Prolonged nicotine exposure down-regulates presynaptic NMDA receptors in dopaminergic terminals of the rat nucleus accumbens

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• 作者：Alessia Salamone^a ; ¹ ; Stefania Zappettini^a ; ¹ ; Massimo Grilli^a ; Guendalina Olivero^a ; Paula Agostinho^c ; ^e ; Angelo R. Tomé ; ^b ; ^c ; Jiayang Chen^a ; Anna Pittaluga^a ; ^d ; Rodrigo A. Cunha^c ; ^e ; Mario Marchi^a ; ^d ; ^{mario.marchi@tin.it" class="auth_mail} ; ^{marchi@pharmatox.unige.it" class="auth_mail}
• 关键词：Nicotinic receptors ; NMDA receptors ; Calcium levels ; Neurotransmitter release ; Isolated nerve endings ; Nucleus accumbens
• 刊名：Neuropharmacology
• 出版年：April, 2014
• 年：2014
• 卷：79
• 期：Complete
• 页码：488-497
• 全文大小：1494 K

文摘

The presynaptic control of dopamine release in the nucleus accumbens (NAc) by glutamate and acetylcholine has a profound impact on reward signaling. Here we provide immunocytochemical and neurochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartic acid (NMDA) receptors in dopaminergic terminals of the NAc. Most NAc dopaminergic terminals possessed the nAChR 伪4 subunit and the pre-exposure of synaptosomes to nicotine (30聽渭M) or to the 伪4尾2-containing nAChR agonist 5IA85380 (10聽nM) selectively inhibited the NMDA (100聽渭M)-evoked, but not the 4-aminopyridine (10聽渭M)-evoked, [³H] dopamine outflow; this inhibition was blunted by mecamylamine (10聽渭M). Nicotine and 5IA85380 pretreatment also inhibited the NMDA (100聽渭M)-evoked increase of calcium levels in single nerve terminals, an effect prevented by dihydro-尾-erythroidine (1聽渭M). This supports a functional interaction between 伪4尾2-containing nAChR and NMDA receptors within the same terminal, as supported by the immunocytochemical co-localization of 伪4 and GluN1 subunits in individual NAc dopaminergic terminals. The NMDA-evoked [³H]dopamine outflow was blocked by MK801 (1聽渭M) and inhibited by the selective GluN2B-selective antagonists ifenprodil (1聽渭M) and RO 25-6981 (1聽渭M), but not by the GluN2A-preferring antagonists CPP-19755 (1聽渭M) and ZnCl₂ (1聽nM). Notably, nicotine pretreatment significantly decreased the density of biotin-tagged GluN2B proteins in NAc synaptosomes. These results show that nAChRs dynamically and negatively regulate NMDA receptors in NAc dopaminergic terminals through the internalization of GluN2B receptors.