Genetic deletion of the adenosine A2Areceptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain

Abstract

Considerable evidence indicates that adenosine A2Areceptors (A2ARs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A2Aand nAChRs, we examined if the complete genetic deletion of adenosine A2ARs 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 A2AR 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 A2AR 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 A2AR 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 A2ARs 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 A2ARs in the mechanisms of nicotine-induced α7 nAChR upregulation, and identify A2ARs as novel pharmacological targets for modulating the long-term effects of nicotine on α7 receptors. © 2013 Elsevier Ltd. All rights reserved.