Abstract
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.
Highlights
Mechanisms of neuroimmune signaling have been linked to stress [49, 171, 318], as well as neurodegenerative (e.g., Alzheimer’s disease [52, 215]) and neuropsychiatric disorders
The purpose of this review is to bring into focus the role of neuroimmune signaling in driving drug addiction motivation, and based on what we do know regarding interactions of neuroimmune mechanisms and chronic drug use, we outline potentially critical interactions with known drug-induced changes in the glutamate system
This study focused on dopamine release and not glutamate or neuroimmune systems, these results indicate that the reward pathway is likely differentially regulated by steroidal hormones in males and females and supports further research on sex differences in this area
Summary
Mechanisms of neuroimmune signaling have been linked to stress [49, 171, 318], as well as neurodegenerative (e.g., Alzheimer’s disease [52, 215]) and neuropsychiatric disorders (e.g., depression [133]; nicotine and alcohol use disorder [46, 70, 228, 246, 258, 259]). The purpose of this review is to bring into focus the role of neuroimmune signaling in driving drug addiction motivation, and based on what we do know regarding interactions of neuroimmune mechanisms and chronic drug use, we outline potentially critical interactions with known drug-induced changes in the glutamate system. We will begin by outlining potentially important neuroimmune processes with regard to SUD and how they (1) interact with glutamate signaling and (2) influence motivated drug-seeking behavior. We will describe the wellcharacterized role of glutamate homeostasis in drug addiction and bring into focus how neuroimmune processes may interact with this system to influence drugmotivated behavior. The goal of this section is to highlight the dearth of knowledge regarding how ovarian hormones may interact with neuroimmune signaling and glutamate homeostasis in substance use disorders (SUDs) in a sex-specific fashion (as noted in another recent review; see [108]). The goal of this review is to demonstrate how neuroimmune and glutamatergic signaling may interact within the reward pathway to drive drug use vulnerability
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