

Rat a7*, non-a7* Isolated presynaptic Receptor activation Increased presynaptic Ca Dougherty et al. [74]

terminals: hippocampus,

neocortex

Rat a4* Diagonal band nucleus Receptor activation Membrane depolarization, Fu and Jhamandas [75];

increased miniature Chin et al. [73]

excitatory postsynaptic

current (mEPSC) frequency

Mouse a7*, b2* NG108-15 cells, isolated Receptor activation Increased presynaptic Ca Khan et al. [192]

presynaptic terminals:

hippocampus, neocortex

Rat a7*, non-a7* Acute hippocampal slice, Functional antagonism, Decreased probability Pettit et al. [70]

GABAergic interneurons reversible of opening (po)

Rat a7b2* Medial septum/diagonal Functional antagonism, Noncompetitive (choline) Liu et al. [41]

band cholinergic neurons reversible

Rat a7* Cultured hippocampal Functional antagonism, Noncompetitive (ACh) Liu et al. [69]

neurons reversible

Human a7 Xenopus oocytes Functional antagonism, Noncompetitive (ACh) Grassi et al. [193];

reversible Pym et al. [194]

Rat a7 Xenopus oocytes No effect N/A Lamb et al. [72]

Human a4b2 SH-EP1 cells Functional antagonism, Noncompetitive (nicotine) Wu et al. [195]

reversible

Human a4b2 Xenopus oocytes Agonist potentiation Membrane depolarization Pym et al. [194]

(ACh)

Rat a4b2, a2b2, Xenopus oocytes Functional antagonism, N/A Lamb et al. [72]

a4a5b2 reversible

Human a3b4 Xenopus oocytes No effect N/A Pym et al. [194]

Mouse muscle BOSC 23 cells Functional antagonism, Noncompetitive Grassi et al. [193]

g- or e-nAChR reversible

as contribute to Ab-mediated synaptic neural network neocortex [82–84]. In fact, individuals’ levels inversely

dysfunction (Figure 2B) [65,67]. While the extant litera- correlated with neuropsychological tests that are used to

ture appears contradictory, if one considers the stunning help diagnose AD (e.g., Global Cognitive Score and Mini-

complexity of nAChR subunit stoichiometry, brain region, Mental State Examination) [84], suggesting that a7*

and subcellular localization, one must acknowledge that nAChR expression in early AD is a reﬂection of cognitive

the most parsimonious interpretation of nAChR-Ab exper- reserve (a term that refers to superior memory function for

imental results is that Ab can either activate or antagonize the stage of AD pathology seen with currently accepted

a4b2* and a7* nAChRs, depending on the anatomical biomarkers for AD staging [85,86]).

microenvironment as well as the concentration, length, With few exceptions [75], a4b2* nAChRs are antago-

and conformation of Ab peptides [41,68–75]. Given that nized by Ab [41] and lost in early AD, whereas a7* nAChR–

in vivo Ab constituents and conformations will be highly Ab interaction may result in transient receptor activation

heterogeneous, while concentration will increase with dis- [87,88] and downstream signal transduction cascades that

ease state, it is likely that nAChR responses to the Ab promote neuronal survival and function [66,89] (however

microenvironment will vary and be in constant ﬂux. The see [90]) – a potential explanation for recent studies report-

next challenge is to decipher these dynamics to reﬁne ing that a7* nAChRs are preserved in early AD. However,

therapeutic strategies. as Ab concentration increases, receptor desensitization

In advanced AD, it is unequivocal that muscarinic AChR and functional downregulation likely ensues with concom-

levels remain relatively intact [76–78], and upwards of itant receptor upregulation to transiently repopulate the

