Author ORCID Identifier

https://orcid.org/0000-0002-8716-8812

Year of Publication

2020

Degree Name

Master of Science (MS)

Document Type

Master's Thesis

College

Medicine

Department

Medical Sciences

First Advisor

Dr. Pavel Ortinski

Second Advisor

Dr. Chris Richards

Abstract

Methamphetamine is a highly addictive psychostimulant drug. There are currently no FDA-approved pharmacological treatments for methamphetamine addiction. Pharmacologically, (+)-methamphetamine is a dopamine releasing agent and dopamine transporter substrate that redistributes dopamine from intracellular vesicles via the vesicular monoamine transporter 2 (VMAT2) and reverses the direction of dopamine transport in the dopamine transporter. Methamphetamine, cocaine, and other drugs of abuse are also sigma-1 receptor ligands, and previous studies have demonstrated the role of the sigma-1 receptor in modulating the behavioral and cellular effects of these drugs. However, almost all these studies were conducted in cell culture systems or with emphasis on the neuronal effects of sigma-1 receptor binding.

In the literature, the sigma-1 receptor localizes robustly within neurons throughout the brain. However, there are conflicting results regarding localization in astrocytes. Here, immunohistochemical experiments were conducted on rat brain tissue containing either the nucleus accumbens or the prelimbic cortex, two brain regions critical in mediating drugseeking behavior, in order to confirm expression of the sigma-1 receptor in astrocytes. It was determined that the sigma-1 receptor is ubiquitously expressed among neurons and modestly expressed among glial fibrillary acidic protein (GFAP)-positive astrocytes. There were no noted statistically significant differences between the proportion of cell types expressing the sigma-1 receptor in the prelimbic cortex and the nucleus accumbens. Next, the effect of methamphetamine and the role of the sigma-1 receptor on astrocytic morphology and sigma-1 receptor distribution were probed by incubating slices of striatal tissue in methamphetamine solution with or without the sigma-1 receptor antagonist BD1063 and the sigma-1 receptor agonist PRE-084. Only the methamphetamine-treated slice exhibited a significantly different amount of stellations than the other slices. The sigma-1 receptor antagonist BD-1063 and PRE-084 abolished the redistribution of sigma-1 receptor to the processes of the astrocytes induced by methamphetamine. Thus, the data confirms that astrocytes in both the prelimbic cortex and nucleus accumbens express the sigma-1 receptor. Moreover, methamphetamine induces statistically significant redistribution of the sigma-1 receptor that is abolished by BD-1063 and PRE-084.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.363

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