纹状体内输注纳摩尔浓度的犬尿烯酸(KYNA),星形胶质细胞衍生的神经抑制色氨酸代谢物,降低大鼠纹状体的基础细胞外多巴胺(DA)水平。这种作用是通过抑制α7烟碱乙酰胆碱受体(α7nAChRs)对谷氨酸能传入而引起的。本研究旨在在清醒动物中使用纹状体微透析进一步研究KYNA和DA之间的这种功能联系。在老鼠身上,KYNA的增加,由KYNA本身(100nM)或KYNA的生物前体L-犬尿氨酸(2μM)的纹状体内输注引起,与DA的大幅减少有关。KYNA与α7nAChR激动剂加兰他敏(5μM)共输注,但不与NMDA受体激动剂D-丝氨酸(100nM),阻止了这种影响。此外,KYNA还降低了NMDA病变纹状体中的DA水平。相反,当KYNA形成受损时,细胞外DA水平增强,通过用氟柠檬酸盐或通过氨基氧乙酸(AOAA;5mM)灌注星形胶质细胞中毒,KYNA合成的非特异性抑制剂。值得注意的是,AOAA的这种作用通过与100nMKYNA的共灌注而被阻止。在具有犬尿氨酸转氨酶II靶向缺失的21日龄小鼠的纹状体中,细胞外KYNA水平降低67+/-6%,而细胞外DA水平同时增加170+/-14%。一起来看,一张图片出现了KYNA星形细胞产量的波动,可能通过体积传输,反向调节多巴胺能张力。这种新发现的机制可能会在生理和病理条件下深刻影响DA功能。
Intrastriatal infusion of nanomolar concentrations of kynurenic acid (KYNA), an astrocyte-derived neuroinhibitory tryptophan metabolite, reduces basal extracellular dopamine (DA) levels in the rat striatum. This effect is initiated by the inhibition of alpha7 nicotinic acetylcholine receptors (alpha7nAChRs) on glutamatergic afferents. The present study was designed to further investigate this functional link between KYNA and DA using striatal microdialysis in awake animals. In rats, increases in KYNA, caused by intrastriatal infusions of KYNA itself (100 nM) or of KYNA\'s bioprecursor L-kynurenine (2 microM), were associated with substantial reductions in DA. Co-infusion of KYNA with the alpha7nAChR agonist galantamine (5 microM), but not with the NMDA receptor agonist D-serine (100 nM), prevented this effect. Moreover, KYNA also reduced DA levels in the NMDA-lesioned striatum. Conversely, extracellular DA levels were enhanced when KYNA formation was compromised, either by astrocyte poisoning with fluorocitrate or by perfusion with aminooxyacetic acid (AOAA; 5 mM), a non-specific inhibitor of KYNA synthesis. Notably, this effect of AOAA was prevented by co-perfusion with 100 nM KYNA. In the striatum of 21 day-old mice with a targeted deletion of kynurenine aminotransferase II, extracellular KYNA levels were reduced by 67 +/- 6%, while extracellular DA levels were simultaneously increased by 170 +/- 14%. Taken together, a picture emerges where fluctuations in the astrocytic production of KYNA, possibly through volume transmission, inversely regulate dopaminergic tone. This newly uncovered mechanism may profoundly influence DA function under physiological and pathological conditions.