PMID- 26216995
OWN - NLM
STAT- MEDLINE
DCOM- 20151110
LR  - 20181113
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 112
IP  - 32
DP  - 2015 Aug 11
TI  - Action potentials and amphetamine release antipsychotic drug from dopamine neuron 
      synaptic VMAT vesicles.
PG  - E4485-94
LID - 10.1073/pnas.1503766112 [doi]
AB  - Based on lysotracker red imaging in cultured hippocampal neurons, antipsychotic 
      drugs (APDs) were proposed to accumulate in synaptic vesicles by acidic trapping 
      and to be released in response to action potentials. Because many APDs are 
      dopamine (DA) D2 receptor (D2R) antagonists, such a mechanism would be 
      particularly interesting if it operated in midbrain DA neurons. Here, the APD 
      cyamemazine (CYAM) is visualized directly by two-photon microscopy in substantia 
      nigra and striatum brain slices. CYAM accumulated slowly into puncta based on 
      vacuolar H(+)-ATPase activity and dispersed rapidly upon dissipating organelle pH 
      gradients. Thus, CYAM is subject to acidic trapping and released upon 
      deprotonation. In the striatum, Ca(2+)-dependent reduction of the CYAM punctate 
      signal was induced by depolarization or action potentials. Striatal CYAM 
      overlapped with the dopamine transporter (DAT). Furthermore, 
      parachloroamphetamine (pCA), acting via vesicular monoamine transporter (VMAT), 
      and a charged VMAT, substrate 1-methyl-4-phenylpyridinium (MPP(+)), reduced 
      striatal CYAM. In vivo CYAM administration and in vitro experiments confirmed 
      that clinically relevant CYAM concentrations result in vesicular accumulation and 
      pCA-dependent release. These results show that some CYAM is in DA neuron VMAT 
      vesicles and suggests a new drug interaction in which amphetamine induces CYAM 
      deprotonation and release as a consequence of the H(+) countertransport by VMAT 
      that accompanies vesicular uptake, but not by inducing exchange or acting as a 
      weak base. Therefore, in the striatum, APDs are released with DA in response to 
      action potentials and an amphetamine. This synaptic corelease is expected to 
      enhance APD antagonism of D2Rs where and when dopaminergic transmission occurs.
FAU - Tucker, Kristal R
AU  - Tucker KR
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh School 
      of Medicine, Pittsburgh, PA 15261;
FAU - Block, Ethan R
AU  - Block ER
AD  - Department of Cell Biology, University of Pittsburgh School of Medicine, 
      Pittsburgh, PA 15261.
FAU - Levitan, Edwin S
AU  - Levitan ES
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh School 
      of Medicine, Pittsburgh, PA 15261; elevitan@pitt.edu.
LA  - eng
GR  - F32NS078994/NS/NINDS NIH HHS/United States
GR  - R01DA014204/DA/NIDA NIH HHS/United States
GR  - R21 DA038384/DA/NIDA NIH HHS/United States
GR  - F32 NS078994/NS/NINDS NIH HHS/United States
GR  - R01 DA014204/DA/NIDA NIH HHS/United States
GR  - R21DA038384/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150727
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Acids)
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Dopamine Plasma Membrane Transport Proteins)
RN  - 0 (Phenothiazines)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 0 (Vesicular Monoamine Transport Proteins)
RN  - A2JGV5CNU4 (cyamemazine)
RN  - CK833KGX7E (Amphetamine)
SB  - IM
MH  - Acids/metabolism
MH  - Action Potentials/*drug effects
MH  - Amphetamine/*pharmacology
MH  - Animals
MH  - Antipsychotic Agents/*pharmacology
MH  - Dopamine Plasma Membrane Transport Proteins/metabolism
MH  - Dopaminergic Neurons/drug effects/*metabolism
MH  - Male
MH  - Neostriatum/drug effects/metabolism
MH  - Phenothiazines/pharmacology
MH  - Photons
MH  - Rats, Sprague-Dawley
MH  - Serotonin Plasma Membrane Transport Proteins/metabolism
MH  - Substantia Nigra/drug effects/metabolism
MH  - Synaptic Vesicles/drug effects/*metabolism
MH  - Vesicular Monoamine Transport Proteins/*metabolism
PMC - PMC4538645
OTO - NOTNLM
OT  - VMAT
OT  - amphetamine
OT  - antiporter
OT  - multiphoton
OT  - vesicular release
COIS- The authors declare no conflict of interest.
EDAT- 2015/07/29 06:00
MHDA- 2015/11/11 06:00
PMCR- 2016/02/11
CRDT- 2015/07/29 06:00
PHST- 2015/07/29 06:00 [entrez]
PHST- 2015/07/29 06:00 [pubmed]
PHST- 2015/11/11 06:00 [medline]
PHST- 2016/02/11 00:00 [pmc-release]
AID - 1503766112 [pii]
AID - 201503766 [pii]
AID - 10.1073/pnas.1503766112 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4485-94. doi: 
      10.1073/pnas.1503766112. Epub 2015 Jul 27.