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Biochemical Pharmacology (v.82, #8)

Jerry Buccafusco—1949–2010 by Stephen P. Arneric; Michael Williams (pp. 798-799).

Naturally-expressed nicotinic acetylcholine receptor subtypes by Jie Wu; Ronald J. Lukas (pp. 800-807).
Nicotinic acetylcholine receptors (nAChRs) warrant attention, as they play many critical roles in brain and body function and have been implicated in a number of neurological and psychiatric disorders, including nicotine dependence. nAChRs are composed as diverse subtypes containing specific combinations of genetically-distinct subunits and that have different functional properties, distributions, and pharmacological profiles. There had been confidence that the rules that define ranges of assembly partners for specific subunits were well-established, especially for the more prominent nAChR subtypes. However, we review here some newer findings indicating that nAChRs having largely the same, major subunits exist as isoforms with unexpectedly different properties. Moreover, we also summarize our own studies indicating that novel nAChR subtypes exist and/or have distributions not heretofore described. Importantly, the nAChRs that exist as new isoforms or subtypes or have interesting distributions require alteration in thinking about their roles in health and disease.

Keywords: Abbreviations; nAChR(s); nicotinic acetylcholine receptor(s); VTA; ventral tegmental area; DAergic; dopaminergic; DA; dopamine; SN; substantia nigra; ACh; acetylcholine; IPSC(s); inhibitory post synaptic current(s); Bgt; α-bungarotoxin; αCtx; α-conotoxinNicotine; Nicotinic receptor; Acetylcholine; Alzheimer's disease; Drug dependence


Recent advances in gene manipulation and nicotinic acetylcholine receptor biology by Anne Tammimäki; William J. Horton; Jerry A. Stitzel (pp. 808-819).
Pharmacological and immunological methods have been valuable for both identifying some native nicotinic acetylcholine receptor (nAChR) subtypes that exist in vivo and determining the neurobiological and behavioral role of certain nAChR subtypes. However, these approaches suffer from shortage of subtype specific ligands and reliable immunological reagents. Consequently, genetic approaches have been developed to complement earlier approaches to identify native nAChR subtypes and to assess the contribution of nAChRs to brain function and behavior. In this review we describe how assembly partners, knock-in mice and targeted lentiviral re-expression of genes have been utilized to improve our understanding of nAChR neurobiology. In addition, we summarize emerging genetic tools in nAChR research.

Keywords: Abbreviations; 5-HT; 5-hydroxytryptamine; α-BTX; α-bungarotoxin; ADNFLE; autosomal dominant nocturnal frontal lobe epilepsy; BAC; bacterial artificial chromosome; CFP; cyan fluorescent protein; CPP; conditioned place preference; Chrna3-7; α3–7 nicotinic acetylcholine receptor subunit genes; Chrnb2; β2 nicotinic acetylcholine receptor subunit gene; EEG; electroencephalogram; ES cell; embryonic stem cell; GABA; γ-aminobutyric acid; HDA; helper-dependent adenovirus; IPN; interpeduncular nucleus; MHb; medial habenula; nAChR; nicotinic acetylcholine receptor; PrL; prelimbic area of prefrontal cortex; RMGR; recombinase-mediated genomic replacement; RT-PCR; real-time polymerase chain reaction; SN; substantia nigra; SNP; single nucleotide polymorphism; SNpc; substantia nigra pars compacta; TUNEL; terminal deoxytransferase-mediated dUTP-biotin nick end-labeling; VTA; ventral tegmental area; YFP; yellow fluorescent proteinAssembly partners; Knock-in; Lentivirus; Localization; Nicotinic acetylcholine receptors; Targeted re-expression


Nicotinic control of adult-born neuron fate by Nolan R. Campbell; Catarina C. Fernandes; Danielle John; Adrian F. Lozada; Darwin K. Berg (pp. 820-827).
The hippocampus is one of only two regions in the adult brain where neurons are generated in significant numbers throughout the lifetime of the animal. Numerous studies have demonstrated that these adult-born neurons are essential for optimal cognitive function with unimpaired memory formation and retrieval. The extent to which adult-born neurons survive through an early “critical period” and become integrated into functional networks has been shown to depend on the richness of stimulation they receive during these formative stages. The dentate gyrus in the hippocampus – home of the adult-born neurons – receives extensive cholinergic innervation, and newly generated neurons in the adult hippocampus express substantial numbers of both major types of neuronal nicotinic acetylcholine receptors. Early studies indicated that nicotinic signaling may be important for the development of adult-born neurons: repeated exposure to nicotine impaired their long-term survival. Recent studies with mutant mice lacking either one of the two major nicotinic receptor subtypes demonstrate that receptor loss results in fewer adult-born neurons surviving the critical period and becoming integrated into neural networks. The key nicotinic receptor mediating the largest effects is one that has a high relative permeability to calcium. In view of this feature, it may not be surprising that excessive exposure to nicotine can have detrimental effects on survival and maturation of adult-born neurons in the dentate; these same receptors appear to be key. The results pose serious challenges for therapeutic strategies targeting an individual class of nicotinic receptors for global treatment in the recipient.

Keywords: Adult-born; Neurogenesis; Nicotinic; Cholinergic; Neuronal survival; HippocampusAbbreviations; nAChRs; nicotinic acetylcholine receptors; α7-nAChR; homopentameric α7-containing receptor; β2*-nAChR; heteropentameric β2-containing receptor; α7KO; knockout mouse lacking α7-nAChRs; β2KO; knockout mouse lacking β2*-nAChRs; PSCs; postsynaptic currents; MMLV-GFP; Moloney's murine leukemia viral construct expressing green fluorescent protein; RNAi; RNA interference