50% of a4b2* nAChR binding sites are lost from neocortex functional receptor pool [31,61,91]. This model is supported

and hippocampus compared to unaffected humans at simi- by reports that a7* nAChRs are upregulated in several AD

lar age, and a7* nAChRs remain relatively stable in neo- patient cell types, including astrocytes and neurons [92–

cortex, although some reports vary [79,80]. The status of 95], as well as in AD animal models [96], and neuronal cell

nAChRs in mild cognitive impairment (MCI) due to prob- cultures chronically exposed to Ab [97]. Furthermore, the

able AD [81] reﬂects a different dynamic in that ChAT majority of a7* nAChR protein in AD brain is associated

activity and a7* nAChR expression levels have been with Ab [98,99], which upon dissociation, can resurrect a7*

reported to be elevated in the hippocampus and frontal nAChR function. While this suggests a potential therapeutic

Review Trends in Pharmacological Sciences February 2015, Vol. 36, No. 2 β APP α (A) sAPP sAPP

β A P3

γ Secretase β Secretase α Secretase γ Secretase

AICD C99 C83 AICD

(B) A β monomer, 2+ Neuroprotecon α7* Ca small oligomers α4β2* ERK Cholinergic phenotype nAChR Akt PI3K Synapc plascity ↑NT release Learning ↓TNF-α & memory ↑TrkA

Loss of cholinergic phenotype A β Ca2+ oligomers PP2B Synapc plascity α7* deficits α4β2* Step ↓NMDAR Learning nAChR ↑ & Proinflammatory memory markers deficits nAChR silencing Neuroinflammaon Neurodegeneraon

TRENDS in Pharmacological Sciences

Figure 2. (A) Ab is formed through proteolytic cleavage of its precursor protein, a type 1 membrane protein called APP. APP cleavage by b- and g-secretases lead to the

formation of the N- and C-terminal residues of Ab, respectively, in addition to sAPPb and a CTF of 99 amino acids (C99). If APP is cleaved by the a-secretase, then Ab

formation is precluded as this enzyme cleaves APP within the Ab sequence to generate sAPPa and CTF83. When cleaved by g-secretase, CTFs generate the AICD and

either P3 or Ab resulting from a- and b-secretase cleavage, respectively. (B) As Ab accumulates one can postulate that at lower concentration and smaller oligomer

aggregates (upper panel), transient nAChR activation may occur depending on the nAChR subunit composition (Table 2). If activation ensues, it can lead to membrane

depolarization, increased intracellular/presynaptic calcium and synaptic transmission, activation of kinases important for synaptic plasticity, learning and memory, as

well as the induction of genes and proteins necessary for the cholinergic phenotype and neuroprotection. As disease progresses and Ab concentration and oligomer

status increase (lower panel), nAChR function is lost either through loss of receptor protein (a4b2*) or function (a7*) leading to synaptic dysfunction and loss of the

cholinergic phenotype, learning and memory deficits, increased inflammatory status, and progressive neurodegeneration. Abbreviations: Ab, amyloid-b; AICD, APP

intracellular domain; APP, amyloid precursor protein; CTF, C-terminal fragment; ERK, extracellular signal-regulated kinase; nAChR, nicotinic acetylcholine receptor;

NMDAR, NMDA receptor; NT, neurotrophin; PI3K, phosphatidylinositide 3-kinase; PP2B, protein phosphatase 2B; sAPPb, soluble APP; TNF-a, tumor necrosis factor-a;

TrkA, tropomyosin receptor kinase A.

intervention, a recent in vitro study indicates that neuronal gliotransmitters, such as glutamate, in response to astro-

hyperexcitability may be an unintended consequence of cytic calcium elevations that can activate neuronal gluta-

therapeutic interventions that reverse neuronal Ab–a7 mate receptors. Recently, two independent studies [65,67]

nAChR interaction [97]. demonstrated that biologically-relevant concentrations of

An additional level of complexity for the role of a7* Ab elicited a7* nAChR-dependent calcium elevations in

nAChRs in the pathophysiology of AD stems from work astrocytes and induced glutamate gliotransmission to ac-

focused on these receptors expressed by astrocytes. It is tivate neuronal glutamate receptors. Furthermore, in AD

now recognized that astrocytes express a7* nAChRs mouse models for Ab over-production and accumulation,

