Cocaine exposure during adolescence impairs stress induced behavioral and immune responses

Cocaine exposure during adolescence can lead to long-lasting neuroplastic modifications that may subserve altered responses to stimuli, such as stressful events, later in life. The immune system is well known to play a key role in stress response and, more recently, in psychiatric disorders, including drug addiction. Therefore, we hypothesized that developmental exposure to cocaine may the alter immune system at peripheral levels and in the brain, where it can modulate neuro-glia dynamics, ultimately contributing to altered coping responses to stressful events. To test this hypothesis, adolescent Sprague-Dawley male rats were treated with a low dose of cocaine (5 mg/kg/day, subcutaneously) for 15 days, from postnatal day (PND) 28 to PND 42. After 2 weeks of withdrawal (PND 56), animals were subjected to 1 hour of acute restraint stress (ARS) and then to the elevated plus maze (EPM) test to evaluate their behavioral response to a stressful challenge. Molecular analysis has been performed in blood and in the dorsal (dH) and ventral (vH) subregions of the hippocampus, involved in drug-related memory and in the stress response. Stress increased the time spent in the open arms in saline-treated rats, while no changes were observed in cocaine-withdrawn animals, suggesting their impaired ability to cope with the acute challenge. From a molecular standpoint, the prolonged exposure to cocaine and withdrawal induced a significant reduction of circulating erythroid progenitors, CD45+, and of CD4+/CD8+ adaptive immune populations. Of note, stress alone induced similar changes in saline animals, while it did not further compromise these cell counts in cocaine-withdrawn rats. In parallel, in the hippocampus, cocaine withdrawal reduced the number of activated microglial cells (CD45+/CD11b+), which were then significantly increased after the stress exposure. Cocaine withdrawal altered the expression levels of P2ry12, Trem2 and CD68 microglial markers in the dH, suggesting a pro-inflammatory state. Interestingly, whereas ARS exposure in saline treated animals resulted in gene expression patterns consistent with a homeostatic, surveilling microglial state, in cocaine treated rats the same genes remained indicative of a non activated profile. This suggests a potential stress resilient microglial phenotype that recapitulates the observed behavioral outcomes. In vH, withdrawal from cocaine dysregulated the neuro-glial communication system, measured as the Cx3cr1/Cx3cl1 find-me/eat-me signaling. After ARS, this neuro-glia miscommunication persisted only in cocaine-withdrawn animals. These findings show that two weeks of cocaine withdrawal reshape peripheral immunity and differentially modulate microglial and neuro-glial activity across hippocampal subregions. ARS further reorganized these adaptations in cocaine-withdrawn rats. Such long term alterations may contribute to the persistent vulnerability to relapse.