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Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration

Molecular Psychiatry volume 21, pages 1063–1069 (2016)Cite this article

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Abstract

There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining whether the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress, and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate-mediated synaptic currents and dendritic spine morphology. We also determined whether acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders.

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Acknowledgements

This work was supported by grants from NIDA DA015369 (to PWK), DA012513 (to PWK), FONCyT PICT1867 (to LMC), CONICET PID 11420110100354 (to LMC) and SECyT 203/14 (to LMC).

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Authors and Affiliations

  1. Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA

    C Garcia-Keller, C D Gipson, S Spencer, D J Roberts-Wolfe, J A Heinsbroek, A-C Bobadilla & P W Kalivas

  2. Departamento de Farmacología, IFEC-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina

    C Garcia-Keller, F Bollati, M A Esparza & L M Cancela

  3. Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem, Israel

    Y M Kupchik

  4. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia

    R M Brown

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Garcia-Keller, C., Kupchik, Y., Gipson, C. et al. Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration. Mol Psychiatry 21, 1063–1069 (2016). https://doi.org/10.1038/mp.2015.151

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