Gill Kathryn M, Grace Anthony A
University of Pittsburgh, Department of Neuroscience, A210 Langley Hall, Pittsburgh, PA 15260, USA.
Curr Pharm Des. 2014;20(31):5069-76. doi: 10.2174/1381612819666131216114612.
Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5 subunit of the GABA receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity.
目前用于治疗精神分裂症的药物疗法在恢复与该疾病相关的认知功能障碍方面无效。因此，人们一直在寻找更可行的新型药物靶点。参与认知行为与大脑区域（特别是海马体和前额叶皮层）中独特的协同振荡活动有关。在精神分裂症患者中，负责产生网络振荡的前额叶皮层和海马体中γ-氨基丁酸能中间神经元功能的病理改变被认为是认知受损的原因。海马体中γ-氨基丁酸能中间神经元活动的不稳定还与海马体输出异常增加和多巴胺神经元活动增强有关。因此，旨在恢复海马体功能的药物可能会影响振荡活动以及多巴胺水平。来自精神分裂症动物模型的有力证据表明，通过间接改变海马体输出，对γ-氨基丁酸受体α5亚基进行变构调节是解决异常多巴胺系统活动的可行方法。因此，这些化合物有望改善因海马体网络活动功能障碍导致的认知缺陷。
