Dorsal Raphe Dual Serotonin-Glutamate Neurons Drive Reward by Establishing Excitatory Synapses on VTA Mesoaccumbens Dopamine Neurons

Cell Rep. 2019 Jan 29;26(5):1128-1142.e7. doi: 10.1016/j.celrep.2019.01.014.


Dorsal raphe (DR) serotonin neurons provide a major input to the ventral tegmental area (VTA). Here, we show that DR serotonin transporter (SERT) neurons establish both asymmetric and symmetric synapses on VTA dopamine neurons, but most of these synapses are asymmetric. Moreover, the DR-SERT terminals making asymmetric synapses on VTA dopamine neurons coexpress vesicular glutamate transporter 3 (VGluT3; transporter for accumulation of glutamate for its synaptic release), suggesting the excitatory nature of these synapses. VTA photoactivation of DR-SERT fibers promotes conditioned place preference, elicits excitatory currents on mesoaccumbens dopamine neurons, increases their firing, and evokes dopamine release in nucleus accumbens. These effects are blocked by VTA inactivation of glutamate and serotonin receptors, supporting the idea of glutamate release in VTA from dual DR SERT-VGluT3 inputs. Our findings suggest a path-specific input from DR serotonergic neurons to VTA that promotes reward by the release of glutamate and activation of mesoaccumbens dopamine neurons.

Keywords: VGluT3; dorsal raphe nucleus; reward; serotonin; ventral tegmental area.

Publication types

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

MeSH terms

  • Amino Acid Transport Systems, Acidic / metabolism
  • Animals
  • Axons / metabolism
  • Dopaminergic Neurons / metabolism*
  • Dorsal Raphe Nucleus / metabolism*
  • Glutamic Acid / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Nucleus Accumbens / metabolism*
  • Reward*
  • Serotonin / metabolism*
  • Synapses / physiology*
  • Ventral Tegmental Area / metabolism*


  • Amino Acid Transport Systems, Acidic
  • vesicular glutamate transporter 3, mouse
  • Serotonin
  • Glutamic Acid