Use-Dependent Inhibition of Synaptic Transmission by the Secretion of Intravesicularly Accumulated Antipsychotic Drugs
2012 | journal article; research paper. A publication with affiliation to the University of Göttingen.
Jump to:Cite & Linked | Documents & Media | Details | Version history
Cite this publication
Use-Dependent Inhibition of Synaptic Transmission by the Secretion of Intravesicularly Accumulated Antipsychotic Drugs
Tischbirek, C. H.; Wenzel, E. M.; Zheng, F.; Huth, T.; Amato, D.; Trapp, S. & Denker, A. et al. (2012)
Neuron, 74(5) pp. 830-844. DOI: https://doi.org/10.1016/j.neuron.2012.04.019
Documents & Media
Details
- Authors
- Tischbirek, Carsten H.; Wenzel, Eva M.; Zheng, Fang; Huth, Tobias; Amato, Davide; Trapp, Stefan; Denker, Annette; Welzel, Oliver; Lueke, Katharina; Svetlitchny, Alexei; Rauh, Manfred; Deusser, Janina; Schwab, Annemarie; Rizzoli, Silvio ; Henkel, Andreas Wolfram; Mueller, Christian P.; Alzheimer, Christian; Kornhuber, Johannes ; Groemer, Teja Wolfgang
- Abstract
- Antipsychotic drugs are effective for the treatment of 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 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.
- Issue Date
- 2012
- Journal
- Neuron
- ISSN
- 0896-6273
- Language
- English