The corticostriatal and hippocampal circuits contribute to the neurobiological underpinnings of several neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease and schizophrenia. Based on biological function, these circuits can be clustered into motor circuits, associative/cognitive circuits and limbic circuits. Together, dysfunctions in these circuits produce the wide range of symptoms observed in related neuropsychiatric disorders. Intracellular signaling in these circuits is largely mediated through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway with an additional role for the cyclic guanosine monophosphate (cGMP)/ protein kinase G (PKG) pathway, both of which can be regulated by phosphodiesterase inhibitors (PDE inhibitors). Through their effects on cAMP response element-binding protein (CREB) and Dopamine- and cAMP-Regulated PhosphoProtein MR 32 kDa (DARPP-32), cyclic nucleotide pathways are involved in synaptic transmission, neuron excitability, neuroplasticity and neuroprotection. In this clinical review, we provide an overview of the current clinical status, discuss the general mechanism of action of PDE inhibitors in relation to the corticostriatal and hippocampal circuits and consider several translational challenges.

皮质上皮和海马回路促成多种神经精神疾病的神经生物学基础，包括阿尔茨海默氏病，帕金森氏病和精神分裂症。基于生物学功能，这些电路可以分为电机电路，联想/认知电路和边缘电路。在一起，这些回路的功能障碍会产生在相关的神经精神疾病中观察到的各种症状。这些回路中的细胞内信号传导主要通过单磷酸环腺苷（cAMP）/蛋白激酶A（PKA）途径介导，而单磷酸环鸟苷（cGMP）/蛋白激酶G（PKG）途径则具有额外的作用。由磷酸二酯酶抑制剂（PDE抑制剂）调节。通过其对cAMP反应元件结合蛋白（CREB）以及多巴胺和cAMP调控的磷酸蛋白MR 32 kDa（DARPP-32）的影响，环状核苷酸途径参与突触传递，神经元兴奋性，神经可塑性和神经保护作用。在本临床综述中，我们提供了当前临床状况的概述，讨论了PDE抑制剂与皮质口和海马回路有关的一般作用机制，并考虑了一些翻译挑战。