From Stress to Substance Use Disorders: The Expanding Role of Microglia–Astrocyte Crosstalk in Neuroimmune and Glutamate Alterations in the Nucleus Accumbens

This review examines convergent neurobiological mechanisms linking stress and drugs that drive stress-induced drug-related behaviors. 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.