Remodeling the Dysregulated Brain: PPARγ Agonism to Treat Cocaine Use Disorder

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists improve cognition and pathology in multiple neurological disorders, as demonstrated in both rodent models and human participants. Many of the mechanisms of PPARγ agonism are not fully understood in neurological contexts, particularly in the context of cocaine use disorder (CUD). The experiments outlined in this dissertation used a rodent model of CUD in which rats are trained to self-administer cocaine then placed into forced abstinence, during which they receive PPARγ agonist treatment or serve as a control. PPARγ agonist-treated rats in this model demonstrate attenuated cocaine-seeking behavior when re-exposed to the environmental and discrete cues previously paired with cocaine self-administration, and the studies in this dissertation focused on the changes to RNA expression, protein expression, and lipoprotein abundance which might be responsible for this attenuation. PPARγ is a nuclear receptor and transcription factor which forms a complex with phosphorylated extracellular signal-regulated kinase (pERK), and pERK is capable of inducing a signaling cascade that converges upon transcription of cAMP response elements (CREs). This work explored the genes differentially expressed by PPARγ agonism in the rodent model of CUD and, using Ingenuity® Pathway Analysis, determined that many biological functions and canonical pathways regulated by PPARγ agonism were related to cell death and remodeling mechanisms, and some were even enriched for PPAR response elements and/or CREs. Furthermore, the protein expression and lipoprotein abundance studies also supported remodeling, both remodeling driven by PPARγ agonism as well as that by cocaine self-administration/forced abstinence. These studies identified decreased expression of proteolipid protein 1, a protein important to myelination, and increased expression of aquaporin 4, a protein important to osmolarity, in the hippocampus of rats which had self-administered cocaine and received PPARγ agonist treatment compared to those which served as controls. Additionally, several specific white matter tracts demonstrated changes in lipoprotein abundance mediated by cocaine self-administration/forced abstinence or PPARγ agonist treatment, with one of the most notable being the forceps minor/external capsule ~3.24 millimeters lateral from the longitudinal fissure. Collectively, the work herein strongly supports that PPARγ agonism drives brain remodeling to resolve neurological disorder-associated dysregulation.