Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine.
Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine.
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DOI：
10.1371/journal.pone.0060763
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Garris PA
中科院分区：
文献类型：
--
作者：
Covey DP;Juliano SA;Garris PA
苯丙胺是一种高度成瘾的药物，具有治疗效果，它对多巴胺神经元调节行为所使用的基本通讯方式产生矛盾的影响。虽然苯丙胺通过耗尽囊泡储存和通过反向运输驱动非胞吐释放来提高紧张性多巴胺信号，但这种精神刺激剂也通过上调囊泡多巴胺释放来激活相性多巴胺信号。我们假设，这些看似不一致的影响是由于苯丙胺耗尽了储备库和增强了可随时释放的储存库。这一新的假设被用体内伏安法和不同持续时间的刺激序列来验证，以访问不同的囊泡存储。我们发现，苯丙胺在背侧纹状体的作用是刺激依赖的。具体地说，苯丙胺上调了短时间列车引起的囊泡性多巴胺释放，短时间列车询问易释放的多巴胺池，但长时间列车引起的枯竭释放，询问储备池。囊泡性多巴胺释放的这些相反行为与紧张性和相性多巴胺反应的同时增加有关。腹侧纹状体的苯丙胺和两个纹状体亚区的可卡因的结果支持囊泡耗竭和紧张性信号之间的联系，这些结果仅显示囊泡释放和时相信号的增加。我们认为，苯丙胺以不同的多巴胺存储为靶点，调和了强直和相变的多巴胺信号的矛盾激活。总体而言，这些结果进一步突出了苯丙胺独特的和不同地区的细胞机制，并可能对其成瘾和治疗特性产生重要影响。
Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties.
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