Use-dependent inhibition of synaptic transmission by the secretion of intravesicularly accumulated antipsychotic drugs.
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.
Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Carsten H
CH
Tischbirek
Eva M
EM
Wenzel
Fang
F
Zheng
Tobias
T
Huth
Davide
D
Amato
Stefan
S
Trapp
Annette
A
Denker
Oliver
O
Welzel
Katharina
K
Lueke
Alexei
A
Svetlitchny
Manfred
M
Rauh
Janina
J
Deusser
Annemarie
A
Schwab
Silvio O
SO
Rizzoli
Andreas W
AW
Henkel
Christian P
CP
Müller
Christian
C
Alzheimer
Johannes
J
Kornhuber
Teja W
TW
Groemer
D000588:Amines / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology*; D001703:Biophysics; D002478:Cells, Cultured; D003198:Computer Simulation; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D004705:Endocytosis / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D017551:Microdialysis; D008854:Microscopy, Electron; D008959:Models, Neurological; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects*; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D000588:Amines; D014150:Antipsychotic Agents; C092350:FM 4-64; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; C493330:Red DND-99; D026941:Sodium Channel Blockers; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D012701:Serotonin; D013779:Tetrodotoxin; D004298:Dopamine