An autoradiographic survey of mouse brain nicotinic acetylcholine receptors defined by null mutants by Christopher G. Baddick; Michael J. Marks (pp. 828-841).
Nine nicotinic receptor subunits are expressed in the central nervous system indicating that a variety of nicotinic acetylcholine receptors (nAChR) may be assembled. A useful method with which to identify putative nAChR is radioligand binding. In the current study the binding of [125I]α-bungarotoxin, [125I]α-conotoxinMII, 5[125I]-3-((2S)-azetidinylmethoxy)pyridine (A-85380), and [125I]epibatidine has been measured autoradiographically to provide data on many nAChR binding sites. Each binding site was evaluated semi-quantitatively for samples prepared from wild-type and α2, α4, α6, α7, β2, β4, α5 and β3 null mutant mice. Deletion of the α7 subunit completely and selectively eliminated [125I]α-bungarotoxin binding. The binding of [125I]α-conotoxinMII was eliminated in most brain regions by deletion of either the α6 or β2 subunit and is reduced by deletion of either the α4 or β3 subunit. The binding of 5[125I]A-85380 was completely eliminated by deletion of the β2 subunit and significantly reduced by deletion of the α4 subunit. Most, but not all, α4-independent sites require expression of the α6 subunit. The effect of gene deletion on total [125I]epibatidine binding was very similar to that on [125I]A-85380 binding. [125I]Epibatidine also labels β4* nAChR, which was readily apparent for incubations conducted in the presence of 100nM cytisine. The effects of α3 gene deletion could not be evaluated, but persistence of residual sites implies the expression of α3* nAChR. Taken together these results confirm and extend previously published evaluations of the effect of nAChR gene deletion and help to define the nAChR subtypes measurable by ligand binding.

Keywords: Abbreviations; nAChR; nicotinic cholinergic receptor; αBgt; α-bungarotoxin; A-85380; 3-((2S)-azetidinylmethoxy)pyridine; αCtxMII; α-conotoxinMIINicotinic acetylcholine receptor; Null mutant mice; Epibatidine; A-85380; α-Conotoxin MII; α-Bungarotoxin


Endogenous activation of nAChRs and NMDA receptors contributes to the excitability of CA1 stratum radiatum interneurons in rat hippocampal slices: Effects of kynurenic acid by Manickavasagom Alkondon; Edna F.R. Pereira; Edson X. Albuquerque (pp. 842-851).
CA1 stratum radiatum interneurons (SRIs) express α7 nicotinic receptors (nAChRs) and receive inputs from glutamatergic neurons/axons that express α3β4β2 nAChRs. To test the hypothesis that endogenously active α7 and/or α3β4β2 nAChRs control the excitability of CA1 SRIs in the rat hippocampus, we examined the effects of selective receptor antagonists on spontaneous fast current transients (CTs) recorded from these interneurons under cell-attached configuration. The frequency of CTs, which represent action potentials, increased in the absence of extracellular Mg2+ and decreased in the presence of the α3β4β2 nAChR antagonist mecamylamine (3μM) or the NMDA receptor antagonist APV (50μM). However, it was unaffected by the α7 nAChR antagonist MLA (10nM) or the AMPA receptor antagonist CNQX (10μM). Thus, in addition to synaptically and tonically activated NMDA receptors, α3β4β2 nAChRs that are present on glutamatergic axons/neurons synapsing onto SRIs and are activated by basal levels of acetylcholine contribute to the maintenance of the excitability of these interneurons. Kynurenic acid (KYNA), an astrocyte-derived kynurenine metabolite whose levels are increased in the brains of patients with schizophrenia, also controls the excitability of SRIs. At high micromolar concentrations, KYNA, acting primarily as an NMDA receptor antagonist, decreased the CT frequency recorded from the interneurons. At 2μM, KYNA reduced the CA1 SRI excitability via mechanisms independent of NMDA receptor block. KYNA-induced reduction of excitability of SRIs may contribute to sensory gating deficits that have been attributed to deficient hippocampal GABAergic transmission and high levels of KYNA in the brain of patients with schizophrenia.

Keywords: Abbreviations; ACh; acetylcholine; ACSF; artificial cerebrospinal fluid; AMPA; (2R)-amino-5-phosphonovaleric acid; CNQX; 6-cyano-7-nitroquinoxaline-2,3-dione; CT; current transient; EPSC; excitatory postsynaptic current; KYNA; kynurenic acid; MLA; methyllycaconitine; nAChR; nicotinic acetylcholine receptor; SRI; stratum radiatum interneuronAction potential; Nicotinic receptor; NMDA receptor; Kynurenic acid; Hippocampus; Mecamylamine


Characterizing functional α6β2 nicotinic acetylcholine receptors in vitro: Mutant β2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells by Cheng Xiao; Rahul Srinivasan; Ryan M. Drenan; Elisha D.W. Mackey; J. Michael McIntosh; Henry A. Lester (pp. 852-861).
α6* nicotinic acetylcholine receptors (nAChRs) are highly expressed in mesostriatal and nigrostriatal dopaminergic systems, and participate in motor control, reward, and learning and memory. In vitro functional expression of α6* nAChRs is essential for full pharmacological characterization of these receptors and for drug screening, but has been challenging. We expressed eGFP-tagged-α6 and β2 nAChR subunits in Neuro-2a cells, leading to functional channels. Inward currents were elicited with 300μM ACh in 26% (5/19) of cells with evenly expressed α6-eGFP in cytoplasm and periphery. We dramatically increased chances of detecting functional α6-eGFPβ2 nAChRs by (i) introducing two endoplasmic reticulum (ER) export-enhancing mutations into β2 subunits, and (ii) choosing cells with abundant Sec24D-mCherry-labeled ER exit sites. Both manipulations also modestly increased α6-eGFPβ2 nAChR current amplitude. α6-eGFPβ2 nAChRs were also activated by nicotine and by TC-2403. The α6-eGFPβ2 currents were desensitized by 1μM nicotine, blocked by α-conotoxin MII, partially inhibited by dihydro-β-erythroidine, and potentiated by extracellular Ca2+. Single-channel recordings showed that α6-eGFPβ2 nAChRs had similar single-channel conductance to, but longer open time than, α4-eGFPβ2 nAChRs. These methods provide avenues for developing cell lines expressing subtypes of α6* nAChRs for both pharmacological study and drug screening.

