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It first outlines the main theoretical frameworks explaining substance use disorders (SUDs), emphasizing vulnerability factors\u2014particularly stressful life events\u2014that 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\u2013astrocyte 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\u2013neuronal communication, driving the comorbidity between stress and SUDs. A dedicated section focuses on key neuroimmune signaling pathways\u2014particularly the TNF-\u03b1\/NF-\u03baB axis\u2014and 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.<\/jats:p>","DOI":"10.3390\/ijms27010385","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T15:30:32Z","timestamp":1767195032000},"page":"385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["From Stress to Substance Use Disorders: The Expanding Role of Microglia\u2013Astrocyte Crosstalk in Neuroimmune and Glutamate Alterations in the Nucleus Accumbens"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5141-0929","authenticated-orcid":false,"given":"Liliana Marina","family":"Cancela","sequence":"first","affiliation":[{"name":"Instituto de Farmacolog\u00eda Experimental de C\u00f3rdoba (IFEC-CONICET), Departamento de Farmacolog\u00eda Otto Orsingher, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba X5000HUA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethania","family":"Mongi-Bragato","sequence":"additional","affiliation":[{"name":"Instituto de Farmacolog\u00eda Experimental de C\u00f3rdoba (IFEC-CONICET), Departamento de Farmacolog\u00eda Otto Orsingher, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba X5000HUA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Paula","family":"Avalos","sequence":"additional","affiliation":[{"name":"Instituto de Farmacolog\u00eda Experimental de C\u00f3rdoba (IFEC-CONICET), Departamento de Farmacolog\u00eda Otto Orsingher, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba X5000HUA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia Andrea","family":"Bollati","sequence":"additional","affiliation":[{"name":"Instituto de Farmacolog\u00eda Experimental de C\u00f3rdoba (IFEC-CONICET), Departamento de Farmacolog\u00eda Otto Orsingher, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba X5000HUA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Schulkin, J. 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