Transplantation with Lewis bone marrow induces the reinstatement of cocaine-seeking behavior in male F344 resistant rats

•Activity of the immune system may influence specific behavioral responses.•Bone marrow-derived cells can alter behavioral responses to cocaine.•Immune cells and their mediators are implicated in cocaine-seeking behavior.•Drug-evoked long-term memory may be an immune memory to the drug. One of the main challenges to understand drug addiction is defining the biological mechanisms that underlie individual differences in recidivism. Studies of these mechanisms have mainly focused on the brain, yet we demonstrate here a significant influence of the peripheral immune system on this phenomenon. Lewis (LEW) and Fischer 344 (F344) rats have different immunological profiles and they display a distinct vulnerability to the reinforcing effects of cocaine, with F344 more resistant to reinstate cocaine-seeking behavior. Bone marrow from male LEW and F344 rats was transferred to male F344 rats (F344/LEW-BM and F344/F344-BM, respectively), and these rats were trained to self-administer cocaine over 21 days. Following extinction, these animals received a sub-threshold primer dose of cocaine to evaluate reinstatement. F344/LEW-BM but not F344/F344-BM rats reinstated cocaine-seeking behavior, in conjunction with changes in their peripheral immune cell populations to a profile that corresponded to that of the LEW donors. After cocaine exposure, higher CD4+ T-cells and lower CD4+CD25+ T-cells levels were observed in F344/LEW-BM rats referred to control, and the splenic expression of Il-17a, Tgf-β, Tlr-2, Tlr-4 and Il-1β was altered in both groups. We propose that peripheral T-cells respond to cocaine, with CD4+ T-cells in particular undergoing Th17 polarization and generating long-term memory, these cells releasing mediators that trigger central mechanisms to induce reinstatement after a second encounter. This immune response may explain the high rates of recidivism observed despite long periods of detoxification, shedding light on the mechanisms underlying the vulnerability and resilience of specific individuals, and opening new perspectives for personalized medicine in the treatment of relapse.