Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain.

Autor: Freyberg Z; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA., Sonders MS; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA.; Department of Neurology, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA., Aguilar JI; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA., Hiranita T; Psychobiology Section, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA., Karam CS; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA., Flores J; Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA., Pizzo AB; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA., Zhang Y; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA., Farino ZJ; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA., Chen A; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine University of California, Los Angeles, California 90095, USA., Martin CA; UCLA Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, California 90095, USA., Kopajtic TA; Psychobiology Section, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA., Fei H; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine University of California, Los Angeles, California 90095, USA., Hu G; Department of Chemistry, Columbia University, New York, New York 10027, USA., Lin YY; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Republic of China 10055., Mosharov EV; Department of Neurology, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA., McCabe BD; Center for Motor Neuron Biology and Disease, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Department of Pathology and Cell Biology, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Department of Neuroscience, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA., Freyberg R; Department of Psychology, Stern College for Women, Yeshiva University, New York, New York 10016, USA., Wimalasena K; Department of Chemistry, Wichita State University, Wichita, Kansas 67260, USA., Hsin LW; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Republic of China 10055., Sames D; Department of Chemistry, Columbia University, New York, New York 10027, USA., Krantz DE; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine University of California, Los Angeles, California 90095, USA., Katz JL; Psychobiology Section, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA., Sulzer D; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA.; Department of Neurology, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Department of Pharmacology, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA., Javitch JA; Department of Psychiatry, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA.; Department of Pharmacology, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2016 Feb 16; Vol. 7, pp. 10652. Date of Electronic Publication: 2016 Feb 16.
DOI: 10.1038/ncomms10652
Abstrakt: Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT's role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H(+) antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects.
Databáze: MEDLINE