Journal
JOURNAL OF NEUROSCIENCE
Volume 41, Issue 7, Pages 1553-1565Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1452-20.2020
Keywords
cocaine; cytokine; neuroimmune; reinstatement
Categories
Funding
- National Institutes of Health (NIH) [DA-044308, DA-049568, DA-051551, DA-042111, DA-048931]
- National Alliance for Research on Schizophrenia and Depression Young Investigator Awards
- NIH Shared Instrument Grant [1S10OD019967-0, 1S10ODOD018034-01]
- Yale School of Medicine
- Yale/National Institute on Drug Abuse (NIDA) Neuroproteomics Center Grant [DA-018343]
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The research shows that G-CSF can accelerate cocaine extinction and reduce cue-induced cocaine seeking during abstinence by regulating proteins related to synapse and glutamate signaling in the mPFC. These findings suggest that G-CSF may serve as a research target to reduce drug craving or seeking behaviors, and its FDA-approved status could facilitate clinical translation swiftly.
Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Male Sprague Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multiregion discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.
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