| |
| author |
Tanner J. Euston
| | title |
Investigating the role of granulocyte colony stimulating factor as a regulator of the striatal proteome
| | abstract |
Pathologic use of illicit drugs represents a major public health concern and creates
significant economic and social costs. Addiction to cocaine and other psychostimulants remains
a major cause of this morbidity. The pathophysiological mechanisms that lead to persistent and
dysregulated drug use remain incompletely understood, and there are currently no FDA-
approved pharmacotherapies for treatment of psychostimulant use disorders. There is growing
evidence that dysregulation of the immune system plays a role in the pathophysiology of
multiple psychiatric disorders including major depressive disorder and schizophrenia. While
cocaine is known to have immunomodulatory effects, the link between these immune
interactions and pathological use behaviors has only recently been investigated. We recently
identified granulocyte-colony stimulating factor (G-CSF) as a cytokine that is increased in serum
and brain by chronic cocaine. Peripheral administration of G-CSF enhances cocaine place
preference and cocaine intake in a self-administration model, and also facilitates cocaine-
induced neuronal activation in the nucleus accumbens and prefrontal cortex. While G-CSF has
clear effects on synaptic and behavioral plasticity, the molecular mechanisms underlying these
effects remains unclear. To interrogate changes induced by G-CSF in the setting of active
cocaine treatment a 2 x 2 design was utilized with animals injected with Saline or Cocaine
(7.5mg/kg) and PBS or G-CSF once daily for seven days. This was followed by discovery
proteomics analysis of the nucleus accumbens (NAc) using data-independent acquisition mass
spectrometry analysis. As expected, there were many proteins that were significantly altered by
one week of cocaine treatment. However, treatment with G-CSF alone resulted in regulation of
an even larger number of proteins, and co-treatment with the two resulted in the largest
number of significantly regulated proteins — suggesting a significant interaction between the
two. Gene ontology analysis of samples from G-CSF + Cocaine treated animals showed that
there was a strong upregulation of proteins associated with the synaptic compartment, with a
number of both pre and postsynaptic proteins demonstrating significant alterations.
Confirmatory Western blot analysis demonstrate similar increases in levels of PSD-95 and GluR1
by G-CSF + cocaine in a separate cohort of animals. These findings complement our previous
work and suggest that in the presence of G-CSF the ability of cocaine to cause synaptic
remodeling is enhanced.
| | school |
The College of Liberal Arts, Drew University
| | degree |
B.A. (2019)
|
| advisor |
Tina McKittrick
|
| committee |
Graham Cousins
Marvin Bayne
|
| full text | TJEuston.pdf |
| |