Keywords: Nicotinic acetylcholine receptor; α6; β2; Fluorescent protein; Neuro2a cell; Endoplasmic reticulum exit sites


Progress and challenges in the study of α6-containing nicotinic acetylcholine receptors by Sharon R. Letchworth; Paul Whiteaker (pp. 862-872).
Recent progress has been made in the understanding of the anatomical distribution, composition, and physiological role of nicotinic acetylcholine receptors containing the α6 subunit. Extensive study by many researchers has indicated that a collection of α6-containing receptors representing a nicotinic sub-family is relevant in preclinical models of nicotine self-administration and locomotor activity. Due to a number of technical difficulties, the state of the art of in vitro model systems expressing α6-containing receptors has lagged behind the state of knowledge of native α6 nAChR subunit composition. Several techniques, such as the expression of chimeric and concatameric α6 subunit constructs in oocytes and mammalian cell lines have been employed to overcome these obstacles. There remains a need for other critical tools, such as selective small molecules and radioligands, to advance the field of research and to allow the discovery and development of potential therapeutics targeting α6-containing receptors for smoking cessation, Parkinson's disease and other disorders.

Keywords: Abbreviations; α-Ctx; alpha-conotoxin; CNS; central nervous system; GoF; gain-of-function; KO; knock-out; LC; locus coeruleus; MPTP; 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine; nAChRs; nicotinic acetylcholine receptors; PD; Parkinson's disease; PET; positron emission tomography; SNc; substantia nigra pars compacta; SPECT; single photo emission computed tomography; VTA; ventral tegmental areaAlpha6; Nicotinic receptor; Parkinson's disease; Smoking cessation; Addiction


Role of α6 nicotinic receptors in CNS dopaminergic function: relevance to addiction and neurological disorders by Maryka Quik; Xiomara A. Perez; Sharon R. Grady (pp. 873-882).
Although a relative newcomer to the nicotinic acetylcholine receptor (nAChR) family, substantial evidence suggests that α6 containing nAChRs play a key role in CNS function. This subtype is unique in its relatively restricted localization to the visual system and catecholaminergic pathways. These latter include the mesolimbic and nigrostriatal dopaminergic systems, which may account for the involvement of α6 containing nAChRs in the rewarding properties of nicotine and in movement. Here, we review the literature on the role of α6 containing nAChRs with a focus on the striatum and nucleus accumbens. This includes molecular, electrophysiological and behavioral studies in control and lesioned animal models, as well as in different genetic models. Converging evidence suggest that the major α6 containing nAChRs subtypes in the nigrostriatal and mesolimbic dopamine system are the α6β2β3 and α6α4β2β3 nAChR populations. They appear to have a dominant role in regulating dopamine release, with consequent effects on nAChR-modulated dopaminergic functions such as reinforcement and motor behavior. Altogether these data suggest that drugs directed to α6 containing nAChRs may be of benefit for the treatment of addiction and for neurological disorders with locomotor deficits such as Parkinson's disease.

Keywords: Abbreviations; α-CtxMII; α-conotoxinMII; nAChR; nicotinic acetylcholine receptorAddiction; Cyclic voltammetry; Nucleus accumbens; Parkinson's disease; Striatum


Neurobiology of nAChRs and cognition: A mini review of Dr. Jerry J. Buccafusco's contributions over a 25 year career by Alvin V. Terry Jr.; Michael W. Decker (pp. 883-890).
Nicotine improves delayed match to sample performance at long delay intervals in monkeys both at 10min and 24h after administration.This review highlights some of the many contributions of the late Dr. Jerry J. Buccafusco to the neurobiology of nicotinic acetylcholine receptors (nAChRs) and cognition over a 25 year period. The article is written by two of Dr. Buccafusco's professional colleagues, one from academia and one from the pharmaceutical industry. While Dr. Buccafusco's expertise in the cholinergic field was extensive, his insights into the practical relevance of his work (with a long-term goal of formulating new drug development strategies) were unique, and a great asset to both the basic science community and pharmaceutical companies. In 1988, Dr. Buccafusco's laboratory was the first to report the cognitive enhancing action of low doses of nicotine in non-human primates. Since that time he studied a large number of novel pro-cognitive agents from several pharmacological classes in rodents as well as monkeys. Based on years of observing paradoxical effects of nicotinic ligands in vitro and in vivo, Dr. Buccafusco made the provocative argument that it might be possible to develop new chemical entities (with pro-cognitive actions) that have the ability to desensitize nAChRs without producing an antecedent agonist action. Some of his more recent work focused on development of single molecular entities that act on multiple CNS targets (including nAChRs) to enhance cognition, provide neuroprotection, and/or provide additional therapeutic actions (e.g., antipsychotic effects). Dr. Buccafusco's influence will live on in the work of the numerous graduate students, postdoctoral fellows, and junior faculty that he mentored over the years who now serve in prestigious positions throughout the world.

Keywords: Nicotinic; Nicotine; Acetylcholine; Learning and memory; Drug development


Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease by Tanya L. Wallace; Richard H.P. Porter (pp. 891-903).
A promising drug target currently under investigation to improve cognitive deficits in neuropsychiatric and neurological disorders is the neuronal nicotinic alpha7 acetylcholine receptor (α7nAChR). Improving cognitive impairments in diseases such as Alzheimer's (AD) and schizophrenia remains a large unmet medical need, and the α7nAChR has many properties that make it an attractive therapeutic target. The α7nAChR is a ligand gated ion channel that has particularly high permeability to Ca2+ and is expressed in key brain regions involved in cognitive processes (e.g., hippocampus). The α7nAChRs are localized both pre-synaptically, where they can regulate neurotransmitter release, and post-synaptically where they can activate intracellular signaling cascades and influence downstream processes involved in learning and memory. In particular, activation of the α7nAChR with small molecule agonists enhances long-term potentiation, an in vitro model of synaptic plasticity, and improves performance across multiple cognitive domains in rodents, monkeys, and humans. Positive allosteric modulation of the α7nAChR offers an alternate approach to direct agonism that could prove to be particularly beneficial in certain disease populations where smoking nicotine is prevalent (e.g., schizophrenia) and could interfere with an orthosteric agonist approach. The current review focuses on the neurobiology of the α7nAChR, its role in cognition and the development status of some of the most promising molecules advancing for the treatment of cognitive dysfunction in disease.

