|dc.description.abstract||Although the neurobiological mechanisms of cocaine are well studied, the extent of cocaine’s influence on the body has not been fully characterized. Similarly, the mechanisms by which cocaine induces these effects are not completely understood. This series of studies addressed this deficit by testing the hypothesis that cocaine induces alterations in hippocampal p21 expression via epigenetic mechanisms, and these alterations mediate cocaine-induced response. Both experimenter-administered, non-contingent and self- administered, contingent cocaine exposure increased p21 expression in the brain of rodents exclusively in the ventral sector of the hippocampus. Further, cocaine increased histone 3 acetylation of the p21 promoter region specifically in the ventral hippocampus, correlating to the increased expression observed. Suggestive to its wide breadth of physiological effects, cocaine also significantly altered the blood lipidome of mice, particularly affecting sphingolipids.
We utilized a knockout mouse model to determine the role of p21 on drug- induced response. Genetic ablation of p21 resulted in altered cocaine-induced
behavior in two separate assays. p21-/- mice portrayed a decreased locomotor response to an initial cocaine exposure, as well as increased cocaine-induced conditioned place preference and κ-opioid-induced conditioned place aversion. The effects of p21 also extended to the blood lipidome, as the abundance of several lipid species involved in various neurological processes significantly differed between the two mouse models. p21-/- mice also expressed higher levels of NeuN and DCX, two markers of neurogenesis, in the dorsal hippocampus compared to wild-type mice. While the behavioral differences observed between the two models could be attributed to this increased neurogenesis and, subsequently, enhanced cognitive ability, these inherent differences between p21-/- and wild-type mice could have implications reaching beyond addiction.
The data presented here demonstrate the novel findings that cocaine increases p21 expression in the brain region-specifically, correlating to alterations in the epigenetic status of p21. We observed that mice lacking functional p21 respond differently to cocaine exposure. Moreover, basal differences in neurogenesis and lipid profile between p21-/- and wild-type mice suggest a more comprehensive role for this cyclin-dependent kinase inhibitor in neuronal functions.||