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

C. Garcia-Keller, Y. M. Kupchik, C. D. Gipson, R. M. Brown, S. Spencer, F. Bollati, M. A. Esparza, D. J. Roberts-Wolfe, J. A. Heinsbroek, A. C. Bobadilla, L. M. Cancela, P. W. Kalivas

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1063-1069
Number of pages7
JournalMolecular psychiatry
Issue number8
StatePublished - Aug 1 2016
Externally publishedYes

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© 2016 Macmillan Publishers Limited.


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