Cocaine-induced changes in CX₃CL1 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 (CX₃CL1) has been reported to regulate hippocampus-dependent neuroinflammation and synaptic plasticity via CX₃C-receptor 1 (CX₃CR1), but little is known about the impact of cocaine. This study is mainly focused on the characterization of CX₃CL1, 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 CX₃CL1 and IL1β concentrations after cocaine, although repeated cocaine produced an enhancement of CX₃CL1 concentrations. CX₃CL1 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 CX₃CL1 concentrations, which are associated with IL1β concentrations, and activates convergent inflammatory pathways in the hippocampus. Furthermore, the CX₃CL1/CX₃CR1 signaling could mediate the processes involved in the extinction of cocaine-induced CPP.