Keywords: Cognitive; Memory; Attention; Nicotine; Alzheimer's; Schizophrenia


The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of α7*nAChR function by Tanguy Araud; Sharon Graw; Ralph Berger; Michael Lee; Estele Neveu; Daniel Bertrand; Sherry Leonard (pp. 904-914).
The human α7 neuronal nicotinic acetylcholine receptor gene ( CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the α7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca2+, that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. Schizophrenic patients have low levels of α7*nAChR, as measured by binding of the ligand [125I]-α-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene ( CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of α7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with α7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans.

Keywords: Abbreviations; CHRNA7; human α7 nicotinic acetylcholine receptor gene; Chrna7; mouse α7 nicotinic acetylcholine receptor gene; α7; α7 receptor subunit protein; α7*nAChR; α7 assembled surface pentameric receptor; CHRFAM7A; duplicated; CHRNA7; gene; CHRFAM7AΔ2; bp; duplicated gene containing a 2; bp deletion in exon 6; I-BTX; [; 125; I]-α-bungarotoxin; α-BTX; α-bungarotoxin; PNU-120596; 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-ureaCHRNA7; Schizophrenia; Nicotinic receptor; CHRFAM7A


Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: Advantages and limitations by Dustin K. Williams; Jingyi Wang; Roger L. Papke (pp. 915-930).
Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high-affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues.

Keywords: Abbreviations; A-585539; (1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane; A-867744; 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 5-HI; 5-hydroxyindole; 5-HT; 5-hydroxytryptamine; α-btx; α-bungarotoxin; ACh; acetylcholine; CCMI; N-(4-chlorophenyl)-alpha-[[(4-chloro-phenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide; CNS; central nervous system; dFBr; desformylflustrabromine; D; i; type II modulator-insensitive desensitization; D; s; type II modulator-sensitive desensitization; ERK1/2; extracellular signal-related kinase-1 and -2; GTS-21; 3-(2,4-dimethoxybenzylidene)-anabaseine; JNJ-1930942; 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol; LY-2087101; [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiophen-3-yl-methanone; nAChR; nicotinic acetylcholine receptor; MWC; Monod, Wyman, Changeux; NS-1738; 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea; PAM; positive allosteric modulator; PNU-120596; 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea; PNU-282987; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide; SB-206553; 3,5-dihydro-5-methyl-N-3-pyridinylbenzo [1,2-b:4,5-b′]-di pyrrole-1(2H)-carboxamide; SLURP-1; secreted mammalian Ly-6/uPAR related protein 1; TM; transmembrane; TQS; 4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta[c]quinoline-8-sulfonic acid amideAlzheimer's disease; Schizophrenia; Drug development; Electrophysiology; Modeling


Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer's disease by H. Rheinallt Parri; Caterina M. Hernandez; Kelly T. Dineley (pp. 931-942).
Aberrant amyloid-β peptide (Aβ) accumulation along with altered expression and function of nicotinic acetylcholine receptors (nAChRs) stand prominently in the etiology of Alzheimer's disease (AD). Since the discovery that Aβ is bound to α7 nAChRs under many experimental settings, including post-mortem AD brain, much effort has been expended to understand the implications of this interaction in the disease milieu. This research update will review the current literature on the α7 nAChR–Aβ interaction in vitro and in vivo, the functional consequences of this interaction from sub-cellular to cognitive levels, and discuss the implications these relationships might have for AD therapies.

Keywords: Alzheimer's disease; Cholinergic; Amyloid; Oligomer; Neuroprotection; Review


Functional brain imaging of nicotinic effects on higher cognitive processes by Paul A. Newhouse; Alexandra S. Potter; Julie A. Dumas; Christiane M. Thiel (pp. 943-951).
Schematic illustration of two different groups (placebo vs. nicotine) by condition (task vs. control) interactions in a pharmacological fMRI study.Significant advances in human functional brain imaging offer new opportunities for direct observation of the effects of nicotine, novel nicotinic agonists and nicotinic antagonists on human cognitive and behavioral performance. Careful research over the last decade has enabled investigators to explore the role of nicotinic systems on the functional neuroanatomy and neural circuitry of cognitive tasks in domains such as selective attention, working memory, episodic memory, cognitive control, and emotional processing. In addition, recent progress in understanding functional connectivity between brain regions utilized during cognitive and emotional processes offers new opportunities for examining drug effects on network-related activity. This review will critically summarize available nicotinic functional brain imaging studies focusing on the specific cognitive domains of attention, memory, behavioral control, and emotional processing. Generally speaking, nicotine appears to increase task-related activity in non-smokers and deprived smokers, but not active smokers. By contrast, nicotine or nicotinic stimulation decreases the activity of structures associated with the default mode network. These particular patterns of activation and/or deactivation may be useful for early drug development and may be an efficient and cost-effective method of screening potential nicotinic agents. Further studies will have to be done to clarify whether such activity changes correlate with cognitive or affective outcomes that are clinically relevant. The use of functional brain imaging will be a key tool for probing pathologic changes related to brain illness and for nicotinic drug development.

Keywords: Nicotine; fMRI; Mecamylamine; Physostigmine; Attention; Memory; Emotion


Allosteric modulators of the α4β2 subtype of neuronal nicotinic acetylcholine receptors by Anshul Pandya; Jerrel. L. Yakel (pp. 952-958).
Nicotinic acetylcholine receptors are ligand-gated ion conducting transmembrane channels from the Cys-loop receptor super-family. The α4β2 subtype is the predominant heteromeric subtype of nicotinic receptors found in the brain. Allosteric modulators for α4β2 receptors interact at a site other than the orthosteric site where acetylcholine binds. Many compounds which act as allosteric modulators of the α4β2 receptors have been identified, with both positive and negative effects. Such allosteric modulators either increase or decrease the response induced by agonist on the α4β2 receptors. Here we discuss the concept of allosterism as it pertains to the α4β2 receptors and summarize the important features of allosteric modulators for this nicotinic receptor subtype.

