Interaction Between the Trace Amine-Associated Receptor 1 and the Dopamine D(2) Receptor Controls Cocaine's Neurochemical Actions.
Interaction Between the Trace Amine-Associated Receptor 1 and the Dopamine D(2) Receptor Controls Cocaine's Neurochemical Actions.
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DOI：
10.1038/s41598-017-14472-z
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发表时间：
2017-10-24
影响因子：
4.6
通讯作者：
Canales JJ
中科院分区：
文献类型：
--
作者：
Asif-Malik A;Hoener MC;Canales JJ
最近的证据表明，微量胺相关受体1 （TAAR1）在调节多巴胺（DA）的传递和可卡因的行为中起着关键作用。然而，TAAR1激活介导这些作用的潜在机制尚未阐明。在这里，我们使用快速扫描循环伏安法来测量DA动力学并探索这种机制。首先，我们发现完整的TAAR1激动剂RO5256390在伏隔核切片中剂量依赖性地阻断了可卡因诱导的DA清除抑制。其次，阈下抑制PKA或PKC磷酸化并不能阻止TAAR1对可卡因效应的抑制，而在TAAR1完全激活的情况下，低剂量的DA D2受体拮抗剂L-741,626恢复了可卡因产生DA摄取变化的能力，这表明TAAR1对可卡因效应的调节需要同时激活DA D2受体。可以预见的是，D2/TAAR1异源二聚体激活导致糖原合成酶激酶3 （GSK-3）的抑制，完全再现了TAAR1激活对可卡因诱导的DA传递变化的抑制作用。总的来说，目前的观察结果表明，TAAR1调节可卡因效应的能力与D2自受体和聚集在GSK-3上的相关下游分子靶点的合作相互作用有关，并提出了一种破坏可卡因神经化学作用的新机制。
Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and cocaine’s actions. However, the underlying mechanisms through which TAAR1 activation mediates these effects have not yet been elucidated. Here, we used fast-scan cyclic voltammetry to measure DA dynamics and explore such mechanisms. We show, first, that the full TAAR1 agonist, RO5256390, dose-dependently blocked cocaine-induced inhibition of DA clearance in slices of the nucleus accumbens. Second, subthreshold inhibition of PKA or PKC phosphorylation did not prevent TAAR1 suppression of cocaine effects whereas subeffective doses of the DA D2 receptor antagonist, L-741,626, rescued cocaine’s ability to produce changes in DA uptake in the presence of full TAAR1 activation, thus indicating that TAAR1 modulation of cocaine effects requires simultaneous DA D2 receptor activation. Predictably, inhibition of glycogen synthase kinase-3 (GSK-3), which results from activation of D2/TAAR1 heterodimers, fully reproduced the inhibitory effects of TAAR1 activation on cocaine-induced changes in DA transmission. Collectively, the present observations reveal that the ability of TAAR1 to regulate cocaine effects is linked to cooperative interactions with D2 autoreceptors and associated downstream molecular targets converging on GSK-3 and suggest a new mechanism to disrupt cocaine neurochemical actions.
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影响因子：
5.2
作者：
Lee AM;Messing RO
通讯作者：
Messing RO
影响因子：
3
作者：
Cao, Jiangbei;Tan, Hongying;Mi, Weidong;Zuo, Zhiyi
通讯作者：
Zuo, Zhiyi
安非他明、3,4-亚甲二氧基甲基苯丙胺、麦角酸二乙酰胺和儿茶酚胺神经递质的代谢物是大鼠微量胺受体的激动剂
影响因子：
3.6
作者：
Bunzow, JR;Sonders, MS;Grandy, DK
通讯作者：
Grandy, DK
影响因子：
4.8
作者：
Loder, MK;Melikian, HE
通讯作者：
Melikian, HE
影响因子：
10.6
作者：
McCutcheon, James E.;White, Francis J.;Marinelli, Michela
通讯作者：
Marinelli, Michela