Section of Pharmacology and Toxicology, Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Neuroscience. 2010 May 5;167(2):482-9. doi: 10.1016/j.neuroscience.2010.01.058. Epub 2010 Feb 9.
In this study we investigate on the effect of amyloid-beta1-40 (A beta 1-40) on the oxotremorine (OXO)-induced release of [(3)H] dopamine (DA), [(3)H]GABA and [(3)H]acetylcholine (ACh) from synaptosomes in the rat nucleus accumbens (NAc). OXO in presence of himbacine (HIMBA) was able to increase the basal release of [(3)H]GABA. The OXO-elicited [(3)H]GABA overflow was significantly antagonized by atropine (A; 94%), by the M3 antagonists DAU5884 (96%) and 4-DAMP (70%), and by A beta 1-40 (65%). Exposure of NAc synaptosomes to OXO produced a dose-dependent increase of [(3)H]DA overflow which was antagonized by A, partially inhibited by A beta 1-40 (100 nM) but unaffected by DAU5884 and 4-DAMP. The K(+)-evoked [(3)H]ACh overflow was inhibited by OXO. This effect was counteracted by the M2 antagonist AFDX-116 but not by the selective M4 antagonist mamba toxin 3 (MT3). The K(+)-evoked [(3)H]GABA overflow was also inhibited by OXO but conversely, this effect was counteracted by MT3 and not by AFDX-116. A beta 1-40 (100 nM) did not modify the inhibitory effect of OXO both on the K(+)-evoked [(3)H]ACh and [(3)H]GABA overflow. The results show that in the rat NAc, A beta 1-40 selectively inhibits the function of the muscarinic subtypes which stimulate neurotransmitter release and not those which modulate negatively the stimulated release.
在这项研究中，我们研究了淀粉样β肽 1-40（Aβ1-40）对大鼠伏隔核（NAc）突触体中 oxotremorine（OXO）诱导的[（3）H]多巴胺（DA）、[（3）H]GABA 和[（3）H]乙酰胆碱（ACh）释放的影响。在 himbacine（HIMBA）存在的情况下，OXO 能够增加[（3）H]GABA 的基础释放。阿曲汀（A）、M3 拮抗剂 DAU5884（96%）和 4-DAMP（70%）以及 Aβ1-40（65%）显著拮抗 OXO 诱发的[（3）H]GABA 外溢。NAc 突触体暴露于 OXO 会产生剂量依赖性的[（3）H]DA 外溢增加，这种增加被 A 拮抗，部分被 Aβ1-40（100 nM）抑制，但不受 DAU5884 和 4-DAMP 的影响。K+诱发的[（3）H]ACh 外溢被 OXO 抑制。这种效应被 M2 拮抗剂 AFDX-116 拮抗，但不是由选择性 M4 拮抗剂 mamba 毒素 3（MT3）拮抗。K+诱发的[（3）H]GABA 外溢也被 OXO 抑制，但相反，这种效应被 MT3 拮抗，而不是被 AFDX-116 拮抗。100 nM 的 Aβ1-40 不改变 OXO 对 K+诱发的[（3）H]ACh 和[（3）H]GABA 外溢的抑制作用。结果表明，在大鼠 NAc 中，Aβ1-40 选择性抑制刺激神经递质释放的毒蕈碱亚型的功能，而不抑制负调节刺激释放的毒蕈碱亚型的功能。
