小柯机器人

美国西北大学Jones G. Parker团队近期取得重要工作进展，他们研究发现抗精神病药物疗效与表达D1而非D2受体纹状体投射神经元的调节相关。相关研究成果2023年7月13日在线发表于《自然—神经科学》杂志上。

据介绍，精神病中多巴胺传递的增加被认为是通过表达D1和D2受体的棘突投射神经元（SPN）使纹状体输出失衡。抗精神病药物被认为通过阻断D2受体（D2R）来重新平衡这种输出。

研究人员发现苯丙胺驱动的多巴胺在小鼠中释放不平衡的D1-SPN和D2-SPN Ca²⁺活性，但抗精神病药物的疗效与异常D1-SPN而不是D2-SPN动力学的逆转有关，即使对于D2R选择性或缺乏任何多巴胺受体亲和力的药物也是如此。相比之下，一种临床无效的药物使D2-SPN动力学正常化，但在高多巴胺能条件下加剧了D1-SPN动力学。与抗精神病作用一致，选择性D1-SPN抑制减弱了苯丙胺驱动的运动、感觉运动门控和幻觉样感知的变化。

值得注意的是，抗精神病药物的疗效仅在高多巴胺能条件下与D1-SPN的选择性抑制相关，D1R部分激动作用表现出多巴胺状态依赖性，而非抗精神病D1R拮抗剂则不表现出这种依赖性。

总之，这一发现为抗精神病药物机制提供了新的见解，并揭示了D1-SPN调节的重要作用。

附：英文原文

Title: Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons

Author: Yun, Seongsik, Yang, Ben, Anair, Justin D., Martin, Madison M., Fleps, Stefan W., Pamukcu, Arin, Yeh, Nai-Hsing, Contractor, Anis, Kennedy, Ann, Parker, Jones G.

Issue&Volume: 2023-07-13

Abstract: Elevated dopamine transmission in psychosis is assumed to unbalance striatal output through D1- and D2-receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2 receptors (D2Rs). In this study, we found that amphetamine-driven dopamine release unbalanced D1-SPN and D2-SPN Ca2+ activity in mice, but that antipsychotic efficacy was associated with the reversal of abnormal D1-SPN, rather than D2-SPN, dynamics, even for drugs that are D2R selective or lacking any dopamine receptor affinity. By contrast, a clinically ineffective drug normalized D2-SPN dynamics but exacerbated D1-SPN dynamics under hyperdopaminergic conditions. Consistent with antipsychotic effect, selective D1-SPN inhibition attenuated amphetamine-driven changes in locomotion, sensorimotor gating and hallucination-like perception. Notably, antipsychotic efficacy correlated with the selective inhibition of D1-SPNs only under hyperdopaminergic conditions—a dopamine-state-dependence exhibited by D1R partial agonism but not non-antipsychotic D1R antagonists. Our findings provide new insights into antipsychotic drug mechanism and reveal an important role for D1-SPN modulation.

DOI: 10.1038/s41593-023-01390-9

Source: https://www.nature.com/articles/s41593-023-01390-9

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex