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Biochemical Pharmacology (v.78, #7)

Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science—Editorial Perspective by Daniel Bertrand Guest Editor; Murali Gopalakrishnan Guest Editor; Diana Donnelly-Roberts Guest Editor (pp. 657-657).

nAChR agonist-induced cognition enhancement: Integration of cognitive and neuronal mechanisms by Martin Sarter; Vinay Parikh; William M. Howe (pp. 658-667).
The identification and characterization of drugs for the treatment of cognitive disorders has been hampered by the absence of comprehensive hypotheses. Such hypotheses consist of (a) a precisely defined cognitive operation that fundamentally underlies a range of cognitive abilities and capacities and, if impaired, contributes to the manifestation of diverse cognitive symptoms; (b) defined neuronal mechanisms proposed to mediate the cognitive operation of interest; (c) evidence indicating that the putative cognition enhancer facilitates these neuronal mechanisms; (d) and evidence indicating that the cognition enhancer facilitates cognitive performance by modulating these underlying neuronal mechanisms. The evidence on the neuronal and attentional effects of nAChR agonists, specifically agonists selective for α4β2* nAChRs, has begun to support such a hypothesis. nAChR agonists facilitate the detection of signals by augmenting the transient increases in prefrontal cholinergic activity that are necessary for a signal to gain control over behavior in attentional contexts. The prefrontal microcircuitry mediating these effects include α4β2* nAChRs situated on the terminals of thalamic inputs and the glutamatergic stimulation of cholinergic terminals via ionotropic glutamate receptors. Collectively, this evidence forms the basis for hypothesis-guided development and characterization of cognition enhancers.

Keywords: Cognition enhancers; Cue detection; Schizophrenia; Cognitive disorders


Nicotinic actions on neuronal networks for cognition: General principles and long-term consequences by Rogier B. Poorthuis; Natalia A. Goriounova; Jonathan J. Couey; Huibert D. Mansvelder (pp. 668-676).
Distributed nicotinic receptor expression by interneurons and pyramidal neurons in the neuronal circuitry of the prefrontal cortex exert stimulating actions on cognitive behaviour.Nicotine enhances cognitive performance in humans and laboratory animals. The immediate positive actions of nicotine on learning, memory and attention are well-documented. Several brain areas involved in cognition, such as the prefrontal cortex, have been implicated. Besides acute effects on these brain areas and on brain function, a picture is emerging showing that long-term consequences of nicotine exposure during adolescence can be detrimental for cognitive performance. The majority of adult smokers started the habit during adolescence. Our knowledge on the types of nicotinic receptors in the brain areas that are candidates for mediating nicotine's effects is increasing. However, much less is known about the underlying cellular mechanisms. A series of recent studies have uncovered exciting features of the mechanisms by which nicotine alters prefrontal cortex neuronal activity, synaptic plasticity, gene expression and cognitive function, and how these changes may have a lasting effect on the developing brain. In this review, we discuss these exciting findings and identify several common principles by which nicotinic receptor activation modulates cortical circuits involved in cognition. Understanding how nicotine induces long-term changes in neuronal circuits and alters plasticity in the prefrontal cortex is essential to determining how these mechanisms interact to alter cognition.

Keywords: Acetylcholine; Nicotine; Prefrontal cortex; Neuronal networks; Synaptic plasticity; Development


Multiple roles for nicotine in Parkinson's disease by Maryka Quik; Luping Z. Huang; Neeraja Parameswaran; Tanuja Bordia; Carla Campos; Xiomara A. Perez (pp. 677-685).
There exists a remarkable diversity of neurotransmitter compounds in the striatum, a pivotal brain region in the pathology of Parkinson's disease, a movement disorder characterized by rigidity, tremor and bradykinesia. The striatal dopaminergic system, which is particularly vulnerable to neurodegeneration in this disorder, appears to be the major contributor to these motor problems. However, numerous other neurotransmitter systems in the striatum most likely also play a significant role, including the nicotinic cholinergic system. Indeed, there is an extensive anatomical overlap between dopaminergic and cholinergic neurons, and acetylcholine is well known to modulate striatal dopamine release both in vitro and in vivo. Nicotine, a drug that stimulates nicotinic acetylcholine receptors (nAChRs), influences several functions relevant to Parkinson's disease. Extensive studies in parkinsonian animals show that nicotine protects against nigrostriatal damage, findings that may explain the well-established decline in Parkinson's disease incidence with tobacco use. In addition, recent work shows that nicotine reducesl-dopa-induced abnormal involuntary movements, a debilitating complication ofl-dopa therapy for Parkinson's disease. These combined observations suggest that nAChR stimulation may represent a useful treatment strategy for Parkinson's disease for neuroprotection and symptomatic treatment. Importantly, only selective nAChR subtypes are present in the striatum including the α4β2*, α6β2* and α7 nAChR populations. Treatment with nAChR ligands directed to these subtypes may thus yield optimal therapeutic benefit for Parkinson's disease, with a minimum of adverse side effects.

Keywords: Abbreviations; ANOVA; analysis of variance; α-CtxMII; α-conotoxinMII; MPTP; 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine; nAChR; nicotinic acetylcholine receptor; 6-OHDA; 6-hydroxydopamine; RTI-121; 2β-carboxylic acid isopropyl ester-3β-(4-iodophenyl) tropanel; -dopa-induced dyskinesias; Neuroprotection; Nicotine; Nicotinic; Nigrostriatal; Parkinson's disease


Age dependent nicotinic influences over dopamine neuron synaptic plasticity by Andon N. Placzek; Tao A. Zhang; John A. Dani (pp. 686-692).
The dopamine (DA) system of the ventral midbrain plays a critical role as mammals learn adaptive behaviors driven by environmental salience and reward. Addictive drugs, including nicotine, exert powerful influences over the mesolimbic DA system by activating and desensitizing nicotinic acetylcholine receptors (nAChRs) in a subtype-dependent manner. Nicotine induces synaptic plasticity at excitatory synapses onto DA neurons, thereby sending elevated DA signals that participate during the reinforcement of addictive behaviors. While humans and animals of any developmental age are potentially vulnerable to these drug-induced effects, evidence from clinical and epidemiological studies indicates that adolescents have an increased risk of addiction. Although this risk arises from a complex set of variables including societal and psychosocial influences, a contributing factor involves age dependent sensitivity to addictive drugs. One aspect of that sensitivity is drug-induced synaptic plasticity at excitatory synapses onto the dopamine neurons in the ventral midbrain. A single, acute exposure to addictive drugs, including nicotine, produces long-term potentiation (LTP) that can be quantified by measuring the shift in the subtypes of ionotropic glutamate receptors mediating evoked synaptic transmission. This change in glutamatergic transmission is expressed as an increased ratio of AMPA receptors to NMDA receptors at glutamatergic synapses. Age-related differences in the excitability and the nicotine sensitivity within the midbrain dopamine system may contribute to the greater risk of nicotine addiction in adolescent animals and humans.

