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Background: An excess of exosomes, nanovesicles released from all cells and key regulators of brain plasticity, is an emerging therapeutic target for stress-related mental illnesses. The effects of chronic stress on exosome levels are unknown; even less is known about molecular drivers of exosome levels in the stress response. Methods: We used our state-of-the-art protocol with 2 complementary strategies to isolate neuronal exosomes from plasma, ventral dentate gyrus, basolateral amygdala, and olfactory bulbs of male mice to determine the effects of chronic restraint stress (CRS) on exosome levels. Next, we used RNA sequencing and bioinformatic analyses to identify molecular drivers of exosome levels. Results: We found that CRS leads to an increase in the levels of neuronal exosomes but not total (i.e., not neuronally enriched) exosome levels assayed in plasma and the ventral dentate gyrus, whereas CRS leads to a decrease in neuronal exosome levels but not total exosome levels in the basolateral amygdala. There was a further specificity of effects as shown by a lack of changes in the levels of neuronal exosomes assayed in the olfactory bulbs. In pursuit of advancing translational applications, we showed that acetyl-L-carnitine administration restores the CRS-induced increase in neuronal exosome levels assayed in plasma (the most accessible specimen). Furthermore, the CRS-induced changes in neuronal exosome levels in the ventral dentate gyrus and basolateral amygdala mirrored the opposite pattern of CRS-induced transcriptional changes in these key brain areas, with β-estradiol signaling as a potential upstream driver of neuronal exosome levels. Conclusions: This study provides a foundation for future studies of new forms of local and distant communication in stress neurobiology by demonstrating specific relationships between neuronal exosome levels assayed in plasma and the brain and providing new candidate targets for the normalization of exosome levels.

Though the facilitating influence of stress on drug abuse is well documented, the mechanisms underlying this interaction have yet to be fully elucidated. The present study explores the neurobiological mechanisms underpinning the sensitized response to the psychomotor-stimulating effects of cocaine following chronic restraint stress (CRS), emphasizing the differential contribution of both subcompartments of the nucleus accumbens (NA), the core (NAcore) and shell (NAshell), to this phenomenon. Adult male Wistar rats were restrained for 2 h/day for 7 days and, 2 weeks after the last stress exposure (day 21), all animals were randomly assigned to behavioral, biochemical or neurochemical tests. Our results demonstrated that the enduring CRS-induced increase in psychostimulant response to cocaine was paralleled by an increase of extracellular dopamine levels in the NAcore, but not the NAshell, greater than that observed in the non-stress group. Furthermore, we found that CRS induced an impairment of glutamate homeostasis in the NAcore, but not the NAshell. Its hallmarks were increased basal extracellular glutamate concentrations driven by a CRS-induced downregulation of GLT-1, blunted glutamate levels in response to cocaine and postsynaptic structural remodeling in pre-stressed animals. In addition, ceftriaxone, a known GLT-1 enhancer, prevented the CRS-induced GLT-1 downregulation, increased basal extracellular glutamate concentrations and changes in structural plasticity in the NAcore as well as behavioral cross-sensitization to cocaine, emphasizing the biological importance of GLT-1 in the comorbidity between chronic stress exposure and drug abuse. A future perspective concerning the paramount relevance of the stress-induced disruption of glutamate homeostasis as a vulnerability factor to the development of stress and substance use disorders during early life or adulthood of descendants is provided.