Snyder G L, Zigmond M J
Department of Behavioral Neuroscience, University of Pittsburgh, PA 15260.
Brain Res. 1990 Feb 5;508(2):181-7. doi: 10.1016/0006-8993(90)90394-q.
We have examined the effects of L-dihydroxyphenylalanine (L-DOPA) on endogenous dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) efflux from superfused striatal slices prepared from adult male rats. Superfusion with L-DOPA (10 microM) caused a modest elevation in the tissue levels of DA and greatly increased the basal efflux and stimulation-evoked overflow of DA. Stimulation of slices under Ca2(+)-free conditions abolished DA overflow occurring in the absence of L-DOPA, but reduced DA overflow in the presence of L-DOPA by only 56%. Ca2(+)-independent DA release was not reduced by nomifensine. Destruction of DA terminals by pretreatment with 6-hydroxydopamine did not alter the capacity of L-DOPA to elevate tissue DA content. However, it attenuated the impact of L-DOPA on DA efflux, although this effect was somewhat smaller than was the apparent loss of DA terminals. These results suggest the following conclusions: (1) L-DOPA increases both the spontaneous and depolarization-induced release of DA; (2) some of the DA formed from L-DOPA can be released in response to depolarization by a process that does not involve either Ca2(+)-dependent exocytosis or reverse transport; and (3) most but not all of the DA efflux occurring in the presence of L-DOPA represents DA released from DA terminals. Furthermore, the observations suggest that the loss of DA terminals due to the progression of Parkinson's disease may be importantly involved in the gradual loss of clinical efficacy of the drug during chronic treatment.
我们研究了L-二羟基苯丙氨酸（L-DOPA）对成年雄性大鼠制备的超融合纹状体切片中内源性多巴胺（DA）和二羟基苯乙酸（DOPAC）流出的影响。用L-DOPA（10微摩尔）进行超融合导致DA的组织水平适度升高，并大大增加了DA的基础流出和刺激诱发的溢出。在无钙条件下刺激切片消除了在无L-DOPA时发生的DA溢出，但在有L-DOPA时仅将DA溢出减少了56%。诺米芬辛未降低不依赖钙的DA释放。用6-羟基多巴胺预处理破坏DA终末并未改变L-DOPA升高组织DA含量的能力。然而，它减弱了L-DOPA对DA流出的影响，尽管这种作用略小于DA终末明显丧失的程度。这些结果提示以下结论：（1）L-DOPA增加DA的自发释放和去极化诱导的释放；（2）由L-DOPA形成的一些DA可通过不涉及依赖钙的胞吐作用或逆向转运的过程响应去极化而释放；（3）在有L-DOPA存在时发生的大部分但不是所有的DA流出代表从DA终末释放的DA。此外，这些观察结果提示，帕金森病进展导致的DA终末丧失可能在慢性治疗期间药物临床疗效的逐渐丧失中起重要作用。