Keywords: Abbreviations; AMPA; α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; α-BTX; α-bungarotoxin; ACh; acetylcholine; ADHD; attention-deficit hyperactivity disorder; DHβE; dihydro-β-erythroidine; DA; dopamine; sEPSCs; spontaneous excitatory postsynaptic currents; LTP; long-term potentiation; MLA; methyllycaconitine; NMDA; N-methyl-D-aspartic acid; nAChR; nicotinic acetylcholine receptor; NAc; nucleus accumbens; VTA; ventral tegmental areaNicotinic acetylcholine receptors; Mesolimbic; Long-term potentiation; Development; Ventral tegmental area; Nicotine addiction


Alpha9 nicotinic acetylcholine receptors and the treatment of pain by J. Michael McIntosh; Nathan Absalom; Mary Chebib; Ana Belén Elgoyhen; Michelle Vincler (pp. 693-702).
Chronic pain is a vexing worldwide problem that causes substantial disability and consumes significant medical resources. Although there are numerous analgesic medications, these work through a small set of molecular mechanisms. Even when these medications are used in combination, substantial amounts of pain often remain. It is therefore highly desirable to develop treatments that work through distinct mechanisms of action. While agonists of nicotinic acetylcholine receptors (nAChRs) have been intensively studied, new data suggest a role for selective antagonists of nAChRs. α-Conotoxins are small peptides used offensively by carnivorous marine snails known as Conus. A subset of these peptides known as α-conotoxins RgIA and Vc1.1 produces both acute and long lasting analgesia. In addition, these peptides appear to accelerate the recovery of function after nerve injury, possibly through immune mediated mechanisms. Pharmacological analysis indicates that RgIA and Vc1.1 are selective antagonists of α9α10 nAChRs. A recent study also reported that these α9α10 antagonists are also potent GABA-B agonists. In the current study, we were unable to detect RgIA or Vc1.1 binding to or action on cloned GABA-B receptors expressed in HEK cells or Xenopus oocytes. We review the background, findings and implications of use of compounds that act on α9* nAChRs.11* indicates the possible presence of additional subunits.

Keywords: Abbreviations; nAChRs; nicotinic acetylcholine receptors; ACh; acetylcholine; CCI; chronic constriction injury; PSNL; partial sciatic nerve ligation; STZ; streptozotocin; GPCR; G-protein coupled receptor; GIRK; G-protein-activated inwardly rectifying K; +; channel; CGP54626; [S-(R*,R*)]-[3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl) phosphinic acidα-Conotoxin Vc1.1; α-Contoxin RgIA; Pain; Alpha9 nicotinic; GABA-B


Structural and functional diversity of native brain neuronal nicotinic receptors by Cecilia Gotti; Francesco Clementi; Alice Fornari; Annalisa Gaimarri; Stefania Guiducci; Irene Manfredi; Milena Moretti; Patrizia Pedrazzi; Luca Pucci; Michele Zoli (pp. 703-711).
Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels present in the central and peripheral nervous systems, that are permeable to mono- and divalent cations. They share a common basic structure but their pharmacological and functional properties arise from the wide range of different subunit combinations making up distinctive subtypes.nAChRs are involved in many physiological functions in the central and peripheral nervous systems, and are the targets of the widely used drug of abuse nicotine. In addition to tobacco dependence, changes in their number and/or function are associated with neuropsychiatric disorders, ranging from epilepsy to dementia.Although some of the neural circuits involved in the acute and chronic effects of nicotine have been identified, much less is known about which native nAChR subtypes are involved in specific physiological functions and pathophysiological conditions.We briefly review some recent findings concerning the structure and function of native nAChRs, focusing on the subtypes identified in the mesostriatal and habenulo-interpeduncular pathways, two systems involved in nicotine reinforcement and withdrawal. We also discuss recent findings concerning the effect of chronic nicotine on the expression of native subtypes.

Keywords: Neuronal nicotinic receptors; Subtypes; Subunit composition; Stoichiometry; Mesostriatal pathway; Habenulo-interpeduncular pathway


The nicotinic receptor of cochlear hair cells: A possible pharmacotherapeutic target? by Ana Belén Elgoyhen; Eleonora Katz; Paul A. Fuchs (pp. 712-719).
Targeting α9α10 nicotinic cholinergic receptors in pathologies of the auditory system.Mechanosensory hair cells of the organ of Corti transmit information regarding sound to the central nervous system by way of peripheral afferent neurons. In return, the central nervous system provides feedback and modulates the afferent stream of information through efferent neurons. The medial olivocochlear efferent system makes direct synaptic contacts with outer hair cells and inhibits amplification brought about by the active mechanical process inherent to these cells. This feedback system offers the potential to improve the detection of signals in background noise, to selectively attend to particular signals, and to protect the periphery from damage caused by overly loud sounds. Acetylcholine released at the synapse between efferent terminals and outer hair cells activates a peculiar nicotinic cholinergic receptor subtype, the α9α10 receptor. At present no pharmacotherapeutic approaches have been designed that target this cholinergic receptor to treat pathologies of the auditory system. The potential use of α9α10 selective drugs in conditions such as noise-induced hearing loss, tinnitus and auditory processing disorders is discussed.

Keywords: Abbreviations; ACh; acetylcholine; Chrna9; gene that codes for the α9 nAChR subunit; Chrna10; gene that codes for the α10 nAChR subunit; IHCs; inner hair cells; MOC; medial olivocochlear; nAChRs; nicotinic acetylcholine receptors; NIHL; noise-induced hearing loss, OC olivocochlear; OHCs; outer hair cellsNicotinic cholinergic receptors; Noise trauma; Cochlea; Tinnitus; Efferent feedback


Polypeptide and peptide toxins, magnifying lenses for binding sites in nicotinic acetylcholine receptors by Victor Tsetlin; Yuri Utkin; Igor Kasheverov (pp. 720-731).
At present the cryo-electron microscopy structure at 4Å resolution is known for the Torpedo marmorata nicotinic acetylcholine receptor (nAChR), and high-resolution X-ray structures have been recently determined for bacterial ligand-gated ion channels which have the same type of spatial organization. Together all these structures provide the basis for better understanding functioning of muscle-type and neuronal nAChRs, as well as of other Cys-loop receptors: 5HT3-, glycine-, GABA-A and some other. Detailed information about the ligand-binding sites in nAChRs, necessary both for understanding the receptor functioning and for rational drug design, became available when the X-ray structures were solved for the acetylcholine-binding proteins (AChBP), excellent models for the ligand-binding domains of all Cys-loop receptors. Of special value in this respect are the X-ray structures of AChBP complexes with agonists and antagonists. Among the latter are the complexes with polypeptide and peptide antagonists, that is with protein neurotoxins from snake venoms and peptide neurotoxins (α-conotoxins) from poisonous marine snails of Conus genus. The role of a bridge between the AChBP and nAChRs is played by the X-ray structure of the ligand-binding domain of α1 subunit of nAChR in the complex with α-bungarotoxin.The purpose of this review is to show the role of well-known and new polypeptide and peptide neurotoxins, from the earlier days of nAChRs research until present time, in identification of different nAChR subtypes and mapping their binding sites.

