Ultrastructural localization of the norepinephrine transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to probable dopamine terminals

J Comp Neurol. 2003 Nov 24;466(4):478-94. doi: 10.1002/cne.10898.


The prefrontal cortex (PFC) is a likely site of action for the therapeutic efficacy of antidepressants that inhibit norepinephrine (NE) reuptake. Moreover, drugs that block the NE transporter (NET) increase extracellular levels of both NE and dopamine (DA), an interaction that may contribute to their therapeutic properties. To examine the subcellular localization of NET and to investigate the spatial relationships between presumed NE and DA axons within the rat prelimbic PFC, we combined immunogold-silver localization of NET with immunoperoxidase staining for the catecholamine synthetic enzyme tyrosine hydroxylase (TH). An additional aim was to quantify the proportion of profiles dually labeled for NET and TH to test the common observation that TH immunolabeling is relatively selective for DA axons. NET-immunoreactive (NET-ir) axonal profiles were typically unmyelinated and occasionally were observed to form symmetric axodendritic synapses. The majority of immunogold NET labeling was unexpectedly observed in the cytoplasm rather than on the plasma membrane. Furthermore, in tissue dually labeled for both NET and TH, only 8-10% of profiles contained both markers. Unlike observations for singly labeled profiles, gold-silver particles for NET in dually labeled axons were localized primarily to the plasmalemma. A systematic survey of terminals labeled only for TH revealed that they were typically separated by at least 1.2 mum from NET-ir varicosities, and the two profile types were not seen to contact common targets. These results suggest that, in the rat PFC, NE axons (1) contain predominantly cytoplasmic NET, (2) infrequently contain TH immunolabeling, and (3) may interact with probable DA afferents by means of extrasynaptic mechanisms.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cytosol / metabolism
  • Cytosol / ultrastructure
  • Dopamine / metabolism*
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Male
  • Microscopy, Electron
  • Neural Pathways / cytology
  • Neural Pathways / metabolism
  • Neural Pathways / ultrastructure
  • Norepinephrine / metabolism
  • Norepinephrine Plasma Membrane Transport Proteins
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / ultrastructure*
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / ultrastructure*
  • Rats
  • Rats, Sprague-Dawley
  • Symporters / ultrastructure*
  • Tyrosine 3-Monooxygenase / metabolism


  • Norepinephrine Plasma Membrane Transport Proteins
  • Slc6a2 protein, rat
  • Symporters
  • Tyrosine 3-Monooxygenase
  • Dopamine
  • Norepinephrine