Wu H-Q, Rassoulpour A, Schwarcz R
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA.
J Neural Transm (Vienna). 2007 Jan;114(1):33-41. doi: 10.1007/s00702-006-0562-y. Epub 2006 Aug 24.
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.
向大鼠纹状体内注入纳摩尔浓度的犬尿喹啉酸（KYNA，一种由星形胶质细胞衍生的神经抑制性色氨酸代谢产物），可降低大鼠纹状体内的基础细胞外多巴胺（DA）水平。这种作用是通过抑制谷氨酸能传入神经上的α7烟碱型乙酰胆碱受体（α7nAChRs）引发的。本研究旨在利用清醒动物的纹状体微透析技术进一步探究KYNA与DA之间的这种功能联系。在大鼠中，纹状体内注入KYNA本身（100 nM）或其生物前体L - 犬尿氨酸（2 μM）导致KYNA增加，同时DA大幅降低。将KYNA与α7nAChR激动剂加兰他敏（5 μM）共同注入，但不与NMDA受体激动剂D - 丝氨酸（100 nM）共同注入，可防止这种作用。此外，KYNA还降低了NMDA损伤纹状体内的DA水平。相反，当通过用氟柠檬酸毒害星形胶质细胞或用犬尿氨酸合成的非特异性抑制剂氨氧乙酸（AOAA；5 mM）灌注来损害KYNA形成时，细胞外DA水平会升高。值得注意的是，与100 nM KYNA共同灌注可防止AOAA的这种作用。在靶向缺失犬尿氨酸转氨酶II的21日龄小鼠的纹状体中，细胞外KYNA水平降低了67±6%，而细胞外DA水平同时升高了170±14%。综上所述，出现了这样一种情况：KYNA在星形胶质细胞中的产生波动，可能通过容积传递，反向调节多巴胺能张力。这种新发现的机制可能在生理和病理条件下对DA功能产生深远影响。
