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Aim  We have previously demonstrated that upregulation of CC chemokines through dopamine receptor signaling in the prefrontal cortex (PFC) underlies methamphetamine (Meth)‐induced reward. Given the common pharmacological property of Meth and cocaine (Coca), which are highly addictive psychostimulants, we hypothesized that chemokines may also contribute to Coca‐induced reward. The aim of this study was to identify a key chemokine‐mediating Coca‐induced reward in mice.    Methods  The mRNA expression levels of chemokines were measured by reverse transcription‐quantitative polymerase chain reaction. Coca‐induced reward was evaluated by conditioned place preference test.    Results  We found that mRNA expression levels of CC chemokine ligand 2 (CCL2), CCL7, and CXC chemokine ligand 1 (CXCL1) were upregulated in the PFC after a single administration of Coca (20 mg/kg, s.c.). Upregulation of CXCL1, but not CCL2 and CCL7, mRNA in the PFC was also observed after repeated administration of Coca. A single administration of dopamine D1 receptor agonist SKF 81297 (10 mg/kg, s.c.), but not D2 receptor agonist sumanirole, upregulated CXCL1 mRNA in the PFC. Coca‐induced reward was attenuated by the pretreatment of SB 225002 (5 mg/kg, s.c.), a selective antagonist of CXC chemokine receptor 2 (CXCR2, cognate receptor for CXCL1).    Conclusions  Collectively, we identified CXCL1 as a key regulator in Coca‐induced reward and propose that pharmacological approach targeting CXCL1 could be a novel pharmacotherapy for Coca‐induced reward.

Chemokine CXCL1 is responsible for cocaine‐induced reward in mice