IPA revealed top biological functions of Neurological Disease (including disorders of the basal ganglia) and Cell-to-Cell Signaling (particularly neurotransmission) that served to validate the fractionation and detection procedures. Top canonical pathways differing between EC and IC control rats included PKA Signaling, 14-3-3-Mediated Signaling and Dopamine Receptor Signaling, among many others. Four high-scoring networks point to novel areas such as energy metabolism, NFkB signaling, protein degradation, and AKT signaling. Cocaine self-administration regulated numerous proteins in common for EC and IC rats; however, in every case the cocaine-induced protein regulation was opposite for EC compared to IC rats. Top canonical pathways regulated by cocaine in both EC and IC groups included 14-3-3-mediated signaling, DNA Damage Checkpoint Regulation, Dopamine Receptor Signaling and Protein Ubiquitination Pathway. Many of the cocaine-regulated proteins are downstream of several neurodegenerative proteins including tau, beta-amyloid, presenilin 1 and huntingtin. Common network features regulated by cocaine in EC and IC rats included ERK signaling, insulin signaling and proteasomal degradation. These results confirm our earlier behavioral and biochemical assertions that EC and IC rats show drastically different responses to environmental challenges (e.g. cocaine) and provide exciting new directions in the search for better therapeutic targets for addiction. Current studies are underway in the analysis of nuclear and membrane fractions, as well as determination of PTM sites for many of the proteins discussed above.
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