ACUTE STRESS DYSREGULATES MICROGLIA AND THE EXCITATORY–INHIBITORY BALANCE IN THE HIPPOCAMPUS OF COCAINE-WITHDRAWN ADOLESCENT RATS

Stress events during withdrawal from cocaine are key factor in vulnerability, especially during adolescence, a period of heightened sensitivity to environmental challenges. Emerging evidence suggests that stress-induced neuroimmune adaptations may disrupt synaptic plasticity, promoting substance use–related behaviors. Here, we investigated how microglial dynamics influence neuronal responses to acute restraint stress (ARS) in adolescent male rats with a history of cocaine exposure (5 mg/kg/day for two weeks) and withdrawal (two weeks), focusing on their regulation of glutamatergic and GABAergic systems.
Thirty minutes after the ARS, in the elevated plus maze, saline-exposed rats increased the time spent in the closed arms; conversely, cocaine-withdrawn rats did not show any behavioral responses to the stress, suggesting their inability to cope with an acute challenge.
At a cellular level, we observed a significant reduction in microglial activated cells in the hippocampus of cocaine-withdrawn rats. In the ventral subregion of the hippocampus, involved in stress responses, cocaine-withdrawn rats show a reduced transcriptional profile of pro-inflammatory and microglial markers. In parallel, GAD67, vGAT and PSD9 levels were reduced, suggesting a dysregulation of the excitatory–inhibitory synaptic balance. Indeed, ARS exposure in cocaine-withdrawn rats significantly increased microglial activated cells, upregulated Cx3cl1, and the expression of GABAergic and glutamatergic markers, an effect that may reflect a stress-induced engagement of microglia-mediated synaptic remodeling processes.
Together, these findings indicate that, in cocaine-withdrawn rats, stress-induced microglial and synaptic adaptations in the ventral hippocampus may underlie the maladaptive processing of anxiogenic stimuli induced by a challenge, potentially priming vulnerability to relapse.