Keywords: Abbreviations; ACh; acetylcholine; nAChRs; neuronal nicotinic acetylcholine receptors; dFBr; desformylflustrabromine; PAM; positive allosteric modulator; NAM; negative allosteric modulator; 17-BE; 17-β-EstradiolNicotinic acetylcholine receptor; Allosteric modulation; Positive allosteric modulators; Negative allosteric modulators


α4β2 neuronal nicotinic receptor positive allosteric modulation: An approach for improving the therapeutic index of α4β2 nAChR agonists in pain by Chih-Hung Lee; Chang Zhu; John Malysz; Thomas Campbell; Thomas Shaughnessy; Prisca Honore; James Polakowski; Murali Gopalakrishnan (pp. 959-966).
Positive allosteric modulator alone (PAM) does not have intrinsic activity at the receptor, but can amplify the physiological effects of the endogenous transmitter Ach or agonists (ABT-594, nicotine) in a spatial and temporally restricted manner.Nicotinic acetylcholine receptors (nAChRs) function as ligand-gated ion channels activated by the neurotransmitter acetylcholine. Gene knockout and antisense studies coupled with pharmacological studies with nAChR agonists have documented a role of α4β2 nAChR activation in analgesia. ABT-594, for the first time, provided clinical validation to the nAChR agonist pharmacology as a novel mechanism for treatment of pain. However, ABT-594 was poorly tolerated at the efficacious doses, particularly with respect to the side effects of nausea and emesis, which is thought to be mediated by activation of the ganglionic-type (α3-containing) nAChRs. An alternate approach is to selectively modulate the α4β2 nAChR via positive allosteric modulation. Positive allosteric modulators (PAMs) are compounds that do not interact with the agonist binding sites or possess intrinsic activity at the receptor per se, but potentiate the effects of the agonist. NS9283 (also known as A-969933), the first oxadiazole analog, was found to selectively enhance the potency of a range of nAChR agonists at α4β2, but not α3β4, nAChRs. Studies reported here, along with the accompanying manuscript collectively point to the conclusion, based on preclinical models, that the analgesic efficacy of clinically well-tolerated doses of ABT-594 in humans can be significantly enhanced by co-administration with the α4β2 PAM. Additionally, studies in ferrets demonstrate no exaggeration of emetic effect when ABT-594 is co-dosed with NS9283. Cardiovascular studies in anesthetized dogs achieve supra-therapeutic plasma concentrations of ABT-594 (>20-fold) without hemodynamic or electrophysiological effects using the co-administration paradigm.

Keywords: Positive allosteric modulator; α4β2 nAChR; Pain; Therapeutic index


Potentiation of analgesic efficacy but not side effects: Co-administration of an α4β2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats by Chang Z. Zhu; Chih-liang Chin; Nathan R. Rustay; Chengmin Zhong; Joe Mikusa; Prasant Chandran; Anita Salyers; Erica Gomez; Gricelda Simler; La Geisha Lewis; Donna Gauvin; Scott Baker; Madhavi Pai; Ann Tovcimak; Jordan Brown; Victoria Komater; Gerard B. Fox; Michael W. Decker; Peer B. Jacobson; Murali Gopalakrishnan; Chih-Hung Lee; Prisca Honore (pp. 967-976).
Positive allosteric modulator NS-9283 enhances NNR α4β2 agonist ABT-594 (up to 100nmol/kg)-induced analgesic efficacy in animal models of pain, and cortical neuronal activity, but not side effects.Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) α4β2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5μmol/kg, i.p.) induced a 6-fold leftward shift of the dose–response of ABT-594 (ED50=26 vs. 160nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED50=26 vs. 153nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED50=1.0 vs. 4.6nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose–response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5μmol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the α4β2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of α4β2 nAChR by PAM may represent a novel analgesic approach.

Keywords: Positive modulator; Analgesic profile; nAChR


Acute in vivo nicotine administration enhances synchrony among dopamine neurons by Wei Li; William M. Doyon; John A. Dani (pp. 977-983).
Nicotine increases the firing rates and increases synchronization of dopamine neurons.Altered functional interactions among midbrain dopamine (DA) neurons contribute to the reinforcing properties of environmental stimuli and addictive drugs. To examine correlations among DA neurons, acute nicotine was administrated to rats via an intraperitoneal catheter and unit activity was measured using multi-tetrode in vivo recordings. Nicotine administration enhanced the correlated activity of simultaneously recorded DA neurons from the ventral tegmental area (VTA). The strength of the correlations between DA neuron pairs, as measured by cross covariance among two spike trains, showed dynamic changes over time. Nicotine produced a gradual rise in firing rate and burst activity that reached a stable plateau approximately 20min after the intraperitoneal nicotine infusion. Shortly after that time the cross correlations measured using 5-ms bins increased significantly above baseline. In addition, nicotine increased the firing rates of DA neurons in the posterior VTA more than in the anterior VTA. Unlike nicotine, eticlopride administration also boosted DA neuron firing activity but did not enhance synchronization, indicating that the cross correlations induced by nicotine were not due to a non-specific increase in firing rate. The overall results show that nicotine induces nearly synchronous firing by a subset of DA neurons, and those changes in correlative firing will enhance the DA signal that contributes to nicotine-induced behavioral reinforcement.

Keywords: Abbreviations; ACh; acetylcholine; DHβE; dihydro-β-erythroidine; DA; dopamine; ISI; interspike interval; nAChR; nicotinic acetylcholine receptor; NAc; nucleus accumbens; SNc; substantia nigra compacta; VTA; ventral tegmental areaNicotinic acetylcholine receptors; Mesolimbic; Ventral tegmental area; Nicotine addiction; Synchronization; Correlation


Recent advances in understanding nicotinic receptor signaling mechanisms that regulate drug self-administration behavior by Luis M. Tuesta; Christie D. Fowler; Paul J. Kenny (pp. 984-995).
Tobacco smoking is one of the leading causes of disease and premature death in the United States. Nicotine is considered the major reinforcing component in tobacco smoke responsible for tobacco addiction. Nicotine acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits. The α4β2 nAChRs, particularly those located in the mesoaccumbens dopamine pathway, play a key role in regulating the reinforcing properties of nicotine. Considering that twelve mammalian nAChR subunits have been cloned, it is likely that nAChRs containing subunits in addition to, or other than, α4 and β2 also play a role in the tobacco smoking habit. Consistent with this possibility, human genome-wide association studies have shown that genetic variation in the CHRNA5–CHRNA3–CHRNB4 gene cluster located in chromosome region 15q25, which encode the α5, α3 and β4 nAChR subunits, respectively, increases vulnerability to tobacco addiction and smoking-related diseases. Most recently, α5-containing nAChRs located in the habenulo-interpeduncular tract were shown to limit intravenous nicotine self-administration behavior in rats and mice, suggesting that deficits in α5-containing nAChR signaling in the habenulo-interpeduncular tract increases vulnerability to the motivational properties of nicotine. Finally, evidence suggests that nAChRs may also play a prominent role in controlling consumption of addictive drugs other than nicotine, including cocaine, alcohol, opiates and cannabinoids. The aim of the present review is to discuss recent preclinical findings concerning the identity of the nAChR subtypes that regulate self-administration of nicotine and other drugs of abuse.

