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Access Type

WSU Access

Date of Award

January 2023

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Anna Moszczynska

Abstract

Repetitive administration of methamphetamine (METH) in significant amounts and over an extended period can lead to the development of METH use disorder (MUD), characterized by cognitive, behavioral, and physiological impairments. Studies have shown that many of the clinical symptoms associated with MUD are due to, at least in part, a result of METH-induced neurotoxicity. Our group has previously demonstrated that high-dose binge METH (10 mg/kg, i.p. × 4, at 2-hr intervals) selectively decreased Parkin levels in rat striatal synaptic terminals as early as 1 hour (hr) post METH treatment. We have consistently demonstrated that chronic METH (10 mg/kg/day, i.p. for 10 days) administration in rats leads to persistent decreases in striatal Parkin levels even at ten days post METH treatment. Pathologically, Parkin deficits can culminate into aberrant homeostatic processes, mainly impaired mitochondrial function, increased oxidative stress, dysfunctional UPS, protein aggregation, and astrogliosis, which are also reported to play an underlying role in the development of METH-induced neurotoxicity leading to many of the clinical symptoms associated with MUD. To date, no studies have investigated Parkin's feasibility as a pharmacotherapeutic target in treating MUD. In the current study, we used genetically engineered rats, mainly Parkin knockout (PKO) and Parkin overexpressing (PO) rats, to evaluate Parkin as a potential pharmacotherapeutic target for treating MUD. We found that PKO rats self-administered more METH and spent more time in the METH-paired environment than WT rats, whereas WT rats overexpressing Parkin in the NAc at least sixfold self-administered less METH and spent less time in the METH-paired environment. We also found that PKO rats overexpressing Parkin in the NAc self-administered less METH during the initiation phase of METH self-administration than non-overexpressing PKO rats.Contrary to PKO mice, which exhibit increases in anxiety-like behavior and impaired memory, in the present study, we found that PKO rats exhibit positive prophylactic behavioral overcompensation for lack of Parkin, mainly decreases in anxiety-like behavior and enhanced memory performance. Moreover, the current report supports the view that the pre-existing behavioral neuro-compensation in PKO rats is not linked to an increased propensity for high METH intake; however, during withdrawal, it leads to a raised negative affect stage associated with METH use, whereas overexpression of Parkin in NA is neuroprotective as it lowers the anxiety-related risk factor during METH withdrawal. Furthermore, the Gene Set Enrichment Analysis (GSEA) revealed that PKO rats have significantly downregulated proteins and pathways associated with energy production and oxidative stress. In contrast, we found that rats with high levels of Parkin overexpression in the nucleus accumbens had significantly upregulated energy metabolism and Krebs cycle pathways. In summary, the data from the current report suggest that overexpression of Parkin in the nucleus accumbens is neuroprotective and therapeutic, at least in part, by lowering METH intake during the intoxication stage, by reducing anxiety-related risk factor during METH withdrawal and negative affect stage, and possibly through fulfilling energy requirements of METH-exposed accumbal neurons by strengthening mitochondrial function and oxidative stress response pathway during pre-occupation and anticipation stage.

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