Although the neurochemical and neurobiological effects of various drugs of abuse are well-characterized, there is little information regarding the role of complex lipid remodeling within the context of addiction. The series of studies presented herein addressed these gaps in knowledge by testing the hypothesis that cocaine induces lipid alterations that may serve as indicators of addictive behaviors. Firstly, we demonstrated the effects of dietary fat intake and aging on the blood lipidome. These findings occurred in a stimuli-independent manner across several models, and emphasized the need to consider these factors in experiments prior to assessing the effect of any stimuli on lipidomic changes in the blood. Untargeted lipidomics revealed blood lipid remodeling of phospholipids, glycerolipids, and fatty acyls using both preclinical and clinical models of cocaine exposure. Cocaine exposure demonstrated region-specific changes in the rat brain lipidome that suggest that addictive behaviors, i.e. sensitization, extinction, and reinstatement, can induce widespread lipid alterations. Blood lipid changes could also be correlated to behavioral sensitization to cocaine in both rats and human models of exposure. Cocaine differentially regulated genes involved in fatty acid metabolism and mitochondrial biogenesis region-specifically in the brain. These effects indicate a potential role for cocaine in the maintenance of CNS energetics and lipid regulation. In summary, the data presented here demonstrated comprehensive lipidomic assessment of cocaine-induced lipid remodeling in blood and brain profiles. These findings provide a platform for discerning how changes in the lipidome may mediate some of the molecular adaptions of the brain in response to drugs of abuse.