Keywords: Nicotine; Nicotinic acetylcholine receptor; Tobacco smoking; Cocaine; Alcohol; Opiates; Cannabinoids; Intravenous self-administration; Knockout mice


Mechanistic insights into nicotine withdrawal by Michael Paolini; Mariella De Biasi (pp. 996-1007).
Smoking is responsible for over 400,000 premature deaths in the United States every year, making it the leading cause of preventable death. In addition, smoking-related illness leads to billions of dollars in healthcare expenditures and lost productivity annually. The public is increasingly aware that successfully abstaining from smoking at any age can add years to one's life and reduce many of the harmful effects of smoking. Although the majority of smokers desire to quit, only a small fraction of attempts to quit are actually successful. The symptoms associated with nicotine withdrawal are a primary deterrent to cessation and they need to be quelled to avoid early relapse. This review will focus on the neuroadaptations caused by chronic nicotine exposure and discuss how those changes lead to a withdrawal syndrome upon smoking cessation. Besides examining how nicotine usurps the endogenous reward system, we will discuss how the habenula is part of a circuit that plays a critical role in the aversive effects of high nicotine doses and nicotine withdrawal. We will also provide an updated summary of the role of various nicotinic receptor subtypes in the mechanisms of withdrawal. This growing knowledge provides mechanistic insights into current and future smoking cessation therapies.

Keywords: Abbreviations; AMPA; α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; BLA; basolateral amygdala; BNST; bed nucleus of the stria terminalis; CeA; central nucleus of the amygdala; 5-CSRTT; five-choice serial reaction time task; CPA; conditioned place aversion; CRF; corticotropin-releasing factor; DA; dopamine; DHβE; dihydro-β-erythroidine; EPM; elevated plus maze; GABA; γ-aminobutyric acid; 5-HT; 5-hydroxytryptophan; ICSS; intracranial self-stimulation; LDT; laterodorsal tegmentum; MLA; methyllycaconitine; NMDA; N-methyl-; d; -aspartic acid; NAcc; nucleus accumbens; NE; norepinephrine; PFC; prefrontal cortex; PPT; pedunculopontine tegmentum; VTA; ventral tegmental areaReward; Negative motivation; Dopamine; Withdrawal; VTA; Nucleus accumbens; Habenula; Addiction; Drug abuse; Nicotinic receptors; Nicotinic knockout mice


Exploring behavioral and molecular mechanisms of nicotine reward in adolescent mice by Dena Kota; Sarah Sanjakdar; Michael J. Marks; Omar Khabour; Karem Alzoubi; M. Imad Damaj (pp. 1008-1014).
Tobacco smoking during adolescence has become a prominent preventable health problem faced in the United States. Addictive properties of smoking are thought to have a pronounced effect at a young age, thereby increasing vulnerability to a life-long addiction and decreasing the likelihood of smoking cessation during adulthood. Learning and memory involvement in nicotine reward was assessed in early adolescent (PND 28–34) and adult (PND 70+) male ICR mice by conducting conditioning sessions of nicotine (0.5mg/kg) acquisition at varying time-spans, and evaluating extinction and reinstatement of nicotine preference using Conditioned Place Preference. Acquisition studies resulted in a significant preference for nicotine after 3 days of conditioning for both age groups, but not after only 1 or 2 conditioning days. In the extinction study, adolescent mice exhibited preference for nicotine 72h after the last conditioning session, whereas preference for nicotine was extinct in adult mice by 72h. Reinstatement studies showed adolescent mice, but not adult mice, recovering nicotine preference after a priming injection of 0.1mg/kg nicotine on day 9 after the mice underwent extinction. No significant differences were found when nAChRs were quantified in both early adolescent and adult mice using binding techniques including cytisine sensitive, α-conotoxin-MII sensitive, and α-bungarotoxin sensitive nAChRs. Levels of striatal dopamine release were measured in both age groups using a dopamine release assay over a range of nicotine doses, which also resulted in no significant differences. More sensitive assays may facilitate in understanding the mechanisms of nicotine reward in adolescent mice.

Keywords: Nicotine; Adolescence; Reward; Conditioned place preference; Mice


Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer by Ma. Reina Improgo; Andrew R. Tapper; Paul D. Gardner (pp. 1015-1021).
Despite the known adverse health effects associated with tobacco use, over 45 million adults in the United States smoke. Cigarette smoking is the major etiologic factor associated with lung cancer. Cigarettes contain thousands of toxic chemicals, many of which are carcinogenic. Nicotine contributes directly to lung carcinogenesis through the activation of nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels, expressed in both normal and lung cancer cells, which mediate the proliferative, pro-survival, angiogenic, and metastatic effects of nicotine and its nitrosamine derivatives. The underlying molecular mechanisms involve increases in intracellular calcium levels and activation of cancer signal transduction pathways. In addition, acetylcholine (ACh) acts as an autocrine or paracrine growth factor in lung cancer. Other neurotransmitters and neuropeptides also activate similar growth loops. Recent genetic studies further support a role for nAChRs in the development of lung cancer. Several nAChR antagonists have been shown to inhibit lung cancer growth, suggesting that nAChRs may serve as valuable targets for biomarker-guided lung cancer interventions.

