Schülke Jan-Philip, Brandon Nicholas J
Evotec, Am Klopferspitz 19a, 82152, Martinsried, Germany.
AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, Waltham, MA, 02451, USA.
Adv Neurobiol. 2017;17:15-43. doi: 10.1007/978-3-319-58811-7_2.
The basal ganglia are a forebrain network of interconnected nuclei that are involved in action selection, reward circuits and coordinating movement. PDE10A inhibition has been proposed as a novel way to modulate basal ganglia circuitry and to ameliorate symptoms in Huntington's disease, Parkinson's disease and Schizophrenia. However, despite encouraging results from pre-clinical models, PDE10A inhibitors failed to show efficacy as an antipsychotic in several clinical trials. PDE10A is expressed in the medium spiny neurons of the striatum and works to limit cyclic nucleotide signaling in response to modulatory neurotransmitters like dopamine. In this chapter, we will review the current literature on PDE10A and discuss how inhibition of PDE10A will result in alterations of the basal ganglia circuitry at the biochemical, physiological and behavioral level.
基底神经节是前脑相互连接的核团网络，参与动作选择、奖赏回路和运动协调。抑制磷酸二酯酶10A（PDE10A）已被提议作为调节基底神经节神经回路及改善亨廷顿病、帕金森病和精神分裂症症状的一种新方法。然而，尽管临床前模型研究结果令人鼓舞，但PDE10A抑制剂在多项临床试验中未能显示出抗精神病疗效。PDE10A在纹状体的中等多棘神经元中表达，作用是限制对多巴胺等调节性神经递质产生反应的环核苷酸信号传导。在本章中，我们将综述目前关于PDE10A的文献，并讨论抑制PDE10A如何在生化、生理和行为水平上导致基底神经节神经回路的改变。