Keywords: Acetylcholine-binding proteins; Nicotinic acetylcholine receptors; Three-fingered toxins; α-Conotoxins; α-Neurotoxins


Nicotinic receptor-based therapeutics and candidates for smoking cessation by Linda P. Dwoskin; Andrew M. Smith; Thomas E. Wooters; Zhenfa Zhang; Peter A. Crooks; Michael T. Bardo (pp. 732-743).
Tobacco dependence is the most preventable cause of death and is a chronic, relapsing disorder in which compulsive tobacco use persists despite known negative health consequences. All currently available cessation agents (nicotine, varenicline and bupropion) have limited efficacy and are associated with high relapse rates, revealing a need for more efficacious, alternative pharmacotherapies. The major alkaloid in tobacco, nicotine, activates nicotinic receptors (nAChRs) which increase brain extracellular dopamine producing nicotine reward leading to addiction. nAChRs are located primarily presynaptically and modulate synaptic activity by regulating neurotransmitter release. Subtype-selective nAChR antagonists that block reward-relevant mesocorticolimbic and nigrostriatal dopamine release induced by nicotine may offer advantages over current therapies. An innovative approach is to provide pharmacotherapies which are antagonists at nAChR subtypes mediating nicotine evoked dopamine release. In addition, providing multiple medications with a wider array of targets and mechanisms should provide more treatment options for individuals who are not responsive to the currently available pharmacotherapies. This review summarizes the currently available smoking cessation therapies and discusses emerging potential therapeutic approaches employing pharmacological agents which act as antagonists at nicotinic receptors.

Keywords: Abbreviations; bPiDDB; N; ,; N; ’-dodecane-1,12-diyl-; bis; -3-picolinium dibromide; r-bPiDDB; reduced-bPiDDB; *; indicates putative nAChR subtype assignmentSmoking cessation; Nicotine; Nicotinic acetylcholine receptor; Pharmacotherapies


Nicotinic acetylcholine receptors and the ascending dopamine pathways by Phil D. Livingstone; Susan Wonnacott (pp. 744-755).
Nicotinic acetylcholine receptors (nAChRs) affect dopamine cell firing and release probability in three major ascending pathways; nigrostriatal, mesolimbic and mesocortical. nAChRs are therefore poised to modulate multiple brain functions.Nicotinic acetylcholine receptors (nAChRs) are widely expressed in midbrain dopamine neurons that project to dorsal striatum, nucleus accumbens and prefrontal cortex. Thus nAChRs can influence the functions of these three pathways, notably motor control, ‘reward’ and executive function, respectively. Diverse subtypes of nAChRs have been identified on dopamine cell bodies and terminals as well as on neighbouring afferents and interneurons. Here we review the molecular and cellular mechanisms through which nAChRs exert their influence on these pathways in rodents.

Keywords: Abbreviations; αBgt; alpha-bungarotoxin; CPu; caudate putamen; CREB; cyclic AMP response element binding protein; DARPP-32; dopamine and cyclic AMP regulated phosphoprotein of 32; kDa; DHβE; dihydrobetaerythroidine; ELK; Ets-like transcription factor; EPSC; excitatory postsynaptic current; ERK; extracellular signal-regulated kinase; FSCV; fast-scan cyclic voltammetry; GABA; gamma-aminobutyric acid; iGluR; ionotropic glutamate receptor; IPSC; inhibitory postsynaptic current; LDTn; laterodorsal tegmental nucleus; LTP; long-term potentiation; MLA; methyllycaconitine; NAc; nucleus accumbens; nAChR; nicotinic acetylcholine receptor; NMDA; N-methyl-; d; -aspartate; PFC; prefrontal cortex; PKA; protein kinase A; PPn; pedunculopontine tegmental nucleus; RRF; retrorubral field; SNc; substantia nigra pars compacta; SNr; substantia nigra pars reticulata; VTA; ventral tegmental areaNicotine; Acetylcholine; Midbrain; Nucleus accumbens; Prefrontal cortex


Nicotine-induced upregulation of nicotinic receptors: Underlying mechanisms and relevance to nicotine addiction by Anitha P. Govind; Paul Vezina; William N. Green (pp. 756-765).
Potential mechanisms underlying nicotine-induced upregulation of nAChRs.A major hurdle in defining the molecular biology of nicotine addiction has been characterizing the different nicotinic acetylcholine receptor (nAChR) subtypes in the brain and how nicotine alters their function. Mounting evidence suggests that the addictive effects of nicotine, like other drugs of abuse, occur through interactions with its receptors in the mesolimbic dopamine system, particularly ventral tegmental area (VTA) neurons, where nicotinic receptors act to modulate the release of dopamine. The molecular identity of the nicotinic receptors responsible for drug seeking behavior, their cellular and subcellular location and the mechanisms by which these receptors initiate and maintain addiction are poorly defined. In this commentary, we review how nicotinic acetylcholine receptors (nAChRs) are upregulated by nicotine exposure, the potential posttranslational events that appear to cause it and how upregulation is linked to nicotine addiction.

Keywords: Nicotinic; Receptors; Subtypes; Upregulation; Sensitization; Addiction


A review of experimental techniques used for the heterologous expression of nicotinic acetylcholine receptors by Neil S. Millar (pp. 766-776).
Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop family of neurotransmitter-gated ion channels, a family that also includes receptors for γ-aminobutyric acid, glycine and 5-hydroxytryptamine. In humans, nAChRs have been implicated in several neurological and psychiatric disorders and are major targets for pharmaceutical drug discovery. In addition, nAChRs are important targets for neuroactive pesticides in insects and in other invertebrates. Historically, nAChRs have been one of the most intensively studied families of neurotransmitter receptors. They were the first neurotransmitter receptors to be biochemically purified and the first to be characterized by molecular cloning and heterologous expression. Although much has been learnt from studies of native nAChRs, the expression of recombinant nAChRs has provided dramatic advances in the characterization of these important receptors. This review will provide a brief history of the characterization of nAChRs by heterologous expression. It will focus, in particular, upon studies of recombinant nAChRs, work that has been conducted by many hundreds of scientists during a period of almost 30 years since the molecular cloning of nAChR subunits in the early 1980s.

Keywords: Nicotinic acetylcholine receptor; Heterologous expression


Insight in nAChR subtype selectivity from AChBP crystal structures by Prakash Rucktooa; August B. Smit; Titia K. Sixma (pp. 777-787).
Nicotinic acetylcholine receptors (nAChRs) display a broad variety of subtypes, which in turn present a complex subcellular and regional expression pattern in the brain, as well as a specific pharmacological profile. The association of these nAChRs with different types of brain disease has turned them into interesting drug targets for the treatment of Alzheimer's disease or schizophrenia, or for anti-smoking compounds among others. In the same way, muscle-type nAChRs present at neuromuscular junctions are also being targeted by muscle relaxants. However, to date no high-resolution structural data are available on functional pentameric forms of membrane-bound nicotinic receptors. Therefore, characterization of the selectivity profiles of different nicotinic receptor subtypes, enabling efficient drug design, is a serious issue. Over the last eight years various high-resolution structures of acetylcholine binding protein (AChBP), which is homologous to the extracellular ligand-binding domain of the nicotinic acetylcholine receptor, have been obtained. AChBPs in complex with different ligands have provided detailed insight into the neurotransmitter binding site of nicotinic acetylcholine receptors. We present here the various efforts towards rationalizing subtype specificity in these receptors through the structural studies of acetylcholine binding protein–ligand complexes.

