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John J Maurer, Karin Sandager-Nielsen, Heath D Schmidt
RATIONALE: The rewarding and reinforcing effects of nicotine are produced, in large part, by activation of neuronal α4β2* nicotinic acetylcholine receptors (nAChRs), pentameric protein complexes comprised of different stoichiometries of α4 and β2 subunits. However, little is known about the functional role of distinct subtypes of α4β2* nAChRs in nicotine addiction. OBJECTIVES: NS9283 represents a new class of stoichiometry-selective positive allosteric modulators (PAMs) that selectively bind to α4β2 nAChRs containing three α4 and two β2 subunits (3(α4)2(β2) nAChRs)...
February 2017: Psychopharmacology
Scott W Rogers, Lorise C Gahring
High affinity nicotine-binding sites in the mammalian brain are neuronal nicotinic acetylcholine receptors (nAChR) assembled from at least alpha4 and beta2 subunits into pentameric ion channels. When exposed to ligands such as nicotine, these receptors respond by undergoing upregulation, a correlate of nicotine addiction. Upregulation can be measured using HEK293 (293) cells that stably express alpha4 and beta2 subunits using quantification of [3H]epibatidine ([3H]Eb) binding to measure mature receptors. Treatment of these cells with choline also produces upregulation through a hemicholinium3 (HC3)-sensitive (choline kinase) and an HC3-insensitive pathway which are both independent of the mechanism used by nicotine for upregulation...
2015: PloS One
Maegan M Weltzin, Marvin K Schulte
Alterations in expression patterns of α4β2 nicotinic acetylcholine receptors have been demonstrated to alter cholinergic neurotransmission and are implicated in neurologic disorders, including autism, nicotine addiction, Alzheimer's disease, and Parkinson's disease. Positive allosteric modulators (PAMs) represent promising new leads in the development of therapeutic agents for the treatment of these disorders. This study investigates the involvement of the β2-containing subunit interfaces of α4β2 receptors in the modulation of acetylcholine (ACh)-induced responses by the PAM desformylflustrabromine (dFBr)...
August 2015: Journal of Pharmacology and Experimental Therapeutics
F Saika, N Kiguchi, Y Kobayashi, S Kishioka
AIM: Neuropathic pain is often refractory to conventional analgesics including opioids and non-steroidal anti-inflammatory drugs. Evidence suggests nicotinic acetylcholine receptor ligands regulate pain transmission. Effects of α4β2 nicotinic acetylcholine receptor activation on pain behaviours after nerve injury were studied. METHODS: Mice were subjected to partial sciatic nerve ligation (PSL). Nicotinic acetylcholine receptor α4 and β2 subunits localization in injured nerves were evaluated by immunohistochemistry...
February 2015: Acta Physiologica
Iu O Fedotova, H O Frolova
The present work was devoted to the comparative analysis of alpha4beta2 nicotinic acetylcholine receptors (nAChRs) in learning/ memory processes during ovary cycle assessed in adult female rats. RJR-2403 (1.0 mg/kg, i.p.), alpha4beta2 nAChRs agonist and mecamylamine (1.0 mg/kg, i.p.), alpha4beta2 nAChRs antagonist were injected chronically during 14 days. The processes of learning/memory were assessed in different models of learning: passive avoidance performance and Morris water maze. Chronic RJR-2403 administration to female rats improved the passive avoidance performance in proestrous and estrous as compared to the control animals...
2014: Fiziolohichnyĭ Zhurnal
Salomé Llabrés, Sara García-Ratés, Edgar Cristóbal-Lecina, Antoni Riera, José Ignacio Borrell, Jorge Camarasa, David Pubill, F Javier Luque, Elena Escubedo
The α4β2 nicotinic acetylcholine receptor (nAChR) is a molecular target of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug also known as ecstasy, and it modulates the MDMA-mediated reinforcing properties. However, the enantioselective preference of the α4β2 nAChR subtype still remains unknown. Since the two enantiomers exhibit different pharmacological profiles and stereoselective metabolism, the aim of this study is to assess a possible difference in the interaction of the MDMA enantiomers with this nAChR subtype...
June 23, 2014: European Journal of Medicinal Chemistry
Wouter Goutier, Margreet B Kloeze, Andrew C McCreary
The present study focused on the evaluation of behavioral sensitization and cross-sensitization induced by nicotine and varenicline in rats. Furthermore, it examined the influence of varenicline, a partial alpha4beta2 nicotinic receptor agonist, on nicotine-induced sensitization. To assess the development of behavioral sensitization, rats were chronically treated with vehicle, varenicline (0.03-3.0 mg/kg), nicotine (0.4 mg/kg) or combinations for 5 days and locomotor activity was measured. The expression of sensitization was assessed following a withdrawal period (17-26 days)...
March 2015: Addiction Biology
Patricia E Grebenstein, Joseph L Harp, Neil E Rowland
RATIONALE: Increased appetite and weight gain after cessation are deterrents for quitting smoking. Pharmacotherapies that can reduce this weight gain in ex-smokers would be invaluable, and yet are not well studied in this context. OBJECTIVE: To examine the effects of extended daily exposure to intravenous cytisine, an alpha4beta2 nAChR partial agonist used for smoking cessation in some European countries, on body weight and patterns of food intake in rats. METHODS: In the first experiment, programmed infusions of cytisine were administered over 15 h per day...
September 2013: Pharmacology, Biochemistry, and Behavior
Narito Kurioka
Varenicline is an orally administered alpha4beta2 nicotinic acetylcholine receptor partial agonist. It has been widely used in smoking cessation therapy. It reduces craving and withdrawal symptoms during abstinence and lowers the reinforcing effects of nicotine. A third action of the drug is to blunt responses to smoking cues. Varenicline has higher abstinence rates than nicotine transdermal patches or bupropion. As serious neuro-psychiatric symptoms had been reported post market, including drowsiness, suicidal thoughts and suicide, clinicians are recommended to review the patient's psychiatric history and should monitor them for changes in mood and behavior when prescribing this medication...
March 2013: Nihon Rinsho. Japanese Journal of Clinical Medicine
Reiji Yoshimura, Jun Nakamura
Mounting evidence indicates that addictive effects of nicotine occur through interaction with its receptors in the mesolimbic dopamine system, particularly ventral tegmental area neurons, where nicotinic acetylcholine receptors (nAChRs) act to promote the release of dopamine. Indeed chronic treatment with nicotine leads to an up-regulation in the number of alpha4beta2-subunit nAChRs. Moreover, N-methyl-D-aspartate receptors and gamma-aminobutyric acid receptors are also involved in the regulation of dopamine release...
March 2013: Nihon Rinsho. Japanese Journal of Clinical Medicine
Julia Niedźwiecka, Anna K Przybył, Maciej Kubicki
Cytisine is an alkaloid of plant origin. It is a toxic substance, obtained on an industrial scale from Laburnum anagyroides also known as common laburnum. Today is used in the preparation of anti-smoking products as an agonist of nicotinic receptors nAChR-alpha4beta2. Thanks to crystallographic methods we can examine and describe with high accuracy the actual structure of complex chemical compounds. This work aims to present a series of tests carried out on crystals of cytisine salts, after a prior isolation of cytisine from the seeds of laburnum anagyroides...
2012: Przegla̧d Lekarski
Maegan M Weltzin, Yanzhou Huang, Marvin K Schulte
A number of new positive allosteric modulators (PAMs) have been reported that enhance responses of neuronal alpha7 and alpha4beta2 nicotinic acetylcholine receptor subtypes to orthosteric ligands. PAMs represent promising new leads for the development of therapeutic agents for disorders involving alterations in nicotinic neurotransmission including Autism, Alzheimer's and Parkinson's disease. During our recent studies of alpha4beta2 PAMs, we identified a novel effect of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)...
June 5, 2014: European Journal of Pharmacology
Nick C Ortiz, Heidi C O'Neill, Michael J Marks, Sharon R Grady
INTRODUCTION: The smoking cessation aid, varenicline, has higher affinity for the alpha4beta2-subtype of the nicotinic acetylcholine receptor (α4β2*-nAChR) than for other subtypes of nAChRs by in vitro assays. The mechanism of action of acute varenicline was studied in vivo to determine (a) subtype activation associated with physiological effects and (b) dose relationship as an antagonist of nicotine. METHODS: Acute doses of saline, nicotine, and varenicline were given to mice, and locomotor depression and hypothermia were measured...
June 2012: Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco
Jennifer G Plebani, Kevin G Lynch, Qin Yu, Helen M Pettinati, Charles P O'Brien, Kyle M Kampman
BACKGROUND: Cocaine use, abuse and dependence remains a pressing public health problem. Based on its mechanism of action, varenicline, an alpha4beta2 partial agonist seemed to be a likely candidate for treating cocaine dependence. METHODS: Cocaine dependent participants (n=37) were enrolled in a 9-week double-blind placebo controlled clinical trial. Varenicline was titrated up to a target dose of 1mg BID during the first week of medication. RESULTS: Varenicline was associated with lower odds of cocaine use than placebo (OR=2...
