Differential effects of psychoactive substances on human wildtype and polymorphic T356M dopamine transporters (DAT).

Differential effects of psychoactive substances on human wildtype and polymorphic T356M dopamine transporters (DAT). Toxicology. 2019 Apr 19;: Authors: Zwartsen A, Litjens CH, Hondebrink L, van den Heuvel JJ, Greupink R, Russel FG, de Lange DW, Legler J, Koenderink JB, Westerink RH Abstract Many psychoactive substances affect the human dopamine (DA) reuptake transporter (hDAT). Polymorphisms in the encoding gene could affect the functionality of the transporter and consequently alter effects of psychotropic and recreational drugs. Recently, a T356 M single nucleotide polymorphism in the human SLC6A3 gene was described, which resulted in functional impairments of DA uptake. Therefore, we investigated the effects of 10 psychoactive substances (0.01-1000 µM)) on DA uptake in human embryonic kidney (HEK) 293 cells transiently overexpressing wildtype (WT) or T356 M hDAT. Our data shows that T356 M hDAT has a 3 times lower Vmax and a 3 times higher Km compared to WT hDAT. Additionally, all psychoactive substances inhibited DA uptake by T356 M and WT hDAT. The DA reuptake inhibitors (methylphenidate, cocaine, and bupropion) inhibited DA uptake by WT hDAT most potently, followed by amphetamine-type stimulants [4-fluoroamphetamine (4-FA), amphetamine and MDMA], selective serotonin reuptake inhibitors (SSRI; fluoxetine and citalopram) and arylcyclohexylamines [methoxetamine (MXE) and ketamine]. Compared to DA uptake by WT hDAT, buprop...
Source: Toxicology - Category: Toxicology Authors: Tags: Toxicology Source Type: research