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.