Keywords: Nicotinic acetylcholine receptor; Nicotine; Acetylcholine; Smoking; Lung cancer; CHRNA5/A3/B4

Functional examination of human α4β2α5 nicotinic AChRs transfected in SH-EP1 cells by G.R. Abdrakhmanova; A. Simard; P. Whiteaker; R. Lukas; M.I. Damaj; K. Kendler; X. Chen (pp. 1023-1023).
The conundrum of the α5 nicotinic acetylcholine receptor subunit by Sonia Bertrand; Estelle Neveu; Daniel Bertrand; Cecilia Gotti (pp. 1023-1023).
Comparison of binding and functional activity profiles for a set of nicotinic acetylcholine receptor ligands across multiple α6* expression systems by Scott R. Breining; Christopher Hepler; Paul Whiteaker; Maryka Quik; Sharon R. Grady; Daniel Yohannes (pp. 1024-1024).
Construction of cell line heterologously expressing the α6/3β2β3 nicotinic acetylcholine receptor (nAChR) subtype by P. Whiteaker; L. Lucero; R.J. Lukas; C. Hepler; J.P. Strachan; S. Letchworth (pp. 1024-1025).
A methodological comparison of human α4β2 and α3β4 receptor properties using conventional and high-throughput patch-clamp electrophysiology techniques by Lisa C. Benson; Serguei S. Sidach; John D. Graef; Patrick M. Lippiello; Merouane Bencherif; Nikolai B. Fedorov (pp. 1025-1025).
Tethered pentamers—Low sensitivity α4β2-nicotinic acetylcholine receptors by L. Lucero; M. Bhakta; G. Liu; J. Wu; T.A. Hauser; M. Bencherif; I. Bermudez; P. Whiteaker; R.J. Lukas (pp. 1025-1025).
Novel properties of neuronal nicotinic receptors revealed with brief pulses of acetylcholine by John D. Graef; Nikolai B. Fedorov; Lisa C. Benson; Jeremy Hyman; Patrick M. Lippiello; Merouane Bencherif (pp. 1025-1026).
Effects of RG3487 at the α7β2 nicotinic acetylcholine receptor expressed in Xenopus oocytes by Tanya L. Wallace; Richard Porter; Estelle Neveu; Daniel Bertrand (pp. 1026-1027).
Discovery of nicotinic acetylcholine receptor ligands in the chemical universe database GDB-13 by L.C. Blum; R. van Deursen; J. Bürgi; J.-L. Reymond; M. Maver; S. Bertrand; D. Bertrand (pp. 1027-1027).
Ligand-based QSAR modeling of neuronal nicotinic receptor data and its impact on drug design by Philip S. Hammond; Yun-De Xiao; David C. Kombo; Daniel Yohannes (pp. 1027-1028).
A-582941, a pro-cognitive α7 nAChR agonist, differentially modulates mitochondrial membrane potential by Marian Namovic; Min Hu; Vivek Abraham; Danli Towne; Chih-Hung Lee; Murali Gopalakrishnan; Tim Esbenshade; Diana Donnelly-Roberts (pp. 1027-1027).
Scanning mutagenesis of α-conotoxin AuIB reveals a critical residue for activity at the α3β4 nicotinic acetylcholine receptor by D.J. Adams; A.A. Grishin; A. Hung; R.J. Clark; K. Akondi; P.F. Alewood; D.J. Craik (pp. 1028-1028).
Acetylcholine binding protein-nicotinic receptor chimeras for delineating structure and determinants of ligand selectivity by Todd T. Talley; Akos Nemecz; John G. Yamauchi; Joshua Wu; Kwok-Yiu Ho; Banumathi Sankaran; Palmer Taylor (pp. 1028-1029).
The twin drug approach for novel nicotinic acetylcholine receptor (nAChR) ligands: Synthesis and structure–affinity relationships by I. Tomassoli; C. Eibl; M. Wulf; R.L. Papke; M.R. Picciotto; D. Gündisch (pp. 1028-1028).
Pharmacological properties of sazetidine A, a selective ligand of α4β2 nicotinic acetylcholine receptors by Yingxian Xiao; Edward Tuan; Robert P. Yasuda; Niaz Sahibzada; Barry B. Wolfe; Lindsay Horton; Thao Tran; Nour Al-Muhtasib; Adaku F. Iwueze; James R. Dipietro; Teresa Xie; Mikell Paige; Milton L. Brown; Kenneth J. Kellar (pp. 1029-1029).
The (α4)3(β2)2 nAChR has a benzodiazepine-like modulatory binding site in the αα-subunit interface as revealed by studies with NS9283 by Philip K. Ahring; Dan Peters; Jeppe K. Christensen; Marianne L. Jensen; Kasper Harpsøe; Thomas Balle (pp. 1029-1030).
In vitro pharmacological characterization of ABT-779, a novel positive allosteric modulator of α7 nAChRs by John Malysz; Jens Halvard Gronlien; Clark A. Briggs; David J. Anderson; Rachid El-Kouhen; Karla Drescher; Hilde Ween; Kristen Thorin-Hagene; Kathleen Mortell; Chih-Hung Lee; Murali Gopalakrishnan (pp. 1030-1030).
Electrophysiological characterization of NS9283, a novel positive allosteric modulator of α4β2 nicotinic receptors by M. Grupe; M. Grunnet; J.K. Christensen; A.A. Jensen; P.K. Ahring (pp. 1030-1030).
Allosteric modulation of neuronal nicotinic acetylcholine receptors requires inter-subunit movement by Mark Levandoski; Angela Cao; Molly Wingfield (pp. 1031-1031).
Positive and negative cooperativity of agonist and allosteric modulator binding in alpha7 nAChR: Looking for the therapeutic window by Roger L. Papke; Dustin K. Williams; Jingyi Wang; Nicole A. Horenstein (pp. 1031-1031).
Ascorbic acid is a positive modulator of α9α10 nicotinic cholinergic receptors by Juan Carlos Boffi; Carolina Wedemeyer; Eleonora Katz; Daniel Juan Calvo; Ana Belén Elgoyhen (pp. 1032-1032).