[21,22,27] and participate in synaptic communication tonic glutamate receptor [67] and spontaneous astrocytic

through intimate interactions with neurons [100–102]. calcium elevations [65] were of higher frequency compared

A principal mechanism is through the release of to controls – observations that laid the foundation for the

100

Review Trends in Pharmacological Sciences February 2015, Vol. 36, No. 2

newly explored hypothesis that a signiﬁcant aspect of AD neurogenesis during brain development [114,115]. Here

pathophysiology is epileptiform dysfunction [103,104]. we discuss the role of nAChRs in two of the most common

The cholinergic deﬁcit in early AD has led to the devel- neurodevelopmental disorders, autism and schizophre-

opment of drugs able to prevent ACh hydrolysis (e.g., nia.

AChE inhibitors). While these drugs do not change the

course of the disease, AChE inhibitors improve memory Autism

and other cognitive functions throughout most of the du- Autism is a neurodevelopmental disorder, also known as

ration of the disease. The pharmacological activity of these autism spectrum disorder (ASD), which is characterized by

drugs suggests an effect beyond the mere increase of ACh deﬁcits in socialization and a lack of verbal as well as non-

levels; for example, galantamine (Razadyne) has been verbal communication with pronounced cognitive im-

shown to act also as a positive allosteric modulator pairment [116,117]. Neuropathological data suggests that

(PAM) on a7* and a4b2* nAChRs [105,106], and both abnormalities in the cholinergic system may be related to

donepezil (Aricept) and galantamine increase nAChR den- autism [118]. In a study carried out on adult post-mortem

sity [107]. Nonetheless, long-term clinical assessments autistic brains using quantitative RT-PCR for measuring

indicate that the main effect of AChE drugs is symptomatic mRNA expression together with protein level expression

treatment with limited disease modifying actions [108]. and speciﬁc radioligand receptor binding, it was found that

The a4b2* and a7* nAChRs within the basal forebrain there was a decrease of 40–50% in the expression of the a3,

cholinergic system are important for the types of cognitive a4, and b2 nAChR subunits in the cerebral cortex, while

performance that are impaired in early AD. Thus, several there was no change in the expression of the a7 subunit

subtype-selective agonists and partial agonists that target [119]. The reduced gene expression of the a4 and b2

a4b2* as well as a7* nAChRs have been tested [109]. While receptor subunits in the cerebral cortex is a major feature

study design and placebo effects may account for some of of the neurochemical pathology of ASD [119]. If there is a

the variability, it is now evident that many AD clinical loss of cholinergic tone in the autistic brain, then nAChR

trials likely ‘fail’ due to enrollment of patients at advanced ligands that restore or improve cholinergic transmission

disease stages. There is an emerging consensus that the may be used to compensate for such loss [120,121]. There-

best strategy for AD clinical efﬁcacy is to treat people fore, agonists and PAMs for a4b2* nAChRs may be

during the earliest stages of disease [110]; for example, employed to compensate for the loss of nAChR function

prodromal Alzheimer’s or MCI due to AD [111]. The cur- in the autistic brain.

rent challenge is to reliably diagnose at such early stages In contrast to this, it has also been suggested that

using a combination of biomarkers, brain imaging, and nicotinic cholinergic antagonism may provide symptomatic

cognitive testing [85,112]. Currently in trial development relief in ASD [122]. This was based primarily on the low

(clinicaltrials.gov) targeting nAChRs for mild to moderate prevalence of smoking in the ASD population [123,124],

