title: Genetic deletion of the adenosine A(2A) receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain.
abstract: Considerable evidence indicates that adenosine A(2A) receptors (A(2A)Rs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A(2A) and nAChRs, we examined if the complete genetic deletion of adenosine A(2A)Rs in mice induces compensatory alterations in the binding of different nAChR subtypes, and whether the long-term effects of nicotine on nAChR regulation are altered in the absence of the A(2A)R gene. Quantitative autoradiography was used to measure cytisine-sensitive [¹²⁵I]epibatidine and [¹²⁵I]α-bungarotoxin binding to α4β2* and α7 nAChRs, respectively, in brain sections of drug-naïve (n = 6) or nicotine treated (n = 5-7), wild-type and adenosine A(2A)R knockout mice. Saline or nicotine (7.8 mg/kg/day; free-base weight) were administered to male CD1 mice via subcutaneous osmotic minipumps for a period of 14 days. Blood plasma levels of nicotine and cotinine were measured at the end of treatment. There were no compensatory developmental alterations in nAChR subtype distribution or density in drug-naïve A(2A)R knockout mice. In nicotine treated wild-type mice, both α4β2* and α7 nAChR binding sites were increased compared with saline treated controls. The genetic ablation of adenosine A(2A)Rs prevented nicotine-induced upregulation of α7 nAChRs, without affecting α4β2* receptor upregulation. This selective effect was observed at plasma levels of nicotine that were within the range reported for smokers (10-50 ng ml⁻¹). Our data highlight the involvement of adenosine A(2A)Rs in the mechanisms of nicotine-induced α7 nAChR upregulation, and identify A(2A)Rs as novel pharmacological targets for modulating the long-term effects of nicotine on α7 receptors.
authors.affiliation: Sleep, Chronobiology & Addiction Group, Department of Biochemistry & Physiology, Faculty of Health and Medical Sciences, Institute of Health & Medical Sciences, University of Surrey, UK. a.metaxas@hotmail.com
authors.forename: Athanasios
authors.initials: A
authors.lastname: Metaxas
authors.forename: Ream
authors.initials: R
authors.lastname: Al-Hasani
authors.forename: Pamela
authors.initials: P
authors.lastname: Farshim
authors.forename: Kristina
authors.initials: K
authors.lastname: Tubby
authors.forename: Amy
authors.initials: A
authors.lastname: Berwick
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Susanna
authors.initials: S
authors.lastname: Hourani
authors.forename: Ian
authors.initials: I
authors.lastname: Kitchen
authors.forename: Alexis
authors.initials: A
authors.lastname: Bailey
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology; D003367:Cotinine / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D021122:Protein Subunits / Q000819:agonists / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D014029:Tobacco Use Disorder / Q000097:blood / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; C579166:Chrna7 protein, mouse; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D021122:Protein Subunits; D011725:Pyridines; D043705:Receptor, Adenosine A2A; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; C027724:iodo-alpha-bungarotoxin; D003367:Cotinine; C082748:epibatidine