title: Nicotinic receptors in non-human primates: Analysis of genetic and functional conservation with humans.
abstract: Nicotinic acetylcholine receptors (nAChRs) are highly conserved between humans and non-human primates. Conservation exists at the level of genomic structure, protein structure and epigenetics. Overall homology of nAChRs at the protein level is 98% in macaques versus 89% in mice, which is highly relevant for evaluating subtype-specific ligands that have different affinities in humans versus rodents. In addition to conservation at the protein level, there is high conservation of genomic structure in terms of intron and exon size and placement of CpG sites that play a key role in epigenetic regulation. Analysis of single nucleotide polymorphisms (SNPs) shows that while the majority of SNPs are not conserved between humans and macaques, some functional polymorphisms are. Most significantly, cynomolgus monkeys express a similar α5 nAChR Asp398Asn polymorphism to the human α5 Asp398Asn polymorphism that has been linked to greater nicotine addiction and smoking related disease. Monkeys can be trained to readily self-administer nicotine, and in an initial study we have demonstrated that cynomolgus monkeys bearing the α5 D398N polymorphism show a reduced behavioral sensitivity to oral nicotine and tend to consume it in a different pattern when compared to wild-type monkeys. Thus the combination of highly homologous nAChR, higher cortical functions and capacity for complex training makes non-human primates a unique model to study in vivo functions of nicotinic receptors. In particular, primate studies on nicotine addiction and evaluation of therapies to prevent or overcome nicotine addiction are likely to be highly predictive of treatment outcomes in humans. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health &, Science University, Beaverton, OR 97006, USA. Electronic address: shorey@ohsu.edu.
authors: Lyndsey E
authors: LE
authors: Shorey-Kendrick
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health &, Science University, Beaverton, OR 97006, USA. Electronic address: fordma@ohsu.edu.
authors: Matthew M
authors: MM
authors: Ford
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health &, Science University, Beaverton, OR 97006, USA. Electronic address: allendai@ohsu.edu.
authors: Daicia C
authors: DC
authors: Allen
authors: Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: kouriato@mail.med.upenn.edu.
authors: Alexander
authors: A
authors: Kuryatov
authors: Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jslkk@mail.med.upenn.edu.
authors: Jon
authors: J
authors: Lindstrom
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health &, Science University, Beaverton, OR 97006, USA. Electronic address: wilhella@ohsu.edu.
authors: Larry
authors: L
authors: Wilhelm
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health &, Science University, Beaverton, OR 97006, USA. Electronic address: grantka@ohsu.edu.
authors: Kathleen A
authors: KA
authors: Grant
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health &, Science University, Beaverton, OR 97006, USA. Electronic address: spindele@ohsu.edu.
authors: Eliot R
authors: ER
authors: Spindel
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018899:CpG Islands; D006801:Humans / Q000235:genetics; D008253:Macaca mulatta / Q000235:genetics; D023421:Models, Animal; D009538:Nicotine / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012646:Self Administration; D013045:Species Specificity; D040681:Structural Homology, Protein; D014029:Tobacco Use Disorder / Q000235:genetics
chemical_list: D018722:Nicotinic Agonists; D021122:Protein Subunits; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D009538:Nicotine
keywords: Cynomolgus; Macaque; Nicotine; Nicotinic receptor; Non-human primate; Rhesus