AD is EVP-6124 (FORUM Pharmaceuticals), also known although this may due to the loss of expression of the a4b2*

as MT-4666 (Mitsubishi Tanabe Pharma Corporation), an nAChRs early in development and presumably loss of

a7 nAChR partial agonist, varenicline (Pﬁzer), an a4b2* sensitivity to the rewarding properties of nicotine since

nAChR partial agonist, and AZD-3480 (AstraZeneca), a the a4b2* receptors are primarily responsible for the

partial agonist for a4b2 and a2b2 nAChRs [113]. Nicotine addictive properties of nicotine [125,126]. In support of

and acetylcholinesterase inhibitors (e.g., galantamine and this notion, in a placebo-controlled pilot study with a

donepezil) continue to be evaluated for efﬁcacy in AD as nonselective and noncompetitive antagonist of the

well. Furthermore, since a4b2* nAChRs are lost early in nAChRs, mecamylamine, it was found that while this drug

AD, a4b2* nAChR single photon emission computed to- was well tolerated, it lacked efﬁcacy in treating autistic

mography (SPECT) and positron emission tomography symptoms [127].

(PET) radioligands are being developed and tested in Recently it has been reported that AChE inhibitors (e.g.,

clinical trials as potential diagnostic tools and biomarkers donepezil and galantamine), which, in general, increase

123

for AD staging. For example, [ I]5-I-A-85380 (sponsored cholinergic tone at the synapse [128], cause a pronounced

by the National Institutes of Health) is being tested for use improvement in typical symptoms associated with autism

in SPECT and [ F]XTRA (Johns Hopkins University) is (e.g., verbal communication, eye to eye contact, and emo-

currently being tested for use in PET. tional responsiveness) in a single case report [129]. Simi-

The continued design and synthesis of nAChR ligands larly in a randomized, double-blind, placebo-controlled

with the desired pharmacokinetics and pharmacodynam- clinical trial, galantamine was shown to be safe and rela-

ics to target the desired receptor population, in combina- tively effective in alleviating some autism-related symp-

tion with continued elucidation of the disease-stage toms (e.g., irritability and lethargy/social withdrawal)

properties of nAChRs, may ultimately achieve the goal [130]. The lack of efﬁcacy of the nAChR antagonist meca-

of developing an interventional tool to combat the loss of mylamine, combined with the effectiveness of galantamine

cholinergic basal forebrain connectivity in this most prev- and donepezil, suggest that nAChR agonists and PAMs

alent of the devastating neurodegenerative disorders. (rather than antagonists) are more effective in providing

symptomatic relief in autism and ASD. While further

Neurodevelopmental disorders studies are needed to investigate and develop nAChR

The nAChRs are widely expressed on both differentiated drugs as a treatment option for symptoms related to

and undifferentiated CNS cells, and are known to inﬂu- autism and ASD, the FDA-approved AChE inhibitors

ence development and modulate multiple pathways of may provide symptomatic relief in the interim.

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Schizophrenia the development of therapeutic treatments for the cognitive

Schizophrenia is a neurodevelopmental disorder that is impairments associated with schizophrenia. Along these

characterized by cognitive deﬁcits and disordered thoughts lines, we recently found that presynaptic a7* nAChRs,

that manifest as hallucinations, delusions, and paranoia. via a mechanism involving protein kinase A (PKA), en-

Schizophrenia has both genetic and environmental etiolo- hanced hippocampal CA3 mossy ﬁber glutamatergic trans-

gies, and has been previously genetically linked to dysfunc- mission [146]. These types of studies may help to provide a

tion in the hippocampal nAChR system [131]. In contrast mechanistic explanation for the hypothesis that nicotine

to ASD, the schizophrenia patient population exhibits a enhances the mossy ﬁber glutamatergic transmission in the

much higher prevalence for smoking than the general hippocampal CA3 region to compensate for a loss of synaptic

population, which some consider to be a form of self-medi- connection in schizophrenic patients [147].

