The membrane raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila.

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    • Source:
      Publisher: Nature Publishing Group Specialist Journals Country of Publication: England NLM ID: 9607835 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5578 (Electronic) Linking ISSN: 13594184 NLM ISO Abbreviation: Mol Psychiatry Subsets: MEDLINE
    • Publication Information:
      Publication: 2000- : Houndmills, Basingstoke, UK : Nature Publishing Group Specialist Journals
      Original Publication: Houndmills, Hampshire, UK ; New York, NY : Stockton Press, c1996-
    • Subject Terms:
    • Abstract:
      The dopamine transporter (DAT) is the primary molecular target responsible for the rewarding properties of the psychostimulants amphetamine (AMPH) and cocaine. AMPH increases extracellular dopamine (DA) by promoting its nonexocytotic release via DAT-mediated efflux. Previous studies in heterologous cells have shown that phosphorylation of the amino terminus of DAT is required for AMPH-induced DA efflux but not for DA uptake. However, the identity of many of the modulatory proteins and the molecular mechanisms that coordinate efflux and the ensuing behavioral effects remain poorly defined. Here, we establish a robust assay for AMPH-induced hyperlocomotion in Drosophila melanogaster larvae. Using a variety of genetic and pharmacological approaches, we demonstrate that this behavioral response is dependent on DA and on DAT and its phosphorylation. We also show that methylphenidate (MPH), which competitively inhibits DA uptake but does not induce DAT-mediated DA efflux, also leads to DAT-dependent hyperlocomotion, but this response is independent of DAT phosphorylation. Moreover, we demonstrate that the membrane raft protein Flotillin-1 is required for AMPH-induced, but not MPH-induced, hyperlocomotion. These results are the first evidence of a role for a raft protein in an AMPH-mediated behavior. Thus, using our assay we are able to translate molecular and cellular findings to a behavioral level and to differentiate in vivo the distinct mechanisms of two psychostimulants.
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    • Grant Information:
      T32 MH018870 United States MH NIMH NIH HHS; K05 DA022413 United States DA NIDA NIH HHS; P01 DA012408 United States DA NIDA NIH HHS; P01 DA12408 United States DA NIDA NIH HHS; K08 DA031241 United States DA NIDA NIH HHS
    • Accession Number:
      0 (Central Nervous System Stimulants)
      0 (Dopamine Plasma Membrane Transport Proteins)
      0 (Membrane Proteins)
      0 (flotillins)
      207ZZ9QZ49 (Methylphenidate)
      CK833KGX7E (Amphetamine)
    • Publication Date:
      Date Created: 20120620 Date Completed: 20140502 Latest Revision: 20211021
    • Publication Date:
      20240104
    • Accession Number:
      PMC3582826
    • Accession Number:
      10.1038/mp.2012.82
    • Accession Number:
      22710269