Different presynaptic nicotinic receptor subtypes modulate in vivo and in vitro the release of glycine in the rat hippocampus by Mario Marchi; Stefania Zappettini; Elisa Mura; Massimo Grilli; Stefania Preda; Alessia Salamone; Anna Pittaluga; Stefano Govoni (pp. 1032-1033).
A structure–activity study of 4R-cembranoid reversal of diisopropylfluorophosphate-inflicted functional impairment in hippocampal slices by A. del Valle-Rodriguez; D. Pérez; P.A. Ferchmin; K. el Sayed; V.A. Eterović (pp. 1032-1032).
Ethanol interactions with nicotinic receptors in brainstem cholinergic centers by John McDaid; Shannon S. Wolfman; Keith Gallagher; Daniel S. McGehee (pp. 1033-1033).
Nicotinic cholinergic receptors in dorsal root ganglion neurons include the α6β4* subtype by Arik J. Hone; Erin L. Meyer; Melissa McIntyre; J. Michael McIntosh (pp. 1033-1034).
Investigations into nicotinic Stat3 signaling using a luciferase reporter plasmid by Ralph H. Loring; Abishek Chandrashekar; Tom Koperniak; Sharath Madasu (pp. 1034-1035).
Developmental nicotine exposure and the α5 nicotinic acetylcholine receptor by C.D. Bailey; M.K. Tian; E.K. Lambe (pp. 1035-1035).
α6* nAChR expression and function in brain areas influencing DA transmission probed with α6-GFP transgenic mice by Ryan M. Drenan; Elisha D.W. Mackey; Sharon R. Grady; Natalie E. Patzlaff; Charles R. Wageman; J. Michael McIntosh; Michael J. Marks; Henry A. Lester (pp. 1035-1036).
Alpha2* nicotinic acetylcholine receptors as a therapeutic target for memory enhancement by Katumi Sumikawa; Sakura Nakauchi; Yoshihiko Yamazaki; Yousheng Jia (pp. 1036-1036).
Lynx1 balances neuronal activity through nicotinic acetylcholine receptor modulation by R.L. Parker; D.S. Rhee; H.A. Lester; J.M. Miwa (pp. 1037-1037).
LTD deficit in α7 neuronal nicotinic receptor (α7*) knockout mice is strain dependent by Ronald K. Freund; Sharon L. Graw; Kirsten Floyd; Sherry Leonard; Mark L. Dell’Acqua (pp. 1037-1037).
Deviance-based negativity in the conscious rat: Modulation by nicotinic agonists by Siva Digavalli; Ping Chen; Nick Lodge (pp. 1039-1039).
Attentional improvement in rats with the nicotinic agonist AZ12564698 (AZD3480) by Amir H. Rezvani; Marty Cauley; Edwin Johnson; Edward D. Levin (pp. 1040-1041).
In vitro pharmacological characterization and pro-cognitive effects of the novel alpha-7 nicotinic acetylcholine receptor partial agonist, SKL-A4R by C.Y. Maeng; C.M. Joung; H.W. Shin; Y.K. Jang; S.B. Cha; H.R. Cha; E.J. Yi; C.H. Park (pp. 1040-1040).
The alpha-7 receptor agonist EVP-6124 increases dopamine and glutamate efflux in rat medial prefrontal cortex and nucleus accumbens by Mei Huang; Anna R. Felix; Chaya Bhuvaneswaran; Dana Hilt; Gerhard König; Herbert Y. Meltzer (pp. 1040-1040).
Neuronal nicotinic receptor agonists ameliorate 3-acetylpyridine-induced ataxia by L. Wecker; M.E. Engberg; R.M. Philpot; C.S. Lambert; P.C. Bickford; C. Hudson (pp. 1041-1041).
In Vitro neuroprotective effects of ABT-779, a positive allosteric modulator of α7 nAChRs by Min Hu; Jinhe Li; John Malysz; Timothy A. Esbenshade; Chih-Hung Lee; Murali Gopalakrishnan (pp. 1042-1042).
α7 NNR allosteric modulation in behavioral models of cognition by Kathy L. Kohlhaas; Holly Robb; Victoria Roderwald; Stella Markosyan; Katherine Salte; Robert S. Bitner; Eric Mohler; Alvin V. Terry; Jerry Buccafusco; Lynne E. Rueter; Lance Lee; Murali Gopalakrishnan (pp. 1042-1042).
A randomized, double-blind, placebo-controlled Phase 2 study of α4β2 agonist ABT-894 in adults with ADHD by Earle Bain; Weining Robieson; Tushar Garimella; Walid Abi-Saab; George Apostol; Mario D. Saltarelli (pp. 1043-1043).
The use of the scopolamine-induced cognitive impairment model to translate on-target activity for ABT-894 from rodents/monkeys to humans: Preclinical evidences by Lynne E. Rueter; Ana L. Rêlo; Marcel M. van Gaalen; Michael E. Ballard; Alvin V. Terry Jr.; Jerry Buccafusco; Min Zhang (pp. 1043-1043).
A Phase IIa trial assessing the effects of AZD1446 on two cohorts of adult Attention Deficit Hyperactivity Disorder (ADHD) patients: Users and non-users of nicotine-containing products by P.A. Newhouse; J.C. Steiert; J.F. Prater; J.K. Heussy; N. Oskooilar; A.S. Potter; K. Hannesdottir; J. Jaeger; J. Ohd; J. Brogren; D. Sweitzer; D.J. Garcia (pp. 1044-1044).
A cembranoid protects the brain against transient middle cerebral artery occlusion by A.H. Martins; E.A. Santiago; Y.V. Olivera; J.M. Alves; B.D. Ford; Z. Xu; P.A. Ferchmin; V.A. Eterovic (pp. 1044-1044).
4R-cembratrienediol protects against diisopropylfluorophosphate-induced neurodegeneration with a long window of therapeutic opportunity by P. Ferchmin; J.M. Alves; D. Perez; B. Cuadrado; M. Carrasco; J.M. Velez Roman; H.A.B. Martins; A.C. Segarra; V.A. Eterovic (pp. 1045-1045).
Hippocampal Class I Major Histocompatibility Complex genes are differentially expressed in schizophrenic smokers by Melissa L. Sinkus; Sharon Mexal; Ralph Berger; Sherry Leonard (pp. 1046-1047).
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