Nishi Akinori, Shuto Takahide
a Department of Pharmacology , Kurume University School of Medicine , Kurume, Fukuoka , Japan.
Expert Opin Ther Targets. 2017 Mar;21(3):259-272. doi: 10.1080/14728222.2017.1279149. Epub 2017 Jan 13.
Alterations in dopamine neurotransmission has been implicated in pathophysiology of neuropsychiatric and neurodegenerative disorders, and DARPP-32 plays a pivotal role in dopamine neurotransmission. DARPP-32 likely influences dopamine-mediated behaviors in animal models of neuropsychiatric and neurodegenerative disorders and therapeutic effects of pharmacological treatment. Areas covered: We will review animal studies on the biochemical and behavioral roles of DARPP-32 in drug addiction, schizophrenia and Parkinson's disease. In general, under physiological and pathophysiological conditions, DARPP-32 in D1 receptor expressing (D1R) -medium spiny neurons (MSNs) promotes dopamine/D1 receptor/PKA signaling, whereas DARPP-32 in D2 receptor expressing (D2R)-MSNs counteracts dopamine/D2 receptor signaling. However, the function of DARPP-32 is differentially regulated in acute and chronic phases of drug addiction; DARPP-32 enhances D1 receptor/PKA signaling in the acute phase, whereas DARPP-32 suppresses D1 receptor/PKA signaling in the chronic phase through homeostatic mechanisms. Therefore, DARPP-32 plays a bidirectional role in dopamine neurotransmission, depending on the cell type and experimental conditions, and is involved in dopamine-related behavioral abnormalities. Expert opinion: DARPP-32 differentially regulates dopamine signaling in D1R- and D2R-MSNs, and a shift of balance between D1R- and D2R-MSN function is associated with behavioral abnormalities. An adjustment of this imbalance is achieved by therapeutic approaches targeting DARPP-32-related signaling molecules.
多巴胺神经传递的改变与神经精神疾病和神经退行性疾病的病理生理学有关，而DARPP - 32在多巴胺神经传递中起关键作用。DARPP - 32可能影响神经精神疾病和神经退行性疾病动物模型中多巴胺介导的行为以及药物治疗的效果。涵盖领域：我们将综述关于DARPP - 32在药物成瘾、精神分裂症和帕金森病中的生化及行为作用的动物研究。一般来说，在生理和病理生理条件下，表达D1受体（D1R）的中型多棘神经元（MSN）中的DARPP - 32促进多巴胺/D1受体/PKA信号传导，而表达D2受体（D2R）的MSN中的DARPP - 32则抵消多巴胺/D2受体信号传导。然而，DARPP - 32的功能在药物成瘾的急性期和慢性期受到不同调节；DARPP - 32在急性期增强D1受体/PKA信号传导，而在慢性期通过稳态机制抑制D1受体/PKA信号传导。因此，DARPP - 32在多巴胺神经传递中发挥双向作用，这取决于细胞类型和实验条件，并参与与多巴胺相关的行为异常。专家观点：DARPP - 32在D1R -和D2R - MSN中对多巴胺信号进行不同调节，D1R -和D2R - MSN功能之间平衡的改变与行为异常有关。针对与DARPP - 32相关的信号分子的治疗方法可实现这种失衡的调整。
