Role of Selenium in Dopamine Transmission and Modulation by Methamphetamine.

Abstract

Selenium (Se) is an antioxidant trace element that is important for normal brain function. Se is incorporated into selenoproteins, a family of proteins with multiple functions that include protection from oxidative stress. Methamphetamine (METH) increases dopamine (DA) signaling by causing efflux of DA out of nerve terminals, resulting in increased oxidative stress from oxidized DA, and eventual degeneration of dopaminergic terminals. Se protects against METH-induced neurotoxicity while Se deficiency potentiates toxicity. Se may also be involved in DA transmision as Se deficiency increases DA turnover in rodents. We explored the possibility that Se may affect the physiological response to METH by using fast-scan cyclic voltammetry (FSCV) to record DA release and uptake kinetics in mouse brain slices. Action potential-dependent phasic DA release was simulated in the present study by electrically evoking release in brain slices. METH was applied to brain slices and phasic release recorded, as well as DA efflux, which was monitored in the absence of stimulation. Dietary Se restriction lasting 2 weeks reduced METH-induced DA efflux. Inhibition of the selenoprotein glutathione peroxidase (GPx) also reduced DA efflux through mechanisms involving ATP-sensitive K+ channels (KATP channels) and cannabinoid receptor 1 (CB1R). Chronic Se-deficient mice had reduced basal DA uptake rates, but no change in basal release. In response to METH chronic Se deficiency caused reduced DA efflux compared to Se-sufficient mice. METH also caused and increase in phasic DA release in chronic Se-deficient mice that can be attributed to increased DA vesicular release. Selenoprotein P (Sepp1)-KO mice had reduced baseline phasic DA release and uptake rates. In response to METH, phasic release was significantly potentiated due to increased DA vesicular release. METH-induced vesicular DA release in wild-type mice was found to be masked by D2R auto-inhibition, which may be dysfunctional in Sepp1-KO mice. METH-induced vesicular DA release was prevented in Sepp1-KO mice by purified Sepp1 protein acting on ApoER2 to promote D2R function. These results indicate that Se is directly involved in DA neurotransmission and modulates the DA response to METH. Furthermore, specific selenproteins play differential roles in regulating DA physiology.