Gray areas: Neuropeptide circuits linking the Edinger-Westphal and Dorsal Raphe nuclei in addiction

Neuropharmacology. 2021 Oct 15;198:108769. doi: 10.1016/j.neuropharm.2021.108769. Epub 2021 Sep 2.


The circuitry of addiction comprises several neural networks including the midbrain - an expansive region critically involved in the control of motivated behaviors. Midbrain nuclei like the Edinger-Westphal (EW) and dorsal raphe (DR) contain unique populations of neurons that synthesize many understudied neuroactive molecules and are encircled by the periaqueductal gray (PAG). Despite the proximity of these special neuron classes to the ventral midbrain complex and surrounding PAG, functions of the EW and DR remain substantially underinvestigated by comparison. Spanning approximately -3.0 to -5.2 mm posterior from bregma in the mouse, these various cell groups form a continuum of neurons that we refer to collectively as the subaqueductal paramedian zone. Defining how these pathways modulate affective behavioral states presents a difficult, yet conquerable challenge for today's technological advances in neuroscience. In this review, we cover the known contributions of different neuronal subtypes of the subaqueductal paramedian zone. We catalogue these cell types based on their spatial, molecular, connectivity, and functional properties and integrate this information with the existing data on the EW and DR in addiction. We next discuss evidence that links the EW and DR anatomically and functionally, highlighting the potential contributions of an EW-DR circuit to addiction-related behaviors. Overall, we aim to derive an integrated framework that emphasizes the contributions of EW and DR nuclei to addictive states and describes how these cell groups function in individuals suffering from substance use disorders. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.

Keywords: Addiction; Dorsal raphe; Edinger-westphal; Midbrain; Neuropeptide; Periaqueductal gray.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Gray Matter / physiology*
  • Gray Matter / physiopathology
  • Humans
  • Nerve Net / physiology*
  • Nerve Net / physiopathology
  • Neuropeptides / physiology*
  • Periaqueductal Gray / physiology*
  • Periaqueductal Gray / physiopathology
  • Raphe Nuclei / physiology*
  • Raphe Nuclei / physiopathology
  • Substance-Related Disorders / physiopathology


  • Neuropeptides