Keywords: Nicotinic acetylcholine receptor selectivity; Acetylcholine binding protein; X-ray structure


Nicotinic antagonist effects in the mediodorsal thalamic nucleus: Regional heterogeneity of nicotinic receptor involvement in cognitive function by Reginald Cannady; Ruth Weir; Boyoung Wee; Emily Gotschlich; Nadeem Kolia; Edward Lau; Jesse Brotherton; Edward D. Levin (pp. 788-794).
Nicotine has been found in many studies to improve cognitive function. However, some studies have not found this effect and others have seen nicotine-induced impairments. Systemic administration bathes the brain with drugs. However, the brain is quite intricately organized with various regions playing very different roles in the bases of cognitive function. We have examined the role of nicotinic receptors in a variety of brain areas for memory. In the hippocampus and amygdala, local infusions of both α7 and α4β2 antagonists methyllyaconitine (MLA) and dihydro-β-erythroidine (DHβE) significantly impair memory. In the current studies we locally infused acute and chronic doses of MLA and DHβE into the mediodorsal thalamic nucleus and tested memory function on a 16-arm radial maze. The rats also received systemic nicotine to determine the impact of more generalized nicotine effects. Since nicotinic treatments are being developed for cognitive impairment of schizophrenia, interactions were studied with the antipsychotic drug clozapine. In the acute study, the 6.75μg/side of DHβE improved working memory. Co-administration of MLA reversed the DHβE-induced improvement. Chronic DHβE infusions into the mediodorsal thalamic nucleus also improved working memory. Systemic nicotine reversed this effect. Clozapine had no significant interaction. Nicotinic α4β2 receptors in the mediodorsal thalamic nucleus appear to play an opposite role with regard to working memory than those in the hippocampus and amygdala. Heterogeneity in response to nicotinic drugs given systemically may be due to anatomically distinct nicotinic systems in the brain and their unique roles in the neural bases of cognitive function.

Keywords: Abbreviations; MLA; methyllyaconitine; DHβE; dihydro-β-erythroidineMediodorsal thalamic nucleus; Nicotinic; MLA; DHβE; Memory


Selectivity of ABT-089 for α4β2* and α6β2* nicotinic acetylcholine receptors in brain by Michael J. Marks; Charles R. Wageman; Sharon R. Grady; Murali Gopalakrishnan; Clark A. Briggs (pp. 795-802).
Numerous pharmaceutical efforts have targeted neuronal nicotinic receptors (nAChRs) for amelioration of cognitive deficits. While α4β2 and α7 are the more prominent nAChR in brain, other heteromeric nAChR can have important impact on agonist pharmacology. ABT-089 is a pioneer nAChR agonist found to enhance cognitive function with an exceptionally low incidence of adverse effects. To further investigate the mechanism of action of ABT-089, we evaluated its function in mouse brain preparations in which we have characterized the subunit composition of native nAChR. Among α4β2*-nAChR, ABT-089 had partial agonist activity (7–23% of nicotine) and high selectivity for α4α5β2 nAChR as evidenced by loss of activity in thalamus of α5−/− mice. ABT-089 stimulated [3H]-dopamine release (57%) exceeded the activity at α4β2* nAChR, that could be explained by the activity at α6β2* nAChR. The concentration–response relationship for ABT-089 stimulation of α6β2* nAChR was biphasic. EC50 and efficacy values for ABT-089, respectively, were 28μM and 98% at the less sensitive α6β2* nAChR and 0.11μM and 36% at the more sensitive subtype (the most sensitive target for ABT-089 identified to date). ABT-089 had essentially no agonist or antagonist activity at concentrations ≤300μM at α3β4-nAChR measured by [3H]-acetylcholine release from interpeduncular nucleus. Thus, ABT-089 is a β2* nAChR ligand with demonstrable agonist activity at α4β2* and α6β2* receptors. As one form of α6β2* nAChR is sensitive to sub-μM concentrations, we propose that this receptor in particular may contribute to the enhanced cognitive performance following low doses of ABT-089.

Keywords: Nicotinic acetylcholine receptor; Dopamine; Thalamus; Striatum; Cortex; Desensitization


TC-5619: An alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia by T.A. Hauser; A. Kucinski; K.G. Jordan; G.J. Gatto; S.R. Wersinger; R.A. Hesse; E.K. Stachowiak; M.K. Stachowiak; R.L. Papke; P.M. Lippiello; M. Bencherif (pp. 803-812).
The novel alpha7 neuronal nicotinic receptor-selective agonist TC-5619 demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia.A growing body of evidence suggests that the alpha7 neuronal nicotinic receptor (NNR) subtype is an important target for the development of novel therapies to treat schizophrenia, offering the possibility to address not only the positive but also the cognitive and negative symptoms associated with the disease. In order to probe the relationship of alpha7 function to relevant behavioral correlates we employed TC-5619, a novel selective agonist for the alpha7 NNR subtype. TC-5619 binds with very high affinity to the alpha7 subtype and is a potent full agonist. TC-5619 has little or no activity at other nicotinic receptors, including the α4β2, ganglionic (α3β4) and muscle subtypes. The transgenic th( tk−)/ th( tk−) mouse model that reflects many of the developmental, anatomical, and multi-transmitter biochemical aspects of schizophrenia was used to assess the antipsychotic effects of TC-5619. In these mice TC-5619 acted both alone and synergistically with the antipsychotic clozapine to correct impaired pre-pulse inhibition (PPI) and social behavior which model positive and negative symptoms, respectively. Antipsychotic and cognitive effects of TC-5619 were also assessed in rats. Similar to the results in the transgenic mice, TC-5619 significantly reversed apomorphine-induced PPI deficits. In a novel object recognition paradigm in rats TC-5619 demonstrated long-lasting enhancement of memory over a wide dose range. These results suggest that alpha7-selective agonists such as TC-5619, either alone or in combination with antipsychotics, could offer a new approach to treating the constellation of symptoms associated with schizophrenia, including cognitive dysfunction.

Keywords: Nicotinic receptor; Alpha7; Acetylcholine; Cholinergic; Schizophrenia; Antipsychotic


Preclinical pharmacology of the α4β2 nAChR partial agonist varenicline related to effects on reward, mood and cognition by Hans Rollema; Mihály Hajós; Patricia A. Seymour; Rouba Kozak; Mark J. Majchrzak; Victor Guanowsky; Weldon E. Horner; Doug S. Chapin; William E. Hoffmann; David E. Johnson; Stafford Mclean; Jody Freeman; Kathryn E. Williams (pp. 813-824).
Effects of the α4β2 nAChR partial agonist varenicline, an efficacious smoking cessation aid, in animal models of addiction, depression, cognition and attention.The pharmacological properties and pharmacokinetic profile of the α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline provide an advantageous combination of free brain levels and functional potencies at the target receptor that for a large part explain its efficacy as a smoking cessation aid. Since α4β2 and other nAChR subtypes play important roles in mediating central processes that control reward, mood, cognition and attention, there is interest in examining the effects of selective nAChR ligands such as varenicline in preclinical animal models that assess these behaviors. Here we describe results from studies on varenicline's effects in animal models of addiction, depression, cognition and attention and discuss these in the context of recently published preclinical and preliminary clinical studies that collected data on varenicline's effects on mood, cognition and alcohol abuse disorder. Taken together, the preclinical and the limited clinical data show beneficial effects of varenicline, but further clinical studies are needed to evaluate whether the preclinical effects observed in animal models are translatable to the clinic.

