Repeated cocaine exposure and prolonged withdrawal drive morphological and molecular remodeling of hippocampal microglia in response to acute stress.

Abstract

Repeated cocaine exposure during adolescence disrupts physiological brain maturation, inducing persistent neuroplastic adaptations that evolve throughout withdrawal. Because stressful experiences are among the most powerful triggers of relapse during abstinence, uncovering how cocaine withdrawal affects the neurobiological mechanisms of stress adaptation and emotional responses remains a critical challenge in addiction research. Here, we investigated whether prolonged withdrawal from adolescent cocaine exposure alters hippocampal neuroimmune responses to a subsequent stressful challenge. Male adolescent rats received cocaine (5mg/kg, s.c.) for 15 consecutive days followed by a 14-day withdrawal period. At the end of withdrawal, animals were exposed to acute restraint stress (ARS) and assessed for anxiety-like behavior. Our findings demonstrate that prolonged withdrawal from adolescent cocaine exposure impairs emotional adaptation to acute stress, accompanied by persistent neuroimmune dysregulation across both central and peripheral compartments. Within the hippocampus, a key limbic hub integrating contextual drug-associated memories, emotional processes and stress adaptation, cocaine withdrawal altered microglial homeostasis while reshaping stress-responsive neuro-glial communication pathways in a region-specific manner, particularly the CX3CL1-CX3CR1 axis within the ventral subregion. Stress exposure revealed distinct microglial and synaptic, structural and molecular, adaptations in cocaine-withdrawn rats, characterized by the recruitment of a surveillance-like microglial phenotype and an altered pattern of neuron-microglia communication. These central alterations were accompanied by peripheral lymphopenia and a blunted lymphocyte response to the challenge. Together, these findings support the existence of a latent neuroimmune vulnerability induced by cocaine withdrawal that becomes apparent under challenging conditions potentially driving maladaptive stress processing.