title: Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons.
abstract: Amphetamines modify the brain and alter behavior through mechanisms generally attributed to their ability to regulate extracellular dopamine concentrations. However, the actions of amphetamine are also linked to adaptations in glutamatergic signaling. We report here that when amphetamine enters dopamine neurons through the dopamine transporter, it stimulates endocytosis of an excitatory amino acid transporter, EAAT3, in dopamine neurons. Consistent with this decrease in surface EAAT3, amphetamine potentiates excitatory synaptic responses in dopamine neurons. We also show that the process of internalization is dynamin- and Rho-mediated and requires a unique sequence in the cytosolic C terminus of EAAT3. Introduction of a peptide based on this motif into dopamine neurons blocks the effects of amphetamine on EAAT3 internalization and its action on excitatory responses. These data indicate that the internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, NIH/NIMH, Bethesda, MD 20892, USA. Electronic address: smunderhill@yahoo.com.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Underhill
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Wheeler
authors.affiliation: Department of Neurological Surgery, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Minghua
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Watts
authors.affiliation: Department of Neurological Surgery, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ingram
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, NIH/NIMH, Bethesda, MD 20892, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Amara
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D050580:Excitatory Amino Acid Transporter 3; C493400:SLC1A1 protein, human; D000661:Amphetamine; D020742:rhoA GTP-Binding Protein; D034281:Dynamins