Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons.
Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons.
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DOI：
10.1016/j.neuropharm.2017.06.016
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发表时间：
2017-09-01
影响因子：
4.7
通讯作者：
Beckstead MJ
中科院分区：
文献类型：
--
作者：
Avelar AJ;Cao J;Newman AH;Beckstead MJ
滥用像可卡因这样的精神兴奋剂会抑制多巴胺（DA）通过多巴胺转运体（DAT）的再摄取，这是一个重大的公共卫生问题，然而fda批准的药物疗法尚未开发出来。最近，一类被称为“非典型DAT抑制剂”的配体由于其在增加细胞外多巴胺（DA）水平方面的有效性而没有显示出明显的滥用危险而引起了人们的注意。这些化合物不仅有望作为治疗兴奋剂使用障碍的药物，而且还可以作为实验工具来提高我们对DAT功能的理解。本研究采用膜片钳电生理学方法，探讨两种非典型DAT抑制剂（R-modafinil和JHW 007）对黑质和腹侧被盖区单个DA神经元的生理影响。尽管它们都是缺乏可卡因样行为特征的DAT抑制剂，但这些化合物却表现出令人惊讶的不同细胞效应。与可卡因类似，r-莫达非尼以D2受体依赖的方式减缓DA神经元放电，并迅速增强D2受体介导的中脑电流的振幅和持续时间。相比之下，JHW 007对放电、缓慢的DAT阻断和D2受体介导的电流的意想不到的抑制作用几乎没有影响，这可能是由于D2受体的直接拮抗作用。此外，JHW 007预处理减弱了可卡因的细胞效应，这表明研究类似的DAT抑制剂作为潜在的治疗剂可能是有价值的。对这些和其他非典型DAT抑制剂的进一步探索可能会揭示化合物的重要细胞效应，这些化合物将有潜力作为治疗可卡因使用障碍的药物疗法。
Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed “atypical DAT inhibitors” has gained attention due to their range of effectiveness in increasing extracellular dopamine (DA) levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders.
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DOI：
10.1111/ejn.13046
发表时间：
2015-10
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Apuschkin M;Stilling S;Rahbek-Clemmensen T;Sørensen G;Fortin G;Herborg Hansen F;Eriksen J;Trudeau LE;Egerod K;Gether U;Rickhag M
通讯作者：
Rickhag M
影响因子：
2.5
作者：
Branch, Sarah Y.;Beckstead, Michael J.
通讯作者：
Beckstead, Michael J.
影响因子：
10.6
作者：
Kohut SJ;Hiranita T;Hong SK;Ebbs AL;Tronci V;Green J;Garcés-Ramírez L;Chun LE;Mereu M;Newman AH;Katz JL;Tanda G
通讯作者：
Tanda G
DOI：
10.1016/0169-328x(94)90029-9
发表时间：
1994-03-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
BLANCHARD, V;RAISMANVOZARI, R;AGID, Y
通讯作者：
AGID, Y
影响因子：
7.3
作者：
Agoston, GE;Wu, JH;Newman, AH
通讯作者：
Newman, AH