Effects of Heavy Metals and Psychostimulants on Dopamine Transporter Function

Abstract

Heavy metals may alter the abuse liability of drugs due to actions on the dopamine transporter (DAT). This study examined the effects of extended, low-level heavy metal and psychostimulant co-exposure on DAT function. SK-N-SH cells, incubated in the presence of multiple concentrations of lead (Pb), mercury (Hg), cocaine (COC) and methamphetamine (MA), were used to measure LDH activity to determine optimum time/concentration for sublethal exposure assays. Parallel studies were conducted on non-neuronal vs. neuronal cell lines, COS-7(hDAT) and N2A(hDAT) respectively. [3H]GBR12935 binding assays were performed to determine DAT expression at the plasma membrane. [3H]Dopamine uptake assays were conducted to establish effects on DAT functioning. LDH activity significantly increased in both a concentration- and time-dependent manner. Sublethal concentrations of drugs/metals were chosen for further studies (10 ?M for HgCl2 and PbCl2; 100 nM for COC and MA), using a 72 h exposure. COS-7(hDAT) cells revealed expression of DAT, but no DA uptake. N2A(hDAT) cells showed higher expression of functioning DAT. Statistical analysis of the treatment effect on DAT density or DA uptake through the DAT revealed no significance in either cell line. Overall, a trend was observed where DAT density was increased, but caused functional decreases in DA clearance were observed. Individuals exposed to low-levels of Hg, may be at risk for increased DA neurotransmission/ turnover following psychostimulant use, resulting in an elevated addictive, or toxic, potential of these already addictive drugs.