Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum.
Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum.
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DOI：
10.1007/s12640-014-9459-y
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发表时间：
2014-08
影响因子：
3.7
通讯作者：
Garris PA
中科院分区：
文献类型：
--
作者：
Robinson JD;Howard CD;Pastuzyn ED;Byers DL;Keefe KA;Garris PA
阶段性多巴胺（DA）信号与强化学习有关，在此过程中，多巴胺神经元的突发放电会在被称为DA瞬态的终端场中产生短暂的细胞外DA升高。在甲基苯丙胺（methamphetamine，简称冰毒）诱导的神经毒性中，相性DA信号中断可能与DA消耗和认知行为障碍有关。在这里，我们通过评估甲基安非他明预处理对氯氯pride（一种D2 DA受体拮抗剂）和诺非芬辛（一种多巴胺转运体（DAT）抑制剂）混合药物引起的DA瞬态的影响，进一步研究了这种破坏。这种方法的一个优点是，药理学激活提供了大量的、高质量的数据集，这些数据集是由DA神经元的内源性突发放电引起的，用于分析区域差异和神经毒性。采用快速扫描循环伏安法对麻醉大鼠背内侧纹状体（DM）和背外侧纹状体（DL）的药理学诱发的DA瞬态进行了测量。电诱发的DA水平也被记录下来，以量化DA的释放和摄取，并通过放射自显影来确定DAT的结合，以指示DA去神经支配。尽管通过电诱发的DA信号对两个亚区DA释放和摄取进行了相似的药物前和药物后评估，但在完整动物中，与DL纹状体相比，药物诱发的DA瞬态在DM中表现出更大的振幅和频率，持续时间更短。甲基苯丙胺预处理降低了瞬时活性。甲基安非他明预处理对纹状体亚区瞬态的最显著影响是振幅降低，这反映了DAT结合的减少，并伴有DA释放的减少。总的来说，这些结果确定了DA瞬态活性在纹状体内的显著差异，这些差异似乎独立于DA释放和摄取的突触前机制，并进一步支持了甲基苯丙胺诱导的神经毒性大鼠中DA释放减少所介导的阶段性DA信号中断。
Phasic dopamine (DA) signaling, during which burst firing by dopamine neurons generates short-lived elevations in extracellular DA in terminal fields called DA transients, is implicated in reinforcement learning. Disrupted phasic DA signaling is proposed to link DA depletions and cognitive-behavioral impairment in methamphetamine (METH)-induced neurotoxicity. Here we further investigated this disruption by assessing effects of METH pretreatment on DA transients elicited by a drug cocktail of raclopride, a D2 DA receptor antagonist, and nomifensine, an inhibitor of the dopamine transporter (DAT). One advantage of this approach is that pharmacological activation provides a large, high-quality data set of transients elicited by endogenous burst firing of DA neurons for analysis of regional differences and neurotoxicity. These pharmacologically evoked DA transients were measured in the dorsomedial (DM) and dorsolateral (DL) striatum of urethane-anesthetized rats by fast-scan cyclic voltammetry. Electrically evoked DA levels were also recorded to quantify DA release and uptake, and DAT binding was determined by autoradiography to index DA denervation. Pharmacologically evoked DA transients in intact animals exhibited a greater amplitude and frequency and shorter duration in the DM compared to the DL striatum, despite similar pre- and post-drug assessments of DA release and uptake in both sub-regions as determined from the electrically evoked DA signals. METH pretreatment reduced transient activity. The most prominent effect of METH pretreatment on transients across striatal sub-region was decreased amplitude, which mirrored decreased DAT binding and was accompanied by decreased DA release. Overall, these results identify marked intrastriatal differences in the activity of DA transients that appear independent of presynaptic mechanisms for DA release and uptake and further support disrupted phasic DA signaling mediated by decreased DA release in rats with METH-induced neurotoxicity.
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