Serotonergic dystrophy induced by excess serotonin

Mol Cell Neurosci. 2010 Jul;44(3):297-306. doi: 10.1016/j.mcn.2010.04.001. Epub 2010 Apr 13.

Abstract

Administration of certain serotonin-releasing amphetamine derivatives (fenfluramine and/or 3,4-methylenedioxymethamphetamine, MDMA, 'ecstasy') results in dystrophic serotonergic morphology in the mammalian brain. In addition to drug administration, dystrophic serotonergic neurites are also associated with neurodegenerative disorders. We demonstrate here that endogenously elevated serotonin in the Drosophila CNS induces aberrant enlarged varicosities, or spheroids, that are morphologically similar to dystrophic mammalian serotonergic fibers. In Drosophila these spheroids are specific to serotonergic neurons, distinct from typical varicosities, and form only after prolonged increases in cytoplasmic serotonin. Our results also suggest that serotonin levels during early development determine later sensitivity of spheroid formation to manipulations of the serotonin transporter (SERT). Elevated serotonin also interacts with canonical protein aggregation and autophagic pathways to form spheroids. The data presented here support a model in which excess cytoplasmic neurotransmitter triggers a cell-specific pathway inducing aberrant morphology in fly serotonergic neurons that may be shared in certain mammalian pathologies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / metabolism
  • Axons / ultrastructure*
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Drosophila melanogaster / anatomy & histology
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / metabolism*
  • Fenfluramine / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / ultrastructure*
  • Serotonin / metabolism*
  • Serotonin / pharmacology
  • Serotonin Agents / metabolism
  • Serotonin Agents / pharmacology*
  • Transgenes

Substances

  • Serotonin Agents
  • Fenfluramine
  • Serotonin
  • N-Methyl-3,4-methylenedioxyamphetamine