Glutamate synaptic inputs to ventral tegmental area neurons in the rat derive primarily from subcortical sources

Neuroscience. 2007 May 25;146(3):1259-74. doi: 10.1016/j.neuroscience.2007.02.016. Epub 2007 Mar 28.


Dopamine and GABA neurons in the ventral tegmental area project to the nucleus accumbens and prefrontal cortex and modulate locomotor and reward behaviors as well as cognitive and affective processes. Both midbrain cell types receive synapses from glutamate afferents that provide an essential control of behaviorally-linked activity patterns, although the sources of glutamate inputs have not yet been completely characterized. We used antibodies against the vesicular glutamate transporter subtypes 1 and 2 (VGlut1 and VGlut2) to investigate the morphology and synaptic organization of axons containing these proteins as putative markers of glutamate afferents from cortical versus subcortical sites, respectively, in rats. We also characterized the ventral tegmental area cell populations receiving VGlut1+ or VGlut2+ synapses according to their transmitter phenotype (dopamine or GABA) and major projection target (nucleus accumbens or prefrontal cortex). By light and electron microscopic examination, VGlut2+ as opposed to VGlut1+ axon terminals were more numerous, had a larger average size, synapsed more proximally, and were more likely to form convergent synapses onto the same target. Both axon types formed predominantly asymmetric synapses, although VGlut2+ terminals more often formed synapses with symmetric morphology. No absolute selectivity was observed for VGlut1+ or VGlut2+ axons to target any particular cell population. However, the synapses onto mesoaccumbens neurons more often involved VGlut2+ terminals, whereas mesoprefrontal neurons received relatively equal synaptic inputs from VGlut1+ and VGlut2+ profiles. The distinct morphological features of VGlut1 and VGlut2 positive axons suggest that glutamate inputs from presumed cortical and subcortical sources, respectively, differ in the nature and intensity of their physiological actions on midbrain neurons. More specifically, our findings imply that subcortical glutamate inputs to the ventral tegmental area expressing VGlut2 predominate over cortical sources of excitation expressing VGlut1 and are more likely to drive the behaviorally-linked bursts in dopamine cells that signal future expectancy or attentional shifting.

Publication types

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

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / ultrastructure
  • Brain / cytology*
  • Brain / physiology*
  • Brain / ultrastructure
  • Data Interpretation, Statistical
  • Dendrites / ultrastructure
  • Fluorescent Dyes
  • Glutamic Acid / physiology*
  • Image Processing, Computer-Assisted
  • Immunoenzyme Techniques
  • Male
  • Microscopy, Electron
  • Neurons / physiology*
  • Neurons / ultrastructure
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / physiology
  • Nucleus Accumbens / ultrastructure
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / physiology
  • Prefrontal Cortex / ultrastructure
  • Rats
  • Rats, Sprague-Dawley
  • Stilbamidines
  • Synapses / physiology*
  • Tyrosine 3-Monooxygenase / metabolism
  • Ventral Tegmental Area / cytology*
  • Ventral Tegmental Area / physiology*
  • Ventral Tegmental Area / ultrastructure
  • Vesicular Glutamate Transport Protein 1 / metabolism
  • Vesicular Glutamate Transport Protein 2 / metabolism


  • 2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt
  • Fluorescent Dyes
  • Stilbamidines
  • Vesicular Glutamate Transport Protein 1
  • Vesicular Glutamate Transport Protein 2
  • Glutamic Acid
  • Tyrosine 3-Monooxygenase