cation as it may normalize some of the cognitive and

sensory deﬁcits [132,133]. Nicotine exposure (either Pain

through smoking, nicotine gum, nasal spray, or the patch) Pain is an unpleasant sensory feeling that includes neuro-

appears to improve or normalize sensory deﬁcits in schizo- pathic, nociceptive, and psychogenic pain [148]. If the pain

phrenia [133]; however, due to the adverse health effects persists for longer than a few months, the condition is said to

and toxicity of nicotine, other ligands acting on nAChRs be chronic (as opposed to acute) pain [149]. The most com-

may prove useful as a treatment option for symptoms mon reason for neuropathic pain is a disruption in the

related to schizophrenia. normal functioning of the somatosensory system

Indeed the nAChR partial agonist, varenicline, improves [150]. The nAChRs have been known for some time to be

cognition in schizophrenic patients [134,135]. For example involved in the process of mediating pain, and as such the

in a randomized, double-blind, placebo-controlled clinical analgesic effects of nAChR agonists as well as positive

trial for patients diagnosed with schizophrenia, varenicline allosteric modulators (PAMs) have long been investigated

improved some aspects of cognitive function (e.g., Digital [151]. The microinjection of nicotine into different regions of

Symbol Substitution and the Wisconsin Card Sorting tests) the brainstem produced an antinociceptive effect [152]. In

compared to controls [136]. However, it is unclear which rats, the antinociception induced by nicotine was further

nAChR subtypes may be involved since it is a partial agonist shown to be inhibited by the administration of the general

for the a4b2 nAChRs and a full agonist for the a7 nAChRs nAChR antagonist mecamylamine [153]. Apart from nico-

[137]. tine, the frog skin-derived alkaloid epibatidine, which acts as

A robust feature of the schizophrenic brain is a decrease a nonselective agonist for nAChRs, was shown to have

in the number of a7* nAChRs (particularly in the hippo- analgesic properties [154,155]. When epibatidine and mor-

campus) [131]. In fact, a direct genetic linkage to the a7 phine were tested in the mouse straub tail response, both

subunit was ﬁrst reported in 1997 where it was found that compounds were able to reduce pain [156,157]. As expected,

a polymorphism existed at chromosome site 15q13–14, the the analgesic effect of morphine was blocked by naloxone,

site of the a7 nAChR subunit gene [138,139]. In support of but not that of epibatidine [156,158]. Upon further investi-

a mechanistic role for a7* nAChRs in schizophrenia, stud- gation it was found that while epibatidine caused antinoci-

ies on auditory gating (investigated using the P50 audito- ception in animal models of pain, it also produced several

ry-evoked response), in which deﬁcits are known to be major adverse effects like dose-dependent decreases in loco-

associated with schizophrenia, have been done. The sys- motor activity, and a similar decrease in body temperature

temic administration of the type II a7 nAChR PAMs (PNU- [154]. Epibatidine is a nonselective agonist since it activates

120596 or JNJ-1930942) improved auditory gating deﬁcits multiple subtypes of the neuronal nAChRs, as well as the

caused by amphetamine or MK-801 [(+)-5-methyl-10,11- neuromuscular receptor [159], which accounts for its various

dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate)] adverse effects [160], limiting its use as a therapeutic.

in rodent models that reﬂect circuit level disturbances Based upon these observations, the research focus has

associated with schizophrenia [140–142]. Furthermore, since shifted to develop compounds that would selectively

several clinical trials support the use of a7 nAChR agonists target speciﬁc neuronal nAChR subtypes with the purpose

to treat cognitive deﬁcits in schizophrenia. For example, of maintaining the analgesic effect while reducing or elim-

cognitive and/or sensory deﬁcits were improved with the a7 inating the adverse effects that are seen with nonselective

partial agonists GTS-21 [143], DMXB-A [144], or EVP- agonists such as epibatidine. The a4b2 subtype-selective

