Quantification of reserve pool dopamine in methionine sulfoxide reductase A null mice

Abstract

Methionine sulfoxide reductase A knockout (MsrA−/−) mice, which serve as a potential model for neurodegeneration, suffer from increased oxidative stress and have previously been found to have chronically elevated brain dopamine (DA) content levels relative to control mice. Additionally, these high levels parallel the increased presynaptic DA release. In this study, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to quantify striatal reserve pool DA in knockout mice and wild-type control mice. Reserve pool DA efflux, induced by amphetamine (AMPH), was measured in brain slices from knockout and wild type (WT) mice in the presence of α-methyl-p-tyrosine, a DA synthesis inhibitor. Additionally, the stimulated release of reserve pool DA, mobilized by cocaine (COC), was measured. Both efflux and stimulated release measurements were enhanced in slices from knockout mice, suggesting that these mice have greater reserve pool DA stores than wild-type and that these stores are effectively mobilized. Moreover, dopamine transporter (DAT) labeling data indicate that the difference in measured DA efflux was likely not caused by altered DAT protein expression. Additionally, slices from MsrA−/− and wild-type mice were equally responsive to increasing extracellular calcium concentrations, suggesting that potential differences in either calcium entry or intracellular calcium handling are not responsible for increased reserve pool DA release. Collectively, these results demonstrate that MsrA−/− knockout mice maintain a larger DA reserve pool than wild-type control mice, and that this pool is readily mobilized.