Interactions of neuroimmune signaling and glutamate plasticity in addiction

Cassandra D. Gipson, Scott Rawls, Michael D. Scofield, Benjamin M. Siemsen, Emma O. Bondy, Erin E. Maher

Research output: Contribution to journalReview articlepeer-review

14 Scopus citations


Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.

Original languageEnglish
Article number56
JournalJournal of Neuroinflammation
Issue number1
StatePublished - Dec 2021

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health Grant DA050427 (to BMS), DA040004 (to MDS), DA046526, DA036569, DA036569-S1, DA044479, DA049130, and DA045881 (all to CDG), DA045499, R01DA039139, and DA047169 (all to SR), and in part by the South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina CTSA, NIH/NCATS Grant Number UL1 TR001450. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS .

Publisher Copyright:
© 2021, The Author(s).


  • Addiction
  • Astroglia
  • Glutamate
  • Microglia
  • Neuroimmune

ASJC Scopus subject areas

  • Neuroscience (all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience


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