Rostral and Caudal Ventral Tegmental Area GABAergic Inputs to Different Dorsal Raphe Neurons Participate in Opioid Dependence

Neuron. 2019 Feb 20;101(4):748-761.e5. doi: 10.1016/j.neuron.2018.12.012. Epub 2019 Jan 10.


Both the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) are involved in affective control and reward-related behaviors. Moreover, the neuronal activities of the VTA and DRN are modulated by opioids. However, the precise circuits from the VTA to DRN and how opioids modulate these circuits remain unknown. Here, we found that neurons projecting from the VTA to DRN are primarily GABAergic. Rostral VTA (rVTA) GABAergic neurons preferentially innervate DRN GABAergic neurons, thus disinhibiting DRN serotonergic neurons. Optogenetic activation of this circuit induces aversion. In contrast, caudal VTA (cVTA) GABAergic neurons mainly target DRN serotonergic neurons, and activation of this circuit promotes reward. Importantly, μ-opioid receptors (MOPs) are selectively expressed at rVTA→DRN GABAergic synapses, and morphine depresses the synaptic transmission. Chronically elevating the activity of the rVTA→DRN pathway specifically interrupts morphine-induced conditioned place preference. This opioid-modulated inhibitory circuit may yield insights into morphine reward and dependence pathogenesis.

Keywords: Circuit; dorsal raphe; morphine; reward; synaptic plasticity; ventral tegmental area.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • GABAergic Neurons / metabolism*
  • GABAergic Neurons / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Opioid-Related Disorders / metabolism
  • Opioid-Related Disorders / physiopathology*
  • Raphe Nuclei / cytology
  • Raphe Nuclei / metabolism
  • Raphe Nuclei / physiopathology*
  • Receptors, Opioid, mu / metabolism
  • Reward
  • Synaptic Transmission*
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / metabolism
  • Ventral Tegmental Area / physiopathology*


  • Receptors, Opioid, mu