Voltammetric analysis of striatal dopamine dynamics

描述(申请人提供)：多巴胺(DA)系统与精神分裂症和注意力缺陷多动障碍(ADHD)等神经精神障碍密切相关。抗精神病药物通常是与内源性DA竞争的类似D2的DA受体阻滞剂，而ADHD通常使用抑制DA转运体(DAT)的哌醋甲酯治疗。在脑区中，纹状体的DA神经分布最密集，DA受体和DAT的表达最强，表明纹状体DA信号在脑功能中的重要性。纹状体基础细胞外DA浓度([DA]ext)通常估计为静止的，仅5-10 nM，在外界刺激下可能会增加数倍。其他递质，如谷氨酸，可以自发地从突触小泡中释放(量子释放)，从而产生峰值高达1 mm的动态递质谱。我们有证据支持这一假设，即在纹状体DA可以以类似的量子方式自发释放，从而产生具有高[DA]EXT峰的动态DA谱。我们的初步数据还表明，这些自发的水泡性DA事件被临床上相关的低浓度抗精神病药物和哌醋甲酯增强。 选择性5-羟色胺再摄取抑制剂(SSRI)是治疗抑郁症的有效药物。我们的数据支持以下假设：在SSRI型抗抑郁药物治疗过程中，5-羟色胺(5-HT)可能被DA转运体(DAT)重新摄取并积聚在纹状体的DA终末，纹状体是参与奖赏/动机的主要DA投射区域。更重要的是，这种异位储存的5-羟色胺可能与DA共同释放，从而在纹状体诱导空间和时间同步的DA和5-羟色胺共同信号。 根据这些工作假设，我们的目标是在碳纤维微电极上使用快速循环伏安法来研究纹状体DA的动力学、它的调制以及它与5-羟色胺系统的相互作用。这一结果将提供关于纹状体[DA]ext的动态性质以及神经精神疾病治疗药物对其调节的重要新信息。

DESCRIPTION (provided by applicant): The dopamine (DA) system is intimately involved in neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder (ADHD). Antipsychotics are often D2-like DA receptor blockers that compete with endogenous DA while ADHD is commonly treated with methylphenidate that inhibits DA transporter (DAT). Among the brain areas, the striatum has the densest DA innervation and the heaviest expression of DA receptors and DAT, indicating the importance of striatal DA signaling in brain functions. The striatal basal extracellular DA concentration ([DA]ext) is often estimated to he static and only 5-10 nM, which may increase by several fold upon external stimulation. Other transmitters, such as glutamate, can be spontaneously released from synaptic vesicles (quantal release), resulting in dynamic transmitter profiles with peaks up to I mM. We have evidence supporting the hypothesis that in the striatum DA can he spontaneously released in a similar quantal fashion, giving rise to a dynamic DA profile with high [DA]ext spikes. Our preliminary data also suggest that these spontaneous vesicular DA events are enhanced by antipsychotics and methylphenidate at clinically relevant low concentrations. Selective serotonin reuptake inhibitors (SSRIs) are an effective treatment for depression. Our data support the following hypothesis: during SSRI type antidepressant treatment, serotonin (5-HT) may be reuptaken by DA transporter (DAT) and accumulate in DA terminals in the striatum, a major DA projection area participating in reward/motivation. More importantly, this ectopically stored 5-HT may be co-released with DA, thus inducing a spatially and temporally synchronized DA and 5-HT co-signaling in the striatum. Following these working hypotheses, our goals are to use fast cyclic voltammetry at carbon fiber microelectrodes to investigate the striatal DA dynamics, its modulation and its interaction with the 5-HT system. The results will provide important new information about the dynamic nature of the striatal [DA]ext and its regulation by therapeutic agents of neuropsychiatric disorders.