Alvarsson Alexandra, Zhang Xiaoqun, Stan Tiberiu L, Schintu Nicoletta, Kadkhodaei Banafsheh, Millan Mark J, Perlmann Thomas, Svenningsson Per
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden,
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden.
J Neurosci. 2015 Oct 14;35(41):14057-69. doi: 10.1523/JNEUROSCI.1312-15.2015.
Parkinson's disease (PD) is a movement disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by l-DOPA relieves symptoms of PD but causes dyskinesia. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in experimental Parkinsonism and l-DOPA responses has been neglected. Here, we report that TAAR1 knock-out (KO) mice show a reduced loss of dopaminergic markers in response to intrastriatal 6-OHDA administration compared with wild-type (WT) littermates. In contrast, the TAAR1 agonist RO5166017 aggravated degeneration induced by intrastriatal 6-OHDA in WT mice. Subchronic l-DOPA treatment of TAAR1 KO mice unilaterally lesioned with 6-OHDA in the medial forebrain bundle resulted in more pronounced rotational behavior and dyskinesia than in their WT counterparts. The enhanced behavioral sensitization to l-DOPA in TAAR1 KO mice was paralleled by increased phosphorylation of striatal GluA1 subunits of AMPA receptors. Conversely, RO5166017 counteracted both l-DOPA-induced rotation and dyskinesia as well as AMPA receptor phosphorylation. Underpinning a role for TAAR1 receptors in modulating glutamate neurotransmission, intrastriatal application of RO5166017 prevented the increase of evoked corticostriatal glutamate release provoked by dopamine deficiency after 6-OHDA-lesions or conditional KO of Nurr1. Finally, inhibition of corticostriatal glutamate release by TAAR1 showed mechanistic similarities to that effected by activation of dopamine D2 receptors. These data unveil a role for TAAR1 in modulating the degeneration of dopaminergic neurons, the behavioral response to l-DOPA, and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting their relevance to the pathophysiology and, potentially, management of PD.
Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by l-DOPA relieves symptoms of PD but causes severe side effects. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in PD and l-DOPA responses has been neglected. Here, we report that TAAR1 potentiates the degeneration of dopaminergic neurons and attenuates the behavioral response to l-DOPA and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting the relevance of TAAR1 to the pathophysiology and, potentially, management of PD.
帕金森病（PD）是一种运动障碍性疾病，其特征是黑质纹状体多巴胺能神经元进行性丧失。左旋多巴（l-DOPA）恢复多巴胺传递可缓解PD症状，但会导致运动障碍。痕量胺相关受体1（TAAR1）调节多巴胺能传递，但其在实验性帕金森病和l-DOPA反应中的作用一直被忽视。在此，我们报告，与野生型（WT）同窝小鼠相比，TAAR1基因敲除（KO）小鼠在纹状体内注射6-羟基多巴胺（6-OHDA）后，多巴胺能标志物的损失减少。相反，TAAR1激动剂RO5166017加重了WT小鼠纹状体内6-OHDA诱导的变性。对内侧前脑束单侧注射6-OHDA损伤的TAAR1 KO小鼠进行亚慢性l-DOPA治疗，其旋转行为和运动障碍比WT小鼠更明显。TAAR1 KO小鼠对l-DOPA行为敏感性增强的同时，纹状体α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的GluA1亚基磷酸化增加。相反，RO5166017可抵消l-DOPA诱导的旋转和运动障碍以及AMPA受体磷酸化。为了证明TAAR1受体在调节谷氨酸能神经传递中的作用，纹状体内应用RO5166017可防止6-OHDA损伤或Nurr1条件性敲除后多巴胺缺乏引起的诱发皮质纹状体谷氨酸释放增加。最后，TAAR1对皮质纹状体谷氨酸释放的抑制作用与多巴胺D2受体激活的作用在机制上具有相似性。这些数据揭示了TAAR1在调节多巴胺能神经元变性、对l-DOPA的行为反应以及纹状体突触前和突触后谷氨酸能神经传递中的作用，支持了它们与PD病理生理学以及潜在治疗的相关性。
帕金森病（PD）的特征是黑质纹状体多巴胺能神经元进行性丧失。左旋多巴（l-DOPA）恢复多巴胺传递可缓解PD症状，但会引起严重的副作用。痕量胺相关受体1（TAAR1）调节多巴胺能传递，但其在PD和l-DOPA反应中的作用一直被忽视。在此，我们报告TAAR1增强多巴胺能神经元的变性，并减弱对l-DOPA的行为反应以及纹状体突触前和突触后谷氨酸能神经传递，支持TAAR1与PD病理生理学以及潜在治疗的相关性。
