title: Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action.
abstract: To assess the role of exocytotic release in signaling by monoamines, we have disrupted the neuronal vesicular monoamine transporter 2 (VMAT2) gene. VMAT2-/- mice move little, feed poorly, and die within a few days after birth. Monoamine cell groups and their projections are indistinguishable from those of wild-type littermates, but the brains of mutant mice show a drastic reduction in monoamines. Using midbrain cultures from the mutant animals, amphetamine but not depolarization induces dopamine release. In vivo, amphetamine increases movement, promotes feeding, and prolongs the survival of VMAT2-/- animals, indicating that precise, temporally regulated exocytotic release of monoamine is not required for certain complex behaviors. In addition, the brains of VMAT2 heterozygotes contain substantially lower monoamine levels than those of wild-type littermates, and depolarization induces less dopamine release from heterozygous than from wild-type cultures, suggesting that VMAT2 expression regulates monoamine storage and release.
authors.affiliation: Department of Neurology, UCSF School of Medicine, University of California, San Francisco 94143, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Fon
authors.forename: E N
authors.initials: EN
authors.lastname: Pothos
authors.forename: B C
authors.initials: BC
authors.lastname: Sun
authors.forename: N
authors.initials: N
authors.lastname: Killeen
authors.forename: D
authors.initials: D
authors.lastname: Sulzer
authors.forename: R H
authors.initials: RH
authors.lastname: Edwards
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015306:Biogenic Monoamines / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D008636:Mesencephalon / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D015306:Biogenic Monoamines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; C493453:Slc18a2 protein, mouse; C493454:Slc18a2 protein, rat; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D011189:Potassium Chloride; D000661:Amphetamine; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid