Serotonin transporters are located on the axons beyond the synaptic junctions: Anatomical and functional evidence

Feng C. Zhou, Jung Hwa Tao-Cheng, Louis Segu, Tushar Patel, Yun Wang

Research output: Contribution to journalArticle

148 Scopus citations


The serotonin (5-HT) transporter (5-HTT) is known to play a role in depression and many 5-HT related diseases, and is the target site for drugs of abuse, such as cocaine, MDMA, and methamphetamine. The major role of the 5-HTT has long been considered to be to inactivate serotonin transmission through the elimination of serotonin at release sites. However, immunocytochemistry using an antibody against the N-terminal of the 5-HTT at the light microscopic (LM) level indicates that the 5-HTT is associated not only with 5-HT varicosities but also with axons. Electron microscopy (EM) reveals that the majority of the 5-HTTs exist on the axolemma outside the synaptic junctions. In studying whether axonal 5-HTTs are involved in the uptake of 5-HT, we found with autoradiography that [3H]citalopram bound to all major 5-HT fibers, not only in the terminal regions, but also in 5-HT axonal bundles such as the cingulum bundle and medial forebrain bundle. Furthermore, voltammetry recordings indicated that serotonin axonal bundles were actively engaged in high affinity serotonin uptake. The evidence indicates that 5-HTTs on 5-HT axons away from the synapse are likely to be functional in a manner similar to the terminal 5-HTT for serotonin uptake. It also suggests that the role of the 5-HTT may not only be for the termination of synaptic transmission, but also for the regulation of 5-HT through extrasynaptic (volume) transmission. Our findings may also impact the understanding of the sites of action of selective serotonin reuptake inhibitors and drug entry into serotonin neurons via the numerous axonal sites.

Original languageEnglish (US)
Pages (from-to)241-254
Number of pages14
JournalBrain research
Issue number1-2
StatePublished - Sep 14 1998


  • Autoradiography
  • Citalopram
  • Cocaine
  • Depression
  • Electron microscopy
  • High-affinity uptake
  • Immunocytochemistry
  • MDMA
  • Methamphetamine
  • Paroxetine
  • Synapse
  • Voltammetry

ASJC Scopus subject areas

  • Neuroscience(all)

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