Keywords: Varenicline; Nicotinic acetylcholine receptors; Cognition; Depression; Addiction


Measurement of affective state during chronic nicotine treatment and withdrawal by affective taste reactivity in mice: The role of endocannabinoids by Victoria C. Wing; Barbara Cagniard; Niall P. Murphy; Mohammed Shoaib (pp. 825-835).
Chronic nicotine treatment and spontaneous withdrawal did not influence taste reactions in mice, whereas AM251 differentially modulated taste reactions in saline and nicotine-treated mice.Despite tobacco being highly addictive, it is unclear if nicotine has significant affective properties. To address this, we studied taste reactions to gustatory stimuli, palatable sucrose and unpalatable quinine, which are believed to reflect ongoing affective state. Taste reactivity was assessed during chronic nicotine administration and spontaneous withdrawal and the role of the endogenous cannabinoids was also investigated. C57BL6J mice were implanted with intraoral fistula to allow passive administration of solutions. In the first study, taste reactivity was tracked throughout chronic vehicle or nicotine (12mg/kg/day) infusion via osmotic minipumps and spontaneous withdrawal following removal of minipumps. In the second study, the endocannabinoid CB1-receptor antagonist AM251 (1, 3 and 10mg/kg, intraperitoneal) or vehicle was acutely administered before taste reactivity measurement during chronic nicotine administration. Chronic nicotine treatment and spontaneous withdrawal did not influence taste reactions to sucrose or quinine. AM251 decreased positive reactions to sucrose and increased negative reactions to quinine. The effects of AM251 were respectively attenuated and enhanced in nicotine infused mice. These results suggest chronic nicotine exposure and withdrawal has no apparent affective sequelae, as probed by taste reactivity, and thus may not explain the difficulty tobacco-users have in achieving abstinence. In contrast, endocannabinoids elevate affective state in drug-naïve animals and changes in endogenous endocannabinoid tone may underlie compensations in affective state during chronic nicotine exposure.

Keywords: Nicotine; Withdrawal; Affective state; Taste reactivity; Endocannabinoids; Mouse


Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors by David B. Sattelle; Steven D. Buckingham; Miki Akamatsu; Kazuhiko Matsuda; Ilse Pienaar; Andrew K. Jones; Benedict M. Sattelle; Andrew Almond; Charles D. Blundell (pp. 836-843).
The human α7 nicotinic acetylcholine receptor (nAChR) subunit and its Caenorhabditis elegans homolog, ACR-16, can generate functional recombinant homomeric receptors when expressed in Xenopus laevis oocytes. Both nAChRs express robustly in the presence of the co-injected chaperone, RIC-3, and show striking differences in the actions of a type I positive allosteric modulator (PAM), ivermectin (IVM). Type I PAMs are characterised by an increase in amplitude only of the response to acetylcholine (ACh), whereas type II PAMs exhibit, in addition, changes in time-course/desensitization of the ACh response. The type I PAMs, ivermectin, 5-hydroxyindole (5-HI), NS-1738 and genistein and the type II PAM, PNU-120596, are all active on human α7 but are without PAM activity on ACR-16, where they attenuate the amplitude of the ACh response. We used the published structure of avermectin B1a to generate a model of IVM, which was then docked into the candidate transmembrane allosteric binding site on α7 and ACR-16 in an attempt to gain insights into the observed differences in IVM actions. The new pharmacological findings and computational approaches being developed may inform the design of novel PAM drugs targeting major neurological disorders.

Keywords: Computational modelling; Electrophysiology; Ivermectin; Nicotinic acetylcholine receptor; Positive allosteric modulators; Ion channels


Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices correlates with the profile of high, but not low, sensitivity α4β2 subunit combination by David J. Anderson; John Malysz; Jens Halvard Grønlien; Rachid El Kouhen; Monika Håkerud; Caroline Wetterstrand; Clark A. Briggs; Murali Gopalakrishnan (pp. 844-851).
α4β2 neuronal nicotinic receptors (nAChRs) can exist in high and low sensitivity states possibly due to distinct stoichiometries during subunit assembly: (α4)2(β2)3 pentamer (high sensitivity, HS) and (α4)3(β2)2 pentamer (low sensitivity, LS). To determine if there is a linkage between HS or LS states and receptor-mediated responses in brain, we profiled several clinically studied α4β2* nAChR agonists for the displacement of radioligand binding to α4β2 [3H]-cytisine sites in rat brain membranes, effects on stimulation of [3H]-dopamine release from slices of rat prefrontal cortex and striatum, and activation of HS and LS human α4β2 nAChRs expressed in Xenopus laevis oocytes. Binding affinities (p Ki) and potency (pEC50) values for [3H]-dopamine release closely correlated with a rank order: varenicline>(−)-nicotine>AZD3480>dianicline≅ABT-089. Further, a good correlation was observed between [3H]-dopamine release and HS α4β2 pEC50 values, but not between [3H]-dopamine release and LS α4β2. The relative efficacies of the agonists ranged from full to partial agonists. Varenicline behaved as a partial agonist in stimulating [3H]-dopamine release and activating both HS and LS α4β2 nAChRs expressed in oocytes. Conversely, ABT-089, AZD3480 and dianicline exhibited little efficacy at LS α4β2 (<5%), were more effective at HS α4β2 nAChRs, and in stimulating cortical and striatal [3H]-dopamine release ≥30%. In the presence of α-conotoxin MII to block α6β2* nAChRs, the α4β2* α-conotoxin-insensitive [3H]-dopamine release stimulated by these ligands correlates well with their interactions at HS, but not LS. In summary, this study provides support for HS α4β2* nAChR involvement in neurotransmitter release.

Keywords: Nicotinic acetylcholine receptor; Cytisine; Dopamine; Striatum; Cortex; Stoichiometry


A reversible model of the cognitive impairment associated with schizophrenia in monkeys: Potential therapeutic effects of two nicotinic acetylcholine receptor agonists by Jerry J. Buccafusco; Alvin V. Terry Jr. (pp. 852-862).
In monkeys proficient in the performance of a computer-assisted delayed response task, administration of sub-sedative doses of ketamine significantly impaired task performance after the 2mg/kg dose, producing a decrease in accuracies across all four delay intervals. Ketamine elicited occasional and inconsistent increases in task latencies. But in general processing speed was not dramatically affected by the test dose. Pretreatment with the α7 nicotinic receptor agonist GTS-21 (DMXB-A) [3-[(3E)-3-[(2,4-dimethoxyphenyl) methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine] produced a dose-dependent attenuation of ketamine-induced decreases in task accuracies. In fact, the best dose of GTS-21 completely reversed the effects of ketamine. The nicotine metabolite cotinine is a cognitive-enhancer, and active in models predictive of antipsychotic activity. Pretreatment with cotinine did not reverse the task deficits produced by ketamine, and selection of a best dose was necessary to show the activity of cotinine. However, the best dose of cotinine, like GTS-21, completely reversed the ketamine-induced task deficits. Task accuracies were increased relative to their non-ketamine baselines during sessions run 24h later. The cotinine–ketamine order of administration was reversed to provide a more clinically relevant model, and cotinine post-treatment regimen produced a clear reversal of the ketamine-induced task deficits. The protracted task improvement also was still evident. The DMTS task impairment induced by ketamine was capable of being completely reversed by two compounds that are known to improve working memory and cognition. The model could provide a means of late stage preclinical evaluation of new compounds that address the cognitive impairment associated with major psychotic disease.