6124 [145] in schizophrenia cohorts. In addition, in a ligands were the ﬁrst to be developed. ABT-594, which is a

randomized, double-blind, placebo-controlled study of structural analog of epibatidine, was shown to be a potent

schizophrenic patients, the novel and selective a7 nAChR full agonist for the a4b2 nAChRs with a strong analgesic

agonist EVP-6124 provided signiﬁcant improvement in a effect [156,161,162]. In various animal models of pain, the

number of areas of cognitive function that are compro- analgesic activity of ABT-594 was inhibited by the admin-

mised in schizophrenia [145]. istration of the general antagonist mecamylamine

At present, a7* nAChR agonists and PAMs appear to be [160,163]. At lower doses, ABT-594 does not induce any

the most effective hope for the future in the treatment of signiﬁcant analgesic effects, while at higher doses (150–

schizophrenia. What is needed next is a determination of the 300 mg), the analgesic effects of ABT-594 were accompa-

mechanism of synaptic failure in schizophrenia and the nied by signiﬁcant adverse effects like nausea, dizziness,

potential cellular mechanisms of the positive cognitive and vomiting [164], indicating that ABT-594 has a narrow

actions of these selective a7* nAChR ligands in these therapeutic window and may act upon peripheral nAChRs

patients. This information will provide further insight into at higher doses. Subsequently other selective agonists for

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the a4b2 nAChRs (e.g., TC-2696 and TC-6499) were devel- treatment of acute as well as chronic pain to avoid the major

oped [165]. While both TC-2696 and TC-6499 showed adverse effects commonly seen with a nAChR agonist alone.

signiﬁcant analgesic effects in animal models for neuro- Besides the a4b2* and a7* receptors, other nAChRs are

pathic pain, they were not developed further because both also known to be involved in the processing of pain

had a narrow therapeutic window (i.e., the difference in [151]. For example, it is emerging that the a5 nAChR

doses at which they produce analgesic effects and adverse subunit plays a signiﬁcant role in nociception. The a5

effects was small) [165,166], similar to that seen with ABT- subunit can participate in a4b2*, a3b2*, or a3b4* nAChRs

594. Recently, another drug that targets the a4b2 nAChRs, [185]. The antinociception effect of nicotine in a5 subunit

A-366833, was reported to cause signiﬁcant analgesia in a knockout mice was reduced compared to wild type mice,

variety of models for neuropathic pain [167,168]. In this indicating that the a5 subunit may play an important role

scenario, it is thought that the activation of presynaptic in the processing of pain [185]. In addition, there may be a

a4b2* receptors within the spinal cord that modulate role for the a9/a10 nAChRs in pain. Dorsal root ganglion

GABA and glycinergic neurons may lead to an inhibitory neurons express the a9/a10 nAChR subtypes [186].

effect on nociception [151,166,169–173]. However, while There is accumulating evidence, based upon pharmaco-

the activation of a4b2* receptors may be required, it may logical testing and behavioral studies, that strongly impli-

not be sufﬁcient to induce an analgesic effect; the activa- cates nAChRs in the process of nociception and the

tion of other subtypes of nAChRs, speciﬁcally the a3-con- treatment of pain. However, given the complexity of the

taining nAChRs, may also be required [166,109]. nAChR subtypes expressed within the CNS and PNS, as

In addition to a4b2* and a3-containing nAChRs, com- well as the complexity and plasticity of the neuronal

pounds that act on the a7 nAChRs have also been studied circuits involved in the processing of pain, developing

for their effects on pain. Choline, a by-product of ACh therapeutic strategies that target nAChRs to treat acute

enzymatic degradation by AChE and a selective agonist and chronic pain poses signiﬁcant challenges.

for the a7 receptors, has analgesic effects in rodent models

of pain [174,175]. However, other agonists that target a7 Concluding remarks

nAChRs, such as SSR-180711 and tropisetron, fail to in- The distribution of nAChRs in the nervous system is

duce analgesia when tested in the formalin model for pain extensive yet discrete, and historically this has made them

[166], suggesting that targeting a7* nAChRs for pain relief an active target of drug development for treating neuro-

is modality selective. Based on these contradictory results, degenerative diseases such as AD. However, the nAChRs

further work needs to be done to clearly deﬁne the role of a7 are increasingly appreciated for their roles in neurodeve-

nAChR agonists in analgesia. lopment and sensory processing, and thus have been iden-

