Role of the Dopamine Transporter in the Action of Psychostimulants, Nicotine, and Other Drugs of Abuse

Abstract

A number of studies over the last two decades have demonstrated the critical importance of dopamine (DA) in the behavioral pharmacology and addictive properties of abused drugs. The DA transporter (DAT) is a major target for drugs of abuse in the category of psychostimulants, and for methylphenidate (MPH), a drug used for treating attention deficit hyperactivity disorder (ADHD), which can also be a psychostimulant drug of abuse. Other drugs of abuse such as nicotine, ethanol, heroin and morphine interact with the DAT in more indirect ways. Despite the different ways in which drugs of abuse can affect DAT function, one evolving theme in all cases is regulation of the DAT at the level of surface expression. DAT function is dynamically regulated by multiple intracellular and extracellular signaling pathways and several protein-protein interactions. In addition, DAT expression is regulated through the removal (internalization) and recycling of the protein from the cell surface. Furthermore, recent studies have demonstrated that individual differences in response to novel environments and psychostimulants can be predicted based on individual basal functional DAT expression. Although current knowledge of multiple factors regulating DAT activity has greatly expanded, many aspects of this regulation remain to be elucidated; these data will enable efforts to identify drugs that might be used therapeutically for drug dependence therapeutics.

Intracellular Methamphetamine Prevents the Dopamine-induced Enhancement of Neuronal Firing

“…DAT at the cell surface is distributed between oligomers and monomers, where DAT monomers are internalized (Zhu and Reith) after amphetamine (51). Consistent with this idea, data Fleckenstein and co-workers (52) suggest the possibility that methamphetamine induces oligomerization of the transporter, whereas, a report by Reith group has shown that amphetamine promotes the formation of DAT monomers (55).…”

HIV-1 Tat Protein-Induced Rapid and Reversible Decrease in [3H]Dopamine Uptake: Dissociation of [3H]Dopamine Uptake and [3H]2β-Carbomethoxy-3-β-(4-fluorophenyl)tropane (WIN 35,428) Binding in Rat Striatal Synaptosomes

“…DATs are highaffinity targets for cocaine and amphetamine, both of which are highly addictive and widely abused substances (Zhu and Reith, 2008). Clinical studies using positron emission tomography have found that HIV-1-infected patients with HIV-1-associated dementia display a significant reduction in DAT density in the putamen and ventral striatum (Wang et al, 2004;Chang et al, 2008).…”

In-silico analysis of non-synonymous-SNPs of STEAP2: To provoke the progression of prostate cancer

“…It consists of 60 amino acids. When tyrosine is replaced with cysteine in DAT protein it results in decrease uptake of dopamine [67]. R290I: Arginine is replaced with isoleucine at position 290.…”