Multidimensional Top-Down Proteomics of Brain-Region-Specific Mouse Brain Proteoforms Responsive to Cocaine and Estradiol

Cocaine
addiction afflicts nearly 1 million adults in the United
States, and to date, there are no known treatments approved for this
psychiatric condition. Women are particularly vulnerable to developing
a cocaine use disorder and suffer from more serious cardiac consequences
than men when using cocaine. Estrogen is one biological factor contributing
to the increased risk for females to develop problematic cocaine use.
Animal studies have demonstrated that estrogen (17β-estradiol
or E2) enhances the rewarding properties of cocaine. Although E2 affects
the dopamine system, the molecular and cellular mechanisms of E2-enhanced
cocaine reward have not been characterized. In this study, quantitative
top-down proteomics was used to measure intact proteins in specific
regions of the female mouse brain after mice were trained for cocaine-conditioned
place preference, a behavioral test of cocaine reward. Several proteoform
changes occurred in the ventral tegmental area after combined cocaine
and E2 treatments, with the most numerous proteoform alterations on
myelin basic protein, indicating possible changes in white matter
structure. There were also changes in histone H4, protein phosphatase
inhibitors, cholecystokinin, and calmodulin proteoforms. These observations
provide insight into estrogen signaling in the brain and may guide
new approaches to treating women with cocaine use disorder.