Item Details

abstract

Dopamine transporter (DAT) functions to terminate synaptic dopamine (DA) signaling by taking up extracellular DA into neurons. Dysregulation of DAT has been implicated in several neurological and psychiatric diseases including drug addiction, attention deficit and hyperactive disorder, bipolar disorder, schizophrenia and Parkinson’s disease. Thus, it is important to understand the molecular and cellular mechanisms underlying dysfunctional DAT. The function and membrane compartmentalization of DAT are influenced by membrane cholesterol content as demonstrated in cultured cells. Depletion of membrane cholesterol by methyl-β-cyclodextrin reduces DAT reuptake and its localization in lipid rafts where cholesterol is most concentrated on the plasma membrane. This is of particular interest because some of the statins that are commonly used for treating hypercholesterolemia are blood-brain-barrier permeable and could alter DAT function through disruption of membrane cholesterol homeostasis. A few studies have reported deficits in working memory and other mild cognitive impairments in patients who receive treatment with lipophilic statins such as atorvastatin. DA signaling is critically involved in memory and cognition. However, it has yet to be investigated whether statin drugs alter DAT function and impair DA signaling. This study investigates the effects of atorvastatin, a commonly prescribed statin for hypercholesterolemia, on membrane cholesterol content and DAT surface expression using neuroblastoma 2A (N2A) cells stably expressing DAT. We found that atorvastatin dose-dependently reduced membrane free cholesterol levels. Furthermore, atorvastatin dose-dependently reduced DAT surface expression assessed by immunocytochemistry. Future experiments will use complementary approaches to further confirm these results and explore the functional consequence of cholesterol depletion by atorvastatin on DAT internalization and function. The potential effects of statin drugs on DAT expression and function may underlie the observed cognitive impairment in patients who chronically take lipophilic statins for the treatment of hypercholesterolemia. This project highlights brain cholesterol as a potential therapeutic target for restoring DAT function and DA signaling in diseases including addiction.

subject

Atorvastatin

Cholesterol

Dopamine Transporter

Trafficking

contributor

Adams, Kristen (author)

Chen, Rong (committee chair)

Marrs, Glen (committee member)

Howlett, Allyn (committee member)

date

2020-05-29T08:35:46Z (accessioned)

2020 (issued)

degree

Physiology and Pharmacology (discipline)

2025-05-18 (liftdate)

embargo

2025-05-18 (terms)

identifier

http://hdl.handle.net/10339/96807 (uri)

language

en (iso)

publisher

Wake Forest University

title

Atorvastatin Modulates Membrane Cholesterol Content and Surface Dopamine Transporter Levels in Neuroblastoma N2A Cells

type

Thesis