Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain

Picciotto, Marina R.; Zoli, Michèle; Léna, Clément; Bessis, Alain; Lallemand, Yvan; LeNovère, Nicolas; Vincent, Pierre; Pich, Emilio Merlo; Brûlet, Philippe; Changeux, Jean‐Pierre

doi:10.1038/374065a0

Cited by 604 publications

(538 citation statements)

References 22 publications

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“…a gene dose dependent decrease in binding was seen. The finding that α4 and β2 subunits are required to form the cytisine-sensitive high affinity [ 3 H]-epibatidine binding sites mimic exactly that obtained with [ 3 H]-nicotine [71,72] and clearly demonstrate that α4β2* nAChRs are expressed in the striatum. Deletion of the α5, α6, α7, β3 and β4 subunits did not result in a detectable change in cytisine-sensitive [ 3 H]-epibatidine binding.…”

supporting

confidence: 70%

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Grady

Salminen

Laverty

et al. 2007

Biochemical Pharmacology

232

223

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This review summarizes studies that attempted to determine the subtypes of nicotinic acetylcholine receptors (nAChR) expressed in the dopaminergic nerve terminals in the mouse. A variety of experimental approaches has been necessary to reach current knowledge of these subtypes, including in situ hybridization, agonist and antagonist binding, function measured by neurotransmitter release from synaptosomal preparations, and immunoprecipitation by selective antibodies. Early developments that facilitated this effort include the radioactive labeling of selective binding agents, such as [ 125 I]-α-bungarotoxin and [ 3 H]-nicotine, advances in cloning the subunits, and expression and evaluation of function of combinations of subunits in Xenopus oocytes. The discovery of epibatidine and α-conotoxin MII (α-CtxMII), and the development of nAChR subunit null mutant mice have been invaluable in determining which nAChR subunits are important for expression and function in mice, as well as allowing validation of the specificity of subunit specific antibodies. These approaches have identified five nAChR subtypes of nAChR that are expressed on dopaminergic nerve terminals. Three of these contain the α6 subunit (α4α6β2β3, α6β2β3, α6β2) and bind α-CtxMII with high affinity. One of these three subtypes (α4α6β2β3) also has the highest sensitivity to nicotine of any native nAChR that has been studied, to date. The two subtypes that do not have high affinity for α-CtxMII (α4β2, α4α5β2) are somewhat more numerous than the α6* subtypes, but do bind nicotine with high affinity. Given that our first studies detected readily measured differences in sensitivity to agonists and antagonists among these five nAChR subtypes, it seems likely that subtype selective compounds could be developed that would allow therapeutic manipulation of diverse nAChRs that have been implicated in a number of human conditions. Alterations in nicotinic cholinergic receptor (nAChRs) number or function have been implicated in psychopathologies such as anxiety, attention deficit hyperactivity disorder, depression, schizophrenia (reviewed in [1,2,3]), at least one form of familial epilepsy [4], and Parkinson's and Alzheimer's diseases [5]. It is not particularly surprising that nAChRs might play important roles in modulating several human diseases given that binding sites for nicotinic ligands such as [ 125 I]-α-bungarotoxin [6,7,8], [ 3 H]-nicotine [7,8] Corresponding author: Sharon R Grady e-mail: sharon.grady@colorado.edu phone: 303-492-9677 fax: 303-492-8063 mailing address: Institute for Behavioral Genetics University of Colorado 447UCB Boulder, CO 80309. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered w...

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supporting

confidence: 70%

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Grady

Salminen

Laverty

et al. 2007

Biochemical Pharmacology

232

223

View full text Add to dashboard Cite

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“…Given that α4β2* nAChRs are the predominant high-affinity binding sites for nicotine in the brain [47], and that research using genetic knockout (KO) mice has revealed that mice lacking the β2 nAChR subunit have almost no high-affinity binding for nicotine [129], several studies have investigated whether polymorphisms in CHRNB2 are related to smoking phenotypes. In contrast to research on CHRNA4, evidence for the role of CHRNB2 in smoking phenotypes has been less robust; several studies have found no relation between CHRNB2 polymorphisms and nicotine dependence [45,94,99,154].…”

Section: The β2 Nachr Subunit (Chrnb2)mentioning

confidence: 99%

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Portugal

Gould

2008

Behavioural Brain Research

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Tobacco smoking is a leading preventable cause of death in the United States and produces a major health and economic burden. Although the majority of smokers want to quit, few are successful. These data highlight the need for additional research into the neurobiology of tobacco dependence. Addiction to nicotine, the main psychoactive component of tobacco, is influenced by multiple factors that include individual differences in genetic makeup. Twin studies have demonstrated that genetic factors can influence vulnerability to nicotine addiction, and subsequent research has identified genes that may alter sensitivity to nicotine. In humans, genome-wide and candidate gene association studies have demonstrated that genes encoding nicotinic acetylcholine receptor (nAChR) proteins are associated with multiple smoking phenotypes. Similarly, research in mice has provided evidence that naturally occurring variability in nAChR genes is associated with changes in nicotine sensitivity. Furthermore, the use of genetic knockout mice has allowed researchers to determine the nAChR genes that mediate the effects of nicotine, whereas research with knockin mice has demonstrated that changes to nAChR genes can dramatically alter nicotine sensitivity. This review will examine the genetic factors that alter susceptibility to nicotine addiction, with an emphasis on the genes that encode nAChR proteins.

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“…Similarly, nicotine administration also modifies locomotion, anxiety, memory, nociception, and produces rewarding effects in several animal models (Clarke and Kumar, 1983;Hildebrand et al, 1999;Marubio et al, 1999;Picciotto et al, 1995). Neuroanatomical studies have shown a high density of CB1 receptors in neurons of the cerebellum, basal ganglia, limbic cortices, hippocampus, 3 hypothalamus and different nuclei of the extended amygdala (Tsou et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Role of the cannabinoid system in the effects induced by nicotine on anxiety-like behaviour in mice

2006

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Rationale: Acute behavioural effects and motivational responses induced by nicotine can be modulated by the endocannabinoid system supporting the existence of a physiological interaction between these two systems. Objectives: The present study was designed to examine the possible involvement of the cannabinoid system in the anxiolytic-and anxiogenic-like responses induced by nicotine in mice. Methods:

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Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain

Cited by 604 publications

References 22 publications

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Role of the cannabinoid system in the effects induced by nicotine on anxiety-like behaviour in mice

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