Use-Dependent Inhibition of Synaptic Transmission by the Secretion of Intravesicularly Accumulated Antipsychotic Drugs

详细信息	查看全文 | 推荐本文 |

• 作者：Carsten  ; H. Tischbirek¹ ; ⁶ ; Eva  ; M. Wenzel¹ ; ⁶ ; ⁷ ; ⁸ ; Fang Zheng² ; ⁶ ; Tobias Huth² ; Davide Amato¹ ; Stefan Trapp⁴ ; Annette Denker⁵ ; Oliver Welzel¹ ; Katharina Lueke¹ ; Alexei Svetlitchny¹ ; Manfred Rauh³ ; Janina Deusser² ; Annemarie Schwab² ; Silvio  ; O. Rizzoli⁵ ; Andreas  ; W. Henkel¹ ; ⁹ ; Christian  ; P. Mü ; ller¹ ; Christian Alzheimer² ; Johannes Kornhuber¹ ; ⁶ ; Teja  ; W. Groemer¹ ; ⁶ ; ^{teja.groemer@uk-erlangen.de}
• 刊名：Neuron
• 出版年：2012
• 期刊代码：45_08966273
• 类别：neu
• 出版时间：7 June, 2012
• 卷：74
• 期：5
• 页码：830-844
• 文件大小：2138 K

摘要

| Figures/TablesFigures/Tables | ReferencesReferences

Summary

Antipsychotic drugs are effective for the treatment of聽schizophrenia. However, the functional consequences and subcellular sites of their accumulation in nervous tissue have remained elusive. Here, we investigated the role of the weak-base antipsychotics haloperidol, chlorpromazine, clozapine, and risperidone in synaptic vesicle recycling. Using multiple live-cell microscopic approaches and electron microscopy of rat hippocampal neurons as well as in聽vivo microdialysis experiments in chronically treated rats, we demonstrate the accumulation of the antipsychotic drugs in synaptic vesicles and their release upon neuronal activity, leading to a significant increase in extracellular drug concentrations. The secreted drugs exerted an autoinhibitory effect on vesicular exocytosis, which was promoted by the inhibition of voltage-gated sodium channels and depended on the stimulation intensity. Taken together, these results indicate that accumulated antipsychotic drugs recycle with synaptic vesicles and have a use-dependent, autoinhibitory effect on synaptic transmission.