Cocaine-induced changes in CX 3 CL1 and inflammatory signaling pathways in the hippocampus: Association with IL1β

Cocaine induces neuroinflammatory response and interleukin-1 beta (IL1β) is suggested a final effector for many cocaine-induced inflammatory signals. Recently, the chemokine fractalkine (CX CL1) has been reported to regulate hippocampus-dependent neuroinflammation and synaptic plasticity via CX C-receptor 1 (CX CR1), but little is known about the impact of cocaine. This study is mainly focused on the characterization of CX CL1, IL1β and relevant inflammatory signal transduction pathways in the hippocampus in acute and repeated cocaine-treated male mice. Complementarily, the rewarding properties of cocaine were also assessed in Cx3cr1-knockout (KO) mice using a conditioned place preference (CPP). We observed significant increases in CX CL1 and IL1β concentrations after cocaine, although repeated cocaine produced an enhancement of CX CL1 concentrations. CX CL1 and IL1β concentrations were positively correlated in acute (r = +0.61) and repeated (r = +0.82) cocaine-treated mice. Inflammatory signal transduction pathways were assessed. Whereas acute cocaine-treated mice showed transient increases in p-ERK1/2/ERK1/2 and p-p65/p65 NFκB ratios after cocaine injection, repeated cocaine-treated mice showed transient increases in p-ERK1/2/ERK1/2, p-p38/p38 MAPK, p-NFκB p65/NF-κB p65 and p-CREB/CREB ratios. Baseline p-p38/p38 MAPK and p-CREB/CREB ratios were downregulated in repeated cocaine-treated mice. Regarding the cocaine-induced CPP, Cx3cr1-KO mice showed a notably impaired extinction but no differences during acquisition and reinstatement. These results indicate that cocaine induces alterations in CX CL1 concentrations, which are associated with IL1β concentrations, and activates convergent inflammatory pathways in the hippocampus. Furthermore, the CX CL1/CX CR1 signaling could mediate the processes involved in the extinction of cocaine-induced CPP.