目的 探讨阿立哌唑（aripiprazole）治疗儿童期抽动症疗效与多巴胺D3受体（DRD3）第一外显子Ser9Gly多态性关联性.方法 158例符合ICD-10抽动症的诊断患者作为研究对象,采用阿立哌唑治疗8周,用耶鲁抽动症严重程度量表（Yale global tic s...目的 探讨阿立哌唑（aripiprazole）治疗儿童期抽动症疗效与多巴胺D3受体（DRD3）第一外显子Ser9Gly多态性关联性.方法 158例符合ICD-10抽动症的诊断患者作为研究对象,采用阿立哌唑治疗8周,用耶鲁抽动症严重程度量表（Yale global tic severity scale,YGTSS）评定疗效.应用聚合酶链反应-限制性片段长度的多态性技术对抽动症患儿和健康患儿对照（n=187）的基因进行遗传关联分析.结果 ①经过对DRD3基因的Ser9Gly基因型及等位基因频率比较,病例组和对照组之间差异均无统计学意义（P＞0.05）.②病例组中有效组与无效组DRD3 Ser9Gly基因型（Ser/Ser：40 vs 17;Ser/Gly：52 vs 28;Gly/Gly：7 vs 14）及等位基因频率（Ser：132 vs 62;Gly：66 vs 56）比较,均差异有统计学意义（P＜0.05）.③病例组一过性抽动障碍、慢性抽动和发声与多种运动联合抽动障碍（TS）三种类型的DRD3 Ser9Gly基因型及等位基因频率比较,均差异无统计学意义（P＞0.05）.结论 多巴胺D3受体基因多态性与阿立哌唑疗效有关联性,与抽动症分型无关联性.展开更多
Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Cu...Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.展开更多
Dopamine D_(3) receptor(D_(3)R)is implicated in multiple psychotic symptoms.Increasing the D_(3)R selectivity over dopamine D_2 receptor(D_2R)would facilitate the antipsychotic treatments.Herein,novel carbazole and te...Dopamine D_(3) receptor(D_(3)R)is implicated in multiple psychotic symptoms.Increasing the D_(3)R selectivity over dopamine D_2 receptor(D_2R)would facilitate the antipsychotic treatments.Herein,novel carbazole and tetrahydro-carboline derivatives were reported as D_(3)R selective ligands.Through a structure-based virtual screen,ZLG-25(D_(3)R K_i=685 nmol/L;D_2R K_i>10,000 nmol/L)was identified as a novel D_(3)R selective bitopic ligand with a carbazole scaffold.Scaffolds hopping led to the discovery of novel D_(3)R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core.Further functional studies showed that most derivatives acted as h D_(3)R-selective antagonists.Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity.Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction.Furthermore,36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests,and alleviated the MK-801-induced disruption of novel object recognition in mice.Additionally,preliminary studies confirmed the favorable PK/PD profiles,no weight gain and limited serum prolactin levels in mice.These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.展开更多
文摘目的 探讨阿立哌唑（aripiprazole）治疗儿童期抽动症疗效与多巴胺D3受体（DRD3）第一外显子Ser9Gly多态性关联性.方法 158例符合ICD-10抽动症的诊断患者作为研究对象,采用阿立哌唑治疗8周,用耶鲁抽动症严重程度量表（Yale global tic severity scale,YGTSS）评定疗效.应用聚合酶链反应-限制性片段长度的多态性技术对抽动症患儿和健康患儿对照（n=187）的基因进行遗传关联分析.结果 ①经过对DRD3基因的Ser9Gly基因型及等位基因频率比较,病例组和对照组之间差异均无统计学意义（P＞0.05）.②病例组中有效组与无效组DRD3 Ser9Gly基因型（Ser/Ser：40 vs 17;Ser/Gly：52 vs 28;Gly/Gly：7 vs 14）及等位基因频率（Ser：132 vs 62;Gly：66 vs 56）比较,均差异有统计学意义（P＜0.05）.③病例组一过性抽动障碍、慢性抽动和发声与多种运动联合抽动障碍（TS）三种类型的DRD3 Ser9Gly基因型及等位基因频率比较,均差异无统计学意义（P＞0.05）.结论 多巴胺D3受体基因多态性与阿立哌唑疗效有关联性,与抽动症分型无关联性.
基金supported by the National Natural Science Foundation of China,No.82071254(to WZ).
文摘Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.
基金supported by The National Key R&D Program (2022YFC2303700,China)the Ningxia Hui Autonomous Region Key Research and Development Project (2022BEG02042,China)+3 种基金the National Natural Science Foundation of China (82030108,81803351)Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University (KF-202304,China)the China Postdoctoral Science Foundation (2018M641122,China)the National Major Scientific and Technological Special Project for Significant New Drugs Development (2018ZX09711002-013-004,2018ZX09735-001,China)。
文摘Dopamine D_(3) receptor(D_(3)R)is implicated in multiple psychotic symptoms.Increasing the D_(3)R selectivity over dopamine D_2 receptor(D_2R)would facilitate the antipsychotic treatments.Herein,novel carbazole and tetrahydro-carboline derivatives were reported as D_(3)R selective ligands.Through a structure-based virtual screen,ZLG-25(D_(3)R K_i=685 nmol/L;D_2R K_i>10,000 nmol/L)was identified as a novel D_(3)R selective bitopic ligand with a carbazole scaffold.Scaffolds hopping led to the discovery of novel D_(3)R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core.Further functional studies showed that most derivatives acted as h D_(3)R-selective antagonists.Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity.Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction.Furthermore,36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests,and alleviated the MK-801-induced disruption of novel object recognition in mice.Additionally,preliminary studies confirmed the favorable PK/PD profiles,no weight gain and limited serum prolactin levels in mice.These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.
