Function of the Human Dopamine Transporter After Heavy Metal and Psychostimulant Exposure

Abstract

Background
Psychostimulant use combined with environmental exposure to heavy metals may present a special risk to a user's neurological health at the level of dopamine transporter (DAT) function.
Goals
These investigations looked into how human DAT density and function were affected by low-concentration heavy metal and psychostimulant (co)exposure.
Materials and Procedures
PbCl2 (Pb), HgCl2 (Hg), cocaine (COC), and methamphetamine (MA) were administered to Neuro2A neuroblastoma cells (N2A) in order to measure changes in cell survival and the density and function of the human dopamine transporter (hDAT). The assays comprised [3H] dopamine (DA) absorption (hDAT functionality), [3H] GBR12935 binding (hDAT density), and Lactate Dehydrogenase activity (cell viability). The concentration employed in combination exposure experiments (10 μM for Hg and Pb; 100 nM for COC and MA) with an ideal exposure duration of 72 hours is the threshold for changes in cell viability of a metal or stimulant.
Findings
Pb and Hg both decreased cell viability in relation to concentration and exposure duration. N2A cells showed increased resistance to
the cytotoxicity caused by MA and COC. After being exposed to Hg, Pb, COC, or MA, the density of hDAT rose (from 115 to 175%)
in comparison to the vehicle values. In comparison to control values, hDAT density rose 161-288% following exposure to metal-psychostimulant combinations. While COC groups hindered uptake (17–20%), we saw the greatest increase in [3H] DA uptake in the MA group (35-81%). Exposure to each drug, either alone or in combination, raised the density of hDAT. Since changes in [3H] DA absorption did not coincide with changes in density, our findings imply that increased protein content did not correspond to greater functioning.
Conclusion
The ability to remove [3H] DA from the extracellular space is compromised due to decreased function, even if there is more hDAT protein at the cell surface. Therefore, after using psychostimulants, exposure to low levels of heavy metals may raise the risk of altered DA neurotransmission/turnover, which could lead to an exaggerated reaction or an elevated risk of toxicity.