Investigating Proteins Mediating Ubiquitin-Protein Ligase Parkin-Induced Attenuation of Methamphetamine Relapse

Methamphetamine (METH) use disorder (MUD) is a world-wide health problem. In the United States, more than 700,000 people abuse METH and deaths from METH overdose are rapidly rising. Despite numerous clinical trials conducted to date, there is no FDA-approved pharmacotherapy for MUD. Relapse is the biggest challenge in MUD. Preclinical studies have identified several drugs from different classes as effective against METH relapse, including glutamatergic, dopaminergic, and anti-inflammatory drugs but they have not produced desired results in those who use METH heavily. There is a clear need for novel pharmacotherapies for MUD. Novel pharmacotherapies require novel drug targets. The protein-ubiquitin ligase parkin is an attractive novel drug target for pharmacologic intervention because it is involved in several cellular mechanisms mediating relapse. We have demonstrated that young adult Park2-/- knockout rats not only self-administer more METH but also seek METH more than wild-type rats during the drug-primed relapse. Furthermore, we have demonstrated that parkin overexpression in the nucleus accumbens decreases METH self-administration. This proposal aims to determine whether overexpression of parkin in the nucleus accumbens and dorsolateral striatum decreases METH seeking during the relapse more than parkin overexpression in the nucleus accumbens alone, and which proteins and pathways are responsible for parkin effects in the nucleus accumbens vs. dorsolateral striatum. The Specific Aim 1 will determine whether male and female rats overexpressing parkin in the nucleus accumbens and dorsolateral striatum self-administer less METH during extended-access intravenous METH self-administration and during METH-induced relapse than rats overexpressing parkin only in the nucleus accumbens. The Specific Aim 2 will assess the proteomic landscape in the nucleus accumbens and dorsolateral striatum before and after METH-induced relapse. Specifically, we will first identify proteins differentially regulated by parkin overexpression in the nucleus accumbens and dorsolateral striatum. We will subsequently identify overrepresented canonical pathways, upstream regulators, protein networks, biological processes, and functions involving these proteins using bioinformatic approaches. The results from this research have a high potential to identify new protein drug targets downstream of parkin for MUD pharmacotherapy. The project is relevant to the Center’s mission because it will elucidate proteomics of altered signaling in MUD in two brain areas involved in development of cravings and relapse, and will determine which of the METH-induced proteomic changes can be rescued by parkin overexpression. These two data sets will serve as preliminary data for R01 NIH grant application for investigating proteomics of METH-altered signaling in other brain areas involved in relapse to drug use.