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Neuron. 2014 Jul 16;83(2):404-416. doi: 10.1016/j.neuron.2014.05.043.

Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons.

Author information

1
Laboratory of Molecular and Cellular Neurobiology, NIH/NIMH, Bethesda, MD 20892, USA. Electronic address: smunderhill@yahoo.com.
2
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
3
Department of Neurological Surgery, Oregon Health and Science University, Portland, OR 97239, USA.
4
Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
5
Laboratory of Molecular and Cellular Neurobiology, NIH/NIMH, Bethesda, MD 20892, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15260, USA.

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.

PMID:
25033183
PMCID:
PMC4159050
DOI:
10.1016/j.neuron.2014.05.043
[Indexed for MEDLINE]
Free PMC Article

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