February 1, 2012: Drug and Alcohol Dependence
Simone Mazzaferro, Naïl Benallegue, Anna Carbone, Federica Gasparri, Ranjit Vijayan, Philip C Biggin, Mirko Moroni, Isabel Bermudez
Nicotinic acetylcholine receptor (nAChR) α4 and β2 subunits assemble in two alternate stoichiometries to produce (α4β2)(2)α4 and (α4β2)(2)β2, which display different agonist sensitivities. Functionally relevant agonist binding sites are thought to be located at α4(+)/β2(-) subunit interfaces, but because these interfaces are present in both receptor isoforms, it is unlikely that they account for differences in agonist sensitivities. In contrast, incorporation of either α4 or β2 as auxiliary subunits produces isoform-specific α4(+)/α4(-) or β2(+)/β2(-) interfaces...
September 2, 2011: Journal of Biological Chemistry
Rahul Srinivasan, Rigo Pantoja, Fraser J Moss, Elisha D W Mackey, Cagdas D Son, Julie Miwa, Henry A Lester
The up-regulation of α4β2* nicotinic acetylcholine receptors (nAChRs) by chronic nicotine is a cell-delimited process and may be necessary and sufficient for the initial events of nicotine dependence. Clinical literature documents an inverse relationship between a person's history of tobacco use and his or her susceptibility to Parkinson's disease; this may also result from up-regulation. This study visualizes and quantifies the subcellular mechanisms involved in nicotine-induced nAChR up-regulation by using transfected fluorescent protein (FP)-tagged α4 nAChR subunits and an FP-tagged Sec24D endoplasmic reticulum (ER) exit site marker...
January 2011: Journal of General Physiology
Wang-qian Luo, Wen-yu Cui, Hai Wang
AIM: To establish the whole-cell recording techniques of the neuronal alpha4beta2, alpha4beta4, and alpha7-nicotinic acetylcholine receptors heterologously expressed in SH-EP1 cell line and discuss the electrophysiological characteristics of their open states. METHODS: The cells were cultured with DEME medium(high glucose) and suitable for electrophysiological experiments three days after passage. The receptors were induced from resting states into open states by rapid application of nicotine (alpha4beta2, alpha4beta4) or choline (alpha7)...
August 2009: Chinese Journal of Applied Physiology
Shigemitsu Onizawa, Haruko Taniguchi, Tomoko Nozu, Asuka Asano, Hideki Katsura, Kumiko Saiki, Toshio Kiguchi, Mizue Hasegawa, Atsushi Nagai
Varenicline (Champix) is an alpha4beta2 nicotinic receptor antagonist that is used orally for treatment of nicotine dependence. We conducted a study to examine the sustainable efficacy of varenicline in smoking cessation. The subjects were 148 outpatients (113 men, 35 women; average age; 54.4 +/- 14.0 years) at 6 different hospitals, and their adverse events were monitored in each hospital. The 4-week continuous abstinence rates of smoking cessation were 17.6%, 75.0%, and 84.6% in groups treated for 4 or fewer weeks, 5 to 8 weeks, and 9 to 12 weeks, respectively, with the rate showing a significant increase according to treatment period...
November 2010: Nihon Kokyūki Gakkai Zasshi, the Journal of the Japanese Respiratory Society
Kinga Burda, Anna Czubak, Elzbieta Nowakowska, Krzysztof Kus, Jana Metelska, Anna Nowakowska
Cognitive disorders in the course of mental illnesses are one of the most important and most difficult therapeutic problems related to those illnesses and they regard attention, memory, learning and sensory modulation. The limited number of nicotinic receptors (subtypes alpha7 and alpha4beta2) seems to cause the incidence and exacerbation of cognitive deficits in such patients. In patients with schizophrenia, the impairment of cognitive processes is also a side-effect of neuroleptics. The characteristics and intensity of the negative effect of antipsychotics on cognitive functions depends on the pharmacological action of those drugs and on the effect on dopamine and serotoninergic receptors in particular...
2010: Arzneimittel-Forschung
Jae Woo Jung, Eun Ju Jeon, Jae Gyu Kim, Suh-Yoon Yang, Jae Chol Choi, Jong Wook Shin, In Won Park, Byoung Whui Choi, Don-Kyu Kim, Jae Yeol Kim
INTRODUCTION:   Varenicline, a partial agonist/antagonist of the alpha4beta2 nicotinic acetylcholine receptors, is effective in smoking cessation, which was demonstrated by several randomized, controlled clinical trials. OBJECTIVES:   In the present study, we evaluated the practical efficacy of varenicline for smoking cessation in patients who visited a pulmonary clinic at a university-affiliated hospital in South Korea. MATERIALS AND METHODS:   Varenicline was prescribed to smokers after brief, standardized, individual counseling from June 2007 to January 2009...
October 2010: Clinical Respiratory Journal
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