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Granulocyte colony-stimulating factor (G-CSF) enhances cocaine effects in the nucleus accumbens via a dopamine release–based mechanism

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Abstract

Cocaine use disorder is associated with alterations in immune function including altered expression of multiple peripheral cytokines in humans—several of which correlate with drug use. Individuals suffering from cocaine use disorder show altered immune system responses to drug-associated cues, highlighting the interaction between the brain and immune system as a critical factor in the development and expression of cocaine use disorder. We have previously demonstrated in animal models that cocaine use upregulates the expression of granulocyte colony-stimulating factor (G-CSF)—a pleiotropic cytokine—in the serum and the nucleus accumbens (NAc). G-CSF signaling has been causally linked to behavioral responses to cocaine across multiple behavioral domains. The goal of this study was to define whether increases in G-CSF alter the pharmacodynamic effects of cocaine on the dopamine system and whether this occurs via direct mechanisms within local NAc microcircuits. We find that systemic G-CSF injection increases cocaine effects on dopamine terminals. The enhanced dopamine levels in the presence of cocaine occur through a release-based mechanism, rather than through effects on the dopamine transporter—as uptake rates were unchanged following G-CSF treatment. Critically, this effect could be recapitulated by acute bath application of G-CSF to dopamine terminals, an effect that was occluded by prior G-CSF treatment, suggesting a similar mechanistic basis for direct and systemic exposures. This work highlights the critical interaction between the immune system and psychostimulant effects that can alter drug responses and may play a role in vulnerability to cocaine use disorder.

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Acknowledgements

Cocaine hydrochloride was provided by the NIDA Drug Supply Program. Diagrams in all figures were created with Biorender.com with full permission to publish.

Funding

This work was supported by NIDA grants DA-052641 to L.J.B.; DA-044308, DA-049568, and DA-051551 to D.D.K.; and DA-042111 and DA-048931 to E.S.C. as well as by the Brain and Behavior Research Foundation (National Alliance for Research on Schizophrenia and Depression Young Investigator Awards) to E.S.C. and D.D.K., funds from the Seaver Family Foundation to A.O. and D.D.K., the Whitehall Foundation to E.S.C., and the Edward Mallinckrodt Jr. Foundation to E.S.C.

Author information

Author notes

  1. Lillian J. Brady and Kirsty R. Erickson contributed equally.

  2. Drew D. Kiraly and Erin S. Calipari are co-corresponding authors and contributed equally

Authors and Affiliations

  1. Department of Pharmacology, Vanderbilt University, TN, 37232, Nashville, USA

    Lillian J. Brady, Kirsty R. Erickson & Erin S. Calipari

  2. Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, 37232, USA

    Lillian J. Brady, Kirsty R. Erickson & Erin S. Calipari

  3. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA

    Kirsty R. Erickson & Erin S. Calipari

  4. Nash Family Department of Neuroscience, Icahn School of Medicine At Mount Sinai, New York, NY, 10029, USA

    Kelsey E. Lucerne, Aya Osman & Drew D. Kiraly

  5. Friedman Brain Institute, Icahn School of Medicine At Mount Sinai, New York, NY, 10029, USA

    Kelsey E. Lucerne, Aya Osman & Drew D. Kiraly

  6. Department of Psychiatry, Icahn School of Medicine At Mount Sinai, New York, NY, 10029, USA

    Aya Osman & Drew D. Kiraly

  7. Seaver Autism Center for Research and Treatment, Icahn School of Medicine At Mount Sinai, 1 Gustave L Levy Pl - Box 1230, New York, NY, 10029, USA

    Aya Osman & Drew D. Kiraly

  8. Vanderbilt Institute for Infection Immunology and Inflammation, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Erin S. Calipari

  9. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA

    Erin S. Calipari

  10. Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of Medicine, 865F Light Hall, 2215 Garland Avenue, Nashville, TN, 37232, USA

    Erin S. Calipari

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  1. Lillian J. Brady
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  2. Kirsty R. Erickson
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  3. Kelsey E. Lucerne
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  4. Aya Osman
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  5. Drew D. Kiraly
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  6. Erin S. Calipari
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Contributions

L.J.B. and K.R.E. collected data, analyzed data, made figures, and wrote the manuscript. K.E.L. and A.O. analyzed the data, made figures, and wrote the manuscript. E.S.C. and D.D.K. conceptualized the manuscript, analyzed data, made figures, and wrote the manuscript.

Corresponding authors

Correspondence to Drew D. Kiraly or Erin S. Calipari.

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Brady, L.J., Erickson, K.R., Lucerne, K.E. et al. Granulocyte colony-stimulating factor (G-CSF) enhances cocaine effects in the nucleus accumbens via a dopamine release–based mechanism. Psychopharmacology 238, 3499–3509 (2021). https://doi.org/10.1007/s00213-021-05967-9

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  • DOI: https://doi.org/10.1007/s00213-021-05967-9

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