Plasma levels of the chemokine CXCL12 are elevated in mice following acute cocaine exposure and decreased in human cocaine abusers during withdrawal. CXCL12 is also one of the few chemokines located in the brain and can modulate dopamine transmission through activation of its receptor CXCR4. To assess a role for the CXCL12/CXCR4 system in behavioral effects of cocaine, we tested the hypothesis that AMD 3100 (Plerixafor), a CXCR4 antagonist, would inhibit conditioned place preference (CPP) and locomotor activation produced by cocaine. Rats injected with cocaine (10 mg/kg) displayed CPP relative to saline-injected controls following 4 conditioning sessions. AMD 3100 (1, 2.5, 5 mg/kg) administered prior to cocaine conditioning reduced development of cocaine CPP. AMD 3100 (5 mg/kg) also inhibited expression of cocaine-induced CPP in a paradigm in which it was injected once (following cocaine conditioning and just prior to CPP testing). In addition, AMD 3100 (5, 10 mg/kg) pretreatment reduced locomotor activation produced by an acute cocaine injection (15 mg/kg) but did not affect basal locomotor activity relative to saline-injected controls. Repeated cocaine exposure produced a significant increase (1.49-fold) in CXCL12 mRNA expression in the ventral tegmental area (VTA). Our results suggest that the CXCL12/CXCR4 system in the brain reward circuit is impacted by cocaine exposure and influences behavioral effects related to the abuse liability of cocaine. (C) 2016 Elsevier Inc. All rights reserved.