Effect of Cocaine and p21 on the Blood Lipidome

Cocaine is powerfully addictive and induces a breadth of physiological effects, even at low, recreational doses. To begin to discern the full extent of these effects, we used electrospray ionization‐mass spectrometry (ESI‐MS) by direct infusion to investigate drug‐induced alterations on the blood lipidome. Lipids were extracted from the whole blood of mice exposed to cocaine or saline using the Bligh‐Dyer method. ESI‐MS data was analyzed with multivariate principal component analysis to determine changes in lipid profile. Significant m/z features indicated alterations in four categories: fatty acyls, glycerolipids, glycerophospholipids and sphingolipids. Features were further identified into classes within each category, with prominent classes being acyl coenzyme A, triacylglycerol, cardiolipin and ceramide, respectively. While the directionalities varied, the greatest number of altered features were sphingolipids. Remarkably, some features correlated to drug‐seeking behaviors in cocaine‐treated mice, specifically locomotor response. How cocaine‐induced effects occur, including alterations in lipid profile, is not fully understood. Our data using a p21 knockout mouse model suggests a role for the cell cycle regulator in cocaine‐induced response in vivo and the effects of genetic ablation of p21 also extended to the blood lipidome. Knockout mice had distinct lipidomic profiles compared to wild‐type mice, indicating that p21 affects the blood lipidome. Again, the majority of significantly altered features were sphingolipids. Moreover, cocaine exposure also altered the blood lipidome in the knockout mice. Collectively, these results suggest not only a role for cocaine, but also for p21 in regulating the blood lipidome.