Chronic Restraint Stress and Vulnerability to Develop Cocaine Self-Administration: Dysregulation of Glutamate Homeostasis in Nucleus Accumbens Core: In vivo Monitoring of Glutamate and Dopamine by Microdialysis

AVALOS, M. P.; RIGONI, D.; GUZMAN, A.S.; GARCÍA-KELLER, C.; BOLLATI, F.; CANCELA, L.M.

San Diego

Congreso; 2018 Neuroscience Meeting; 2018

Society for Neuroscience

Clinical evidence proved a facilitatory influence of stress on the development of substance use disorders. However, the mechanisms underpinning the comorbidity between stress and drug abuse have not been completely elucidated. Data from our lab demonstrated that chronic exposure to restraint stress engenders long-lasting neuroadaptations in Nucleus Accumbens (NAc), the major limbic-motor integration area, which resulted insensitized response to cocaine (Esparza et al., 2012). We also showed that an acuteexposure to restraint stress revealed that an enduring locomotor sensitization to cocaine is paralleled by an increase in dopamine (DA) within the NAc core, but not the shell. Our lab also found that rats pre-exposed to acute stress showed an increase in basal levels of glutamate (GLU) in the NAc core as measured by the no-net-flux method (Garcia-Keller et al., 2013). A relationship between altered basal GLU and GLT-1 levels was proposed to underlie the facilitation of cocaine self-administration (SA) following acute pre-exposure to stress (Garcia-Keller et al., 2016). The present study attempts to determine the long-term effects of chronic pre-exposure to restraint stress on extracellular levels of DA and GLU in NAc, its impact on locomotor activity and drug SA behavior, and the levels of GLT-1 in the neuropathology of cocaine abuse induced by stress. Male Sprague Dawley rats (300-350g) were exposed to chronic restraint stress (2 h x day for 7 days), and 2 weeks later the following experiments were carried out: 1) Determination of DA and GLU extracellular levels in NAc core and shell after saline or cocaine (15 mg/kg i.p.), by microdialysis followed by High-Performance Liquid Chromatography coupled with electrochemical detection, 2) Basal GLU levels in NAc core by the no-net-flux method, 3) GLT-1 protein expression in NAc (preferentially core) by Western blotting, 4) Cocaine SA behavior and locomotor activity following saline or cocaine challenge injection.This study points out that chronic restraint stress induced a dopaminergic sensitization within NAc core, but not shell, after acute cocaine. Also, an increase of basal extracellular levels of GLU in core was observed following chronic stress, which is consistent with the decreased expression of GLT-1 in NAc. We propose that the chronic restraint stress-induced dysregulation of glutamate homeostasis is related to its influence on the development of cross-sensitization to motor stimulant effect of cocaine and the facilitation of the acquisition of cocaine SA behavior.