Functional impact of the cerebral accumulation of antipsychotic drugs

抗精神病药物（APD）是治疗精神分裂症的主要药物。在以前的研究中，我们发现亚慢性给药后，APD在突触囊泡中积累，使它们能够在大脑突触处局部积累高水平的药物。在该项目的前一部分中，我们还能够证明这种积累是治疗效果发生的原因。虽然APD治疗开始时的疗效可能与多巴胺D2受体阻滞呈正相关，但APD在长期治疗中显示出降低的疗效。这种效果丧失的原因尚不充分清楚。在本项目中，将通过新的、更有效的、但不蓄积的物质类似物来研究APD蓄积在药效团比较中的疗效损失中的作用。计划的研究包括物质合成、现代光学、电生理、微透析和行为生物学技术。

Antipsychotic drugs (APDs) are the mainstay in the treatment of schizophrenia. In previous studies, we found that after sub-chronic administration, APDs accumulate in synaptic vesicles, allowing them to locally build up high levels of the drug at synapses in the brain. In the previous part of the project we were also able to show that this accumulation is causally responsible for the occurrence of a therapeutic effect. While therapeutic efficacy at the beginning of APD treatment may be positively associated with dopamine D2 receptor blockade, APDs show a decreasing therapeutic efficacy in chronic treatment. The reasons for this loss of effect are not yet sufficiently understood. In this project, the role of the accumulation of APDs in the loss of efficacy in pharmacophore comparisons is to be investigated by means of new, more effective, but non-accumulating substance analogues. The planned investigations include substance synthesis, modern optical, electrophysiological, microdialytic and behavioral biological techniques.