Keywords: Schizophrenia; Cognition; Non-human primate; Delayed matching; Hallucinogen; Nicotinic receptor agonist


GTS-21 inhibits pro-inflammatory cytokine release independent of the Toll-like receptor stimulated via a transcriptional mechanism involving JAK2 activation by Matthijs Kox; Jeroen F. van Velzen; Jan C. Pompe; Cornelia W. Hoedemaekers; Johannes G. van der Hoeven; Peter Pickkers (pp. 863-872).
The vagus nerve can limit inflammation via the α7 nicotinic acetylcholine receptor (α7nAChR). Selective pharmacological stimulation of the α7nAChR may have therapeutic potential for the treatment of inflammatory conditions. We determined the anti-inflammatory potential of GTS-21, an α7nAChR-selective partial agonist, on primary human leukocytes and compared it with nicotine, the nAChR agonist widely used for research into the anti-inflammatory effects of α7nAChR stimulation. Furthermore, we investigated whether the effects of both nicotinic agonists were restricted to specific Toll-like receptors (TLRs) stimulated and explored the mechanism behind the anti-inflammatory effect of GTS-21.GTS-21 and nicotine inhibited the release of pro-inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), monocytes and whole blood independent of the TLR stimulated, with higher potency/efficacy for GTS-21 compared to nicotine. The anti-inflammatory cytokine IL-10 was relatively unaffected by both nicotinic agonists. The effects of GTS-21 and nicotine could not be reversed by nAChR antagonists, while the JAK2 inhibitor AG490 abolished the anti-inflammatory effects. GTS-21 downregulated monocyte cell-surface expression of TLR2, TLR4 and CD14. qPCR analysis demonstrated that the anti-inflammatory effect of GTS-21 is mediated at the transcriptional level and involves JAK2-STAT3 activation.In conclusion, GTS-21 has a profound anti-inflammatory effect in human leukocytes and that GTS-21 is more potent/efficacious than nicotine. The absence of a blocking effect of nAChR antagonists in human leukocytes might indicate different pharmacological properties of the α7nAChR in human leukocytes compared to other cell types. GTS-21 may be promising from a therapeutic perspective because of its suitability for human use.

Keywords: Inflammation; Cholinergic anti-inflammatory pathway; Nicotine; Monocytes; Peripheral blood mononuclear cells; α7 nicotinic acetylcholine receptor


Enhanced nicotine reward in adulthood after exposure to nicotine during early adolescence in mice by Dena Kota; Susan E. Robinson; M. Imad Damaj (pp. 873-879).
Approximately one million adolescents begin smoking cigarettes every year. Studies show that adolescents may be particularly vulnerable to various aspects of nicotine dependence. Work on rodents demonstrates parallel findings showing that adolescence is a time of changed sensitivity to both rewarding and aversive effects of nicotine. However, it is unclear if these effects are long-lasting and whether they contribute to a lifetime of nicotine addiction. In this study we have characterized the effects of adolescent nicotine exposure on the rewarding properties of nicotine in adulthood using the CPP model. Specifically, we have addressed whether the phase of adolescence (early, middle, or late adolescence) plays a role in the susceptibility to the enhanced rewarding effects of nicotine. Furthermore, we have investigated the long-term effects of adolescent nicotine exposure on nicotine reward in adulthood and have correlated these behavioral adaptations with possible molecular mechanisms. We observed that early adolescence in the mouse is a unique phase for elevated sensitivity to nicotine reward using a CPP model. In addition, exposure to nicotine during this phase, but not during late adolescence or adulthood, resulted in a lasting enhancement of reward in adulthood. Finally, we have shown that early adolescent nicotine exposure significantly elevates nAChR function in adulthood. Overall, we demonstrate that early adolescence represents a period of development, distinct from middle and late adolescence, during which nicotine exposure can cause persistent changes in behavior and molecular adaptations.

Keywords: Abbreviations; PND; post-natal day; AUC; area under the curve; nAChR; nicotinic acetylcholine receptor; s.c.; subcutaneous injection; CPP; conditioned place preference


Selective α7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes by Simon Sydserff; E.J. Sutton; Dekun Song; Michael C. Quirk; Carla Maciag; Chaoying Li; Gerald Jonak; David Gurley; John C. Gordon; Edward P. Christian; James J. Doherty; Tom Hudzik; Edwin Johnson; Ladislav Mrzljak; Tim Piser; Gennady N. Smagin; Yi Wang; Dan Widzowski; Jeffrey S. Smith (pp. 880-888).
α7 Neuronal nicotinic receptor activation of midbrain dopamine neurons improves selective attention and acquisition of operant and object recognition behaviors.AZD0328, a novel spirofuropyridine neuronal nicotinic receptor partial agonist, was used to investigate the role of α7 neuronal nicotinic receptor (NNR) activation in the modulation of midbrain dopamine neuron function, cortical dopamine release and on two behavioral tasks known to be dependent on optimal levels of cortical dopamine. In vivo recordings from area 10 (ventral tegmental area) in rat brain showed an increased firing of putative dopamine neurons in response to low (0.00138mg/kg) doses of AZD0328. Bursting patterns of dopamine neuron activity remained largely unchanged by application of AZD0328. In vivo microdialysis in awake rats showed an increase in extracellular prefrontal cortical dopamine in response to low doses of AZD0328. Compound-stimulated dopamine release showed an inverted dose effect relation that was maximal at the lowest dose tested (0.00178mg/kg). Peak extracellular dopamine levels were reached 2h after dosing with AZD0328. Acquisition of operant responding with delayed reinforcement in rats was dose dependently enhanced by AZD0328 with a plateau effect measured at 0.003mg/kg. This effect was blocked by pre-treatment of animals with the selective α7 antagonist methyllycaconitine. AZD0328 improved novel object recognition in mice over a broad range of doses (0.00178–1.78mg/kg) and the compound effect was found to be absent in homozygous α7 KO animals. Together, these data indicate that selective interaction with α7 NNRs by AZD0328 selectively enhances midbrain dopaminergic neuronal activity causing an enhancement of cortical dopamine levels; these neurochemical changes likely, underlie the positive behavioral responses observed in two different animal models. Our results suggest selective α7 NNR agonists may have significant therapeutic utility in neurologic and psychiatric indications where cognitive deficits and dopamine neuron dysfunction co-exist.

Keywords: α7 Nicotinic acetylcholine receptor; Neuronal nicotinic receptor; α7 Agonist; Dopamine; Cognition


The novel nicotinic receptor antagonist, N, N′-dodecane-1,12-diyl- bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked [3H]norepinephrine overflow from rat hippocampal slices by Andrew M. Smith; Gurpreet K. Dhawan; Zhenfa Zhang; Kiran B. Siripurapu; Peter A. Crooks; Linda P. Dwoskin (pp. 889-897).
Smoking is a significant health concern and strongly correlated with clinical depression. Depression is associated with decreased extracellular NE concentrations in brain. Smokers may be self-medicating and alleviating their depression through nicotine stimulated norepinephrine (NE) release. Several antidepressants inhibit NE transporter (NET) function, thereby augmenting extracellular NE concentrations. Antidepressants, such as bupropion, also inhibit nicotinic receptor (nAChR) function. The current study determined if a recently discovered novel nAChR antagonist, N, N′-dodecane-1,12-diyl- bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked NE release from superfused rat hippocampal slices. Previous studies determined that bPiDDB potently (IC50=2nM) inhibits nicotine-evoked striatal [3H]dopamine (DA) release in vitro, nicotine-evoked DA release in nucleus accumbens in vivo, and nicotine self-administration in rats. In the current study, nicotine stimulated [3H]NE release from rat hippocampal slices (EC50=50μM). bPiDDB inhibited (IC50=430nM; Imax=90%) [3H]NE release evoked by 30μM nicotine. For comparison, the nonselective nAChR antagonist, mecamylamine, and the α7 antagonist, methyllycaconitine, also inhibited nicotine-evoked [3H]NE release (IC50=31 and 275nM, respectively; Imax=91% and 72%, respectively). Inhibition by bPiDDB and mecamylamine was not overcome by increasing nicotine concentrations; Schild regression slope was different from unity, consistent with allosteric inhibition. Thus, bPiDDB was 200-fold more potent inhibiting nAChRs mediating nicotine-evoked [3H]DA release from striatum than those mediating nicotine-evoked [3H]NE release from hippocampus.

Keywords: Abbreviations; bPiDDB; N,N; ′-dodecane-1,12-diyl-; bis; -3-picolinium dibromide; *; indicates putative nAChR subtype assignmentAntidepressants; Nicotine; Nicotinic acetylcholine receptor; Norepinephrine release; Smoking cessation

The nicotinic acetylcholine receptors of Ascaris suum by H.M. Bennett; S.M. Williamson; S. McCavera; A.P. Robertson; R.J. Martin; T. Williams; D.J. Woods; D.B. Sattelle; A.J. Wolstenholme (pp. 899-900).
Functional consequences of adaptive evolution of the mammalian α9α10 nicotinic receptor by M. Lipovsek; L.F. Franchini; E. Katz; N.S. Millar; P.A. Fuchs; A.B. Elgoyhen (pp. 899-899).
Pharmacological chaperoning of nicotinic receptors begins in the endoplasmic reticulum: High-resolution imaging by Rigo Pantoja; Rahul Srinivasan; Sindhuja Kadambi; Elisha D.W. Mackey; Shelly Tzlil; Fraser J. Moss; Henry A. Lester (pp. 900-901).
Pharmacological chaperoning of nicotinic receptors begins in the endoplasmic reticulum: Compartments and stoichiometries by Rahul Srinivasan; Rigo Pantoja; Sindhuja Kadambi; Elisha D.W. Mackey; Shelly Tzlil; Fraser J. Moss; Henry A. Lester (pp. 900-900).
Functional expression of an α5β2 nicotinic acetylcholine receptor by Tanguy Araud; Mario Wanischeck; Roberta Benfante; Ortrud Steinlein; Diego Fornasari; Daniel Bertrand; Jean-Charles Hoda (pp. 901-901).
Gain of function mutants in human or mouse nAChR β3 subunits interchangeably activate either human or mouse α6β4*-nAChR, but not human or mouse α6β2*-nAChR by Bhagirathi Dash; Minoti Bhakta; Paul Whiteaker; Jerry A. Stizel; Yongchang Chang; Ronald J. Lukas (pp. 901-902).
Labeled peptide and protein neurotoxins for basic study on nicotinic acetylcholine receptors and for practical applications by Igor Kasheverov; Maxim Zhmak; Alexey Khrushchov; Irina Shelukhina; Elena Kryukova; Victor Tsetlin (pp. 902-902).
Radioligand binding characterization of [3H]-A-998679: A novel positive allosteric modulator of α4β2 nAChRs by D.J. Anderson; S. Vaidyanathan; M. Namovic; D. Donnelly-Roberts; L. Lee; M. Gopalakrishnan (pp. 903-904).
Labeling α7 nAChRs on hippocampal neurons using fluorescent analogs of α-conotoxin ArIB[V11L;V16A] by Arik J. Hone; Jesse L. Mohn; Michele Jacob; Paul Whiteaker; J. Michael McIntosh (pp. 903-903).
α3* and α7* nAChR mediated Ca2+ transient generation in neuroblastoma IMR-32 cells by H. Ween; K. Thorin-Hagene; E. Andersen; J.H. Gronlien; L. Lee; M. Gopalakrishnan; J. Malysz (pp. 904-904).
A novel nicotinic antagonist protects the function of hippocampal slices against neurotoxic organophosphates by P.A. Ferchmin; Dinely Perez; A. Henrique Martins; Brenda L. Cuadrado; Marimee Carrasco; Vesna A. Eterovic (pp. 904-905).
Probing the non-competitive binding site within the n-terminal region of α4β2 nicotinic receptors by Gracia X.J. Quek; Jill I. Halliday; Malcolm D. McLeod; Mary Chebib (pp. 905-906).
Isoanatabine, a naturally occurring α4β2 nicotinic receptor agonist by H. Xing; A. Rouchaud; S. Keshwah; W.R. Kem (pp. 906-907).
Mutation of proline enables subtype selectivity of α-conotoxin BuIA by Yelena Filchakova; Amy B. Godoy; Sean Christensen; J. Michael McIntosh (pp. 906-906).
Homology models of the alpha7 acetylcholine receptor based upon bacterial receptors: Comparison of experimental and in silico derived data by Sean C. Barron; Brenda R. Temple; Jennifer A. See; Robert L. Rosenberg; James T. McLaughlin (pp. 907-908).
Novel α7 nAChRs ligands: From virtual screening to functional assays by N. Garcia; K.T. Nguyen; S. Bertrand; D. Bertrand; J.L. Reymond (pp. 907-907).
Automated two-electrode voltage clamp for medium-throughput studies of ion channels with non-destructive sample analysis by Dieter D’hoedt; Victor Tsetlin; Sonia Bertrand; Daniel Bertrand (pp. 907-907).
Selectivity of ABT-089 for α4β2* and α6β2* nicotinic acetylcholine receptors in brain by Michael J. Marks; Charles R. Wageman; Sharon R. Grady; Murali Gopalakrishnan; Clark A. Briggs (pp. 910-910).
Role of Sp1 and AP-2 in the transcriptional regulation of the CHRNA7 gene and the link to schizophrenia by Jessica Finlay Schultz; Margaret Short; Sharon Graw; Sherry Leonard (pp. 910-910).
Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain by Morten S. Thomsen; Anders Hay-Schmidt; Henrik H. Hansen; Jens D. Mikkelsen (pp. 910-910).
Characterization of the alpha-7 nicotinic receptor agonist WYE-103914 in models relevant to schizophrenia and interaction with antipsychotics by K.L. Marquis; T.A. Comery; R.L. Navarra; S. Leiser; S.M. Grauer; C. Pulicicchio; C. Kelley; R. Roncarati; C. Scali; S. Haydar; C. Ghiron; B. Harrison; A. Robichaud; G.C. Terstappen; J. Dunlop (pp. 911-911).
In vitro pharmacological characterization and pro-cognitive effects of the selective alpha-7 nicotinic agonist WYE-103914 by J. Dunlop; T.A. Comery; T. Lock; A. Kramer; D. Kowal; S. Yeola; F. Jow; S. Aschmies; Q. Lin; C.E. Beyer; J. Brennan; C. Kelley; R. Roncarati; C. Scali; S. Haydar; C. Ghiron; K.L. Marquis; B. Harrison; A. Robichaud; G.C. Terstappen (pp. 911-911).
Characterization of JNJ-1930942, a novel positive allosteric modulator of the α7 nicotinic acetylcholine receptor by Anne Lesage; Theo Dinklo; Jan-Willem Thuring; Christopher Grantham; Luc Peeters; Hilde Lavreysen; Hamdy Shaban; Karen E. Stevens; Lijun Zheng (pp. 912-912).
Profile of A-716096, a novel thiazolylidine positive allosteric modulator of the α7 nicotinic acetylcholine receptor by D. Donnelly-Roberts; J. Malysz; R. Faghih; H. Gronlien; M. Haakerud; K. Thorin-Hagne; H. Ween; S.M. Gopalakrishnan; M. Hu; J. Li; D.J. Anderson; K. Kohlhaas; M. Namovic; R. Radek; H. Robb; C.A. Briggs; R.S. Bitner; W.H. Bunnelle; M. Gopalakrishnan (pp. 912-913).
In vitro and in vivo characterization of PheTQS, a novel α7 nAChR positive allosteric modulator by James N.C. Kew; Selina Mok; Annette Weil; Caterina Virginio; Laura Castelletti; Eric Southam; Carol Jennings; Lee A. Dawson; Laurent P. Lacroix; Abbe Martyn; Simon Teague; Zeenat Atcha; Darrel Pemberton; Charlie Reavill; Mark Hill; Jackie Cilia; Kevin Choo; Karen Stevens; Andrew Lightfoot (pp. 913-913).
Dual allosteric modulators of neuronal nicotinic-acetylcholine and GABAA receptors by Kelvin Gee; Derk Hogenkamp; Tim Johnstone (pp. 913-914).
2,2-Dimethylcyclopropyl-benzamides: Novel positive allosteric modulators of α7 nAChRs by Hans Maag; Daisy Joe Du Bois; David G. Loughhead; Jason Manka; Dinah Misner; Sunil Sahdeo; David B. Smith (pp. 913-913).
Effects of 4R,6R-cembratriene diol on human α7 nicotinic acetylcholine receptor by William Castro; Richard Hann; Vesna A. Eterovi (pp. 914-914).
Chronic nicotine exposure differentially alters gene expression in VTA from adolescent and adult rats by Menahem B. Doura; Norman H. Lee; David C. Perry (pp. 914-915).
Effects of nicotine on real-time dopamine dynamics in rat nucleus accumbens: In vivo voltammetric study by V.P. Grinevich; J.A. O’Connor; M. Bencherif; E.A. Budygin (pp. 916-916).
Functional interaction between presynaptic nicotinic and D2 receptors on dopaminergic nerve endings of rat and mouse nucleus accumbens by Mario Marchi; Stefania Zappettini; Massimo Grilli; Federica Lagomarsino; Michele Zoli (pp. 916-916).
GABAB receptor positive modulators: Effects on nicotine self-administration and cue-induced reinstatement of nicotine-seeking behavior in rats by Styliani Vlachou; Sébastien Guery; Wolfgang Froestl; Klemens Kaupmann; Deboshri Banerjee; M.G. Finn; Athina Markou (pp. 917-918).
Preclinical properties of the α4β2 nAChR partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence by H. Rollema; A. Shrikhande; K.M. Ward; J.W. Coe; E. Tseng; E.Q. Wang; M. De Vries; T.H.I.F. Cremers; S. Bertrand; D. Bertrand (pp. 918-919).
The nAChR agonist AMOP-H-OH (‘sazetidine-A’) exhibits reinforcing, but not withdrawal-alleviating, properties in rats by Adrian Hackett; Barbara Caldarone; Alan P. Kozikowski; Afshin Ghavami; Berend Olivier; Taleen Hanania; Neil E. Paterson (pp. 919-919).
Low efficacy partial agonists of the α4β2 nicotinic acetylcholine receptor (nAChR). Does functional efficacy govern in vivo response? by Jotham W. Coe; Paige R. Brooks; Michael C. Wirtz; Michael G. Vetelino; Eric P. Arnold; Steven B. Sands; Thomas I. Davis; Lorraine A. Lebel; Carol B. Fox; Alka Shrikhande; Robert S. Mansbach; Leslie K. Chambers; Charles C. Rovetti; David W. Schulz; F. David Tingley III; Brian T. O’Neill; Hans Rollema (pp. 919-919).
In vitro pharmacological profile of a novel α4β2 positive allosteric modulator NS9283 (A-969933) by J. Malysz; T. Dyhring; P.K. Ahring; G.M. Olsen; D. Peters; J.H. Gronlien; C. Wetterstrand; H. Ween; M. Haakerud; K. Thorin-Hagene; E. Andersen; D.J. Anderson; M. Hu; P.E. Kroeger; C.-H.L. Lee; M. Gopalakrishnan; D.B. Timmermann (pp. 919-920).
In vivo characterization of the co-administration of α4β2 neuronal nicotinic receptor agonist and positive allosteric modulator in experimental pain in rats by Chang Z. Zhu; Chih-liang Chin; Chengmin Zhong; Joe Mikusa; Prasant Chandran; Anita Salyers; Erica Wensink; Gricelda Silmer; La Geisha Lewis; Donna Gauvin; Scott Baker; Ann Tovcimak; Jordan Brown; Nathan Rustay; Gerard B. Fox; Michael W. Decker; Chih-Hung Lee; Murali Gopalakrishnan; Prisca Honore (pp. 920-920).
Improving the efficacy-tolerability profile of nAChR agonists for the treatment of neuropathic pain in combination with positive allosteric modulators by Chih-Hung Lee; Chang Zhu; Thomas Campbell; Thomas Shaughnessy; Prisca Honore; James Polakowski; Murali Gopalakrishnan (pp. 920-920).
GZ556A and ZZ204G are novel small molecule antagonists of α9α10 nAChRs and are analgesic in rats by J.M. McIntosh; L.P. Dwoskin; P.A. Crooks; J.R. Holtman Jr. (pp. 921-921).
Antidepressant-like activity of AMOP-H-OH (‘sazetidine-A’) in the forced swim test is mediated by high affinity nicotinic acetylcholine receptors by B.J. Caldarone; M. Manzano; N.E. Paterson; A.P. Kozikowksi; B.E. Olivier; A. Ghavami (pp. 921-922).
Positive allosteric modulation of α4β2 nicotinic receptors potentiates some CNS effects of the α4β2 agonist, ABT-594 by S.R. Franklin; E.G. Mohler; V.A. Komater; H. Robb; R.J. Radek; N.R. Rustay; J.W. Brown; M. Gopalakrishnan; M.W. Decker; L.E. Rueter (pp. 921-921).
nAChR agonists reducel-dopa-induced dyskinesias in parkinsonian rats by M. Quik; L.Z. Huang; Y. Lee; I.F. Carroll; N. Parameswaran (pp. 922-922).
Expression and characterization of nicotinic receptor polymorphisms in lung cancer cell lines by J.A. Hollister-Smith; P. Song; E.R. Spindel (pp. 923-923).
Role of α7 nicotinic acetylcholine receptors in regulating tumor necrosis factor-α (TNF-α) as Revealed by subtype selective agonists by Jinhe Li; Suzanne L. Mathieu; Richard Harris; Jianguo Ji; David J. Anderson; John Malysz; William H. Bunnelle; Jeffrey F. Waring; Kennan C. Marsh; Anwar Murtaza; Lisa M. Olson; Murali Gopalakrishnan (pp. 924-925).
Anti-inflammatory effects of α4β2 nicotinic receptor activation revealed through microarray analysis of nicotine-induced gene changes by Vishnu Hosur; Scott Leppanen; Adham Abutaha; Michael Marks; Ralph H. Loring (pp. 924-924).
Nicotine suppresses hyperexcitability of inflamed colonic sensory neurons by G.R. Abdrakhmanova; H.I. Akbarali; Sh. Al Sharari; M.I. Damaj (pp. 924-924).
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