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It first outlines theoretical frameworks for substance use disorders (SUDs), emphasizing vulnerability factors such as stressful life events that heighten addiction risk. 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It first outlines the main theoretical frameworks explaining substance use disorders (SUDs), emphasizing vulnerability factors—particularly stressful life events—that increase addiction risk. The analysis integrates preclinical evidence demonstrating that chronic stress facilitates cross-sensitization to psychostimulants and accelerates drug self-administration, underscoring how stress and drugs converge on glutamatergic and dopaminergic transmission within the Nucleus Accumbens (NAc) . Special attention is given to the glial cells, particularly microglia and astrocytes, in mediating stress-induced neuroimmune activation and glutamate dysregulation in the NAc. Three major themes related to microglia–astrocyte crosstalk are addressed: (i) the contribution of these glial cells to neuroimmune and glutamatergic alterations induced by stress; (ii) their role in synaptic and structural plasticity changes within the NAc; and (iii) the mechanisms by which stress and drug exposure reshape glial–neuronal communication, driving the comorbidity between stress and SUDs. A dedicated section focuses on key neuroimmune signaling pathways—particularly the TNF-α/NF-κB axis—and their involvement in stress-induced vulnerability to cocaine addiction. Finally, the review discusses preclinical evidence supporting the therapeutic potential of repurposed glutamate-modulating agents as promising pharmacological candidates for treating comorbid stress and cocaine-use disorder.  \nAcademic Editor: Hiroshi Nakanishi  \nReceived: 26 November 2025  \nRevised: 19 December 2025  \nAccepted: 28 December 2025  \nPublished: 30 December 2025  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nKeywords: microglia; astrocytes; glutamate; Nucleus Accumbens (NAc); neuroimmune signaling; cocaine; substance use disorders (SUDs); stress  \n1. Introduction: A Neurobiological Framework for the Comorbidity of Stress and Substance Use Disorders (SUDs)  \nStress is a physiological and psychological state that arises when environmental demands are perceived to exceed an individual’s capacity to cope. While the stress response is inherently adaptive, enabling the organism to manage acute challenges effectively, its chronic or unpredictable activation imposes significant bioenergetics and neurobiological costs. Prolonged engagement of the stress response can shift the brain from a state of  \nadaptive regulation to a maladaptive and pathophysiological condition, thereby increasing vulnerability to psychiatric disorders, including substance use disorders (SUDs) [1,2] .  \nSUDs are severe neuropathological conditions representing the culmination of a series of neurobehavioral events that define the addictive process. This trajectory involves a progression from voluntary, controlled drug use to a gradual loss of control, culminating in compulsive drug-seeking ","cbCaidd01V9UDKyq","https://ap.wps.com/l/cbCaidd01V9UDKyq","pdf",2090713,48,"English","# Introduction: A Neurobiological Framework for the Comorbidity of Stress and Substance Use Disorders (SUDs)","[{\"question\":\"How does the review explain the relationship between stress and substance use disorders?\",\"answer\":\"It links stress-induced drug-related behaviors to convergent neurobiological mechanisms, especially changes in glutamatergic and dopaminergic transmission in the Nucleus Accumbens.\"},{\"question\":\"Why are microglia and astrocytes emphasized in this review?\",\"answer\":\"The review highlights these glial cells as key mediators of stress-induced neuroimmune activation and glutamate dysregulation in the NAc.\"},{\"question\":\"Which neuroimmune pathway receives special attention for cocaine addiction vulnerability?\",\"answer\":\"A dedicated section focuses on neuroimmune signaling pathways, particularly the TNF-α/NF-κB axis, and their role in stress-induced vulnerability to cocaine addiction.\"}]","From Stress to Substance Use Disorders: The Expanding Role of Microglia–Astrocyte Crosstalk in Neuroimmune and Glutamate Alterations in the Nucleus Accumbens - Review | PDF",1790765283,121]