ObjectiveChemokines, such as CXCL12, are signaling molecules playing an important role in immune regulations. Chemokine upsurge has also been associated with neuroinflammatory conditions characterized with cognitive impairments. Recently, some in-vitro data suggests that CXCL12 is a potential neuromodulator and interacts with GABAergic system, but, so far, whether these effects translate into alterations in neural and behavioral functions has not been investigated. MethodsIn the present study, we used auditory fear conditioning as a model to define the contribution of CXCL12/CXCR4 on fear-related cognitive disorders. We microinjected different dosages of CXCL12 into the bilateral amygdala of rats to investigate their behavioral effects on the acquisition and extinction of conditioned fear memory. Moreover, we pretreated the rats with the selective CXCR4 receptor antagonist (AMD3100), GABAA antagonist (bicuculline) and GABAB antagonist (CGP55845) to examine whether the CXCL12 induced changes could be reversed. ResultsWe found that intra-amygdala infusion of CXCL12 impaired the acquisition and extinction of conditioned fear response. Pretreatment with AMD3100, rescued the CXCL12 induced impairments, indicating that CXCL12 produced the effects by activating CXCR4 receptors. Furthermore, both bicuculline and CGP55845 prevented CXCL12 from impairing the rat's ability of conditioned learning, indicating a crosstalk between CXCL12/CXCR4 and GABAergic system. ConclusionOur data suggest that the chemokine CXCL12 is able to regulate neurotransmitter mechanisms involved in associative learning functions, and the effect of GABAergic agents on CXCL12/CXCR4 may be new therapeutic potentials for neuroinflammatory diseases.