A variety of a4b2 and a7 nAChR PAMs have been tiﬁed as therapeutic targets in autism, schizophrenia, and

evaluated in preclinical models for pain [121,176– neuropathic pain. Unfortunately, no nAChR compounds

178]. For instance, the a7 nAChR PAM PNU-120596 caused have demonstrated disease-modifying properties for any of

a signiﬁcant reduction in mechanical hyperalgesia in rats the disorders in which these receptors are implicated to

[179]. Additionally, PNU-120596 is able to decrease forma- date. Thus we contend that a new generation of nAChR

lin-induced pain by itself, and in combination with the a7 ligands is needed for studies on their ability to treat

nAChR agonists choline, nicotine, and PHA-543613 neurodegenerative or neurodevelopmental disorders, as

[180]. PNU-120596 is also able to reduce edema induced well as neuropathic pain.

by a hind paw infusion of carrageenan in mice [181]. Another What are the prospects for the future? Currently there

a7 nAChR PAM, NS-1738, has also been tested for its effects are at least two main obstacles. First, more mechanistic

on pain. Both NS-1738 and PNU-120596 were able to reduce details about the stoichiometry, expression, and develop-

heat-induced hyperalgesia [181]. In a chronic constriction mental regulation of the various subtypes of nAChRs in the

injury model for neuropathic pain, an anti-hyperalgesic and brain and nervous system are needed, both in neurons and

anti-allodynic effect of PNU-120596 was observed, however non-neuronal cells, and how these receptors are regulating

NS-1738 did not have any effect in the same study [181]. One brain circuit function, excitability, plasticity, and develop-

possible mechanism for this may be the ability of PNU- ment. It is only through this knowledge that we can know

120596 to enhance a7 nAChR activation over a certain which nAChRs we need to target for the design of thera-

threshold, which would indirectly stimulate inhibitory neu- peutics in order to treat disorders and diseases linked with

rons located in the neural circuits for neuropathic pain. nAChRs. This will also help us to understand how we want

The a4b2 nAChR PAM NS-9283 when administered to alter receptor function; for example, in some instances

alone did not affect mechanical allodynia in the spinal nerve we may need to enhance function (either competitively or

ligation test (a model of neuropathic pain), nor on nociception via allosteric modulation), while in other instances we may

and inﬂammation in various rodent models of pain need to block or reduce function (either short- or long-

[182,183]. However, when NS-9283 was co-administered term). Great strides are now being made and will continue,

with the a4b2 receptor agonist ABT-594, the presence of in part through the use of optogenetics, in vivo physiologi-

the a4b2 nAChR PAM increased the anti-allodynic effects of cal studies in live animals, and genetic methods to remove

the agonist alone [182]. In addition NS-9283 was able to or modify speciﬁc nAChR subtypes from speciﬁc brain

strengthen the antinociceptive actions of the a4b2 nAChR regions, cell types, and at speciﬁc developmental stages.

partial agonist NS-3965 [184]. Therefore, combining an Second, a more targeted approach to develop therapeu-

a4b2 receptor PAM with a nAChR full agonist may be a tics acting selectively and effectively on the various nAChR

viable strategy in therapeutic drug development for subtypes is needed. For example, more structural and

103

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Acknowledgments

acetylcholine receptor is geared towards improving cognitive deﬁcits.

This work was supported by the Intramural Research Program, NIEHS/

Pharmacol. Ther. 122, 302–311

NIH to J.L.Y. and A.A.P., a kind gift to K.T.D. from J&W Mohn, and an

27 Velez-Fort, M. et al. (2009) Functional alpha 7-containing nicotinic

Independent Investigator Research Grant from the Alzheimer’s Associa-

receptors of NG2-expressing cells in the hippocampus. Glia 57, 1104–

tion to K.T.D. 1114

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