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In prior work, we demonstrated that the cytokine granulocyte colony stimulating factor (G-CSF) is elevated in mice following cocaine exposure, with circulating levels correlating with cocaine intake and locomotor sensitization. Additionally, exogenous G-CSF enhances cocaine reward and increases low-dose cocaine self-administration. We have further shown that repeated G-CSF administration alters expression of glutamatergic synapse-associated proteins following cocaine-seeking behavior. Building on these findings, the present studies examined the molecular consequences of repeated administration of G-CSF, cocaine, or their combination, with a focus on glutamatergic signaling pathways. We also tested whether altered glutamate receptor expression contributes to G-CSF-mediated enhancement of cocaine reward. Repeated combined administration of G-CSF and cocaine produced robust changes in glutamate-associated and synapse-related protein expression within the nucleus accumbens and medial prefrontal cortex. These molecular adaptations were accompanied by increased synaptic density in the nucleus accumbens. Finally, pharmacological inhibition of calcium-permeable AMPA receptors within the nucleus accumbens reversed the G-CSF-induced enhancement of cocaine conditioned place preference. Together, these findings indicate that G-CSF enhances cocaine reward at least in part by promoting glutamatergic synaptic remodeling in the nucleus accumbens, identifying a neuroimmune-glutamate mechanism that may be leveraged for therapeutic intervention.<\/jats:p>","DOI":"10.64898\/2026.01.30.702629","type":"posted-content","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T02:25:18Z","timestamp":1770085518000},"source":"Crossref","is-referenced-by-count":0,"title":["Granulocyte colony-stimulating factor acts through calcium-permeable AMPA receptors to potentiate cocaine reward"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4381-4173","authenticated-orcid":false,"given":"Rebecca S.","family":"Hofford","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, Wake Forest School of Medicine, Winston-Salem NC"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York NY"},{"name":"Friedman Brain 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