Biphasic mechanisms of amphetamine action at the dopamine terminal (661.4)

Abstract

In light of recent studies suggesting that amphetamine (AMPH) increases spontaneous and electrically evoked dopamine release ([DA]o), we examined discrepancies between these findings and previous literature which has demonstrated marked decreases in [DA]o after AMPH. The current study has refined and expanded the mechanisms of AMPH actions by defining two mechanisms of AMPH effects at high and low doses, one dopamine transporter (DAT)‐independent and one DAT‐dependent, respectively. Using voltammetry in brain slices, we examined the effects of low, moderate, and high concentrations of AMPH across a range of tonic and phasic stimulation parameters (1 pulse; 5 pulse 20 Hz; 24 pulse 60 Hz) in wild‐type (WT) and DAT knockout (KO) mice. We discovered novel, biphasic, concentration‐dependent effects in WT mice, where AMPH increased [DA]o at low concentrations and decreased [DA]o at high concentrations. We then used DAT‐KO animals to examine the mechanisms by which AMPH exerts these effects. In DAT‐KO slices, [DA]o was decreased by all concentrations of AMPH, demonstrating that AMPH‐induced increases in [DA]o are entirely DAT‐dependent, while the decreases at high concentrations are DAT‐independent. We propose that when AMPH concentrations are low, they are insufficient to deplete dopamine vesicles, and therefore AMPH acts solely as a DAT blocker, increasing peak [DA]o. When AMPH concentrations are high, the added mechanism of vesicular depletion leads to reduced [DA]o. The biphasic mechanisms observed here support and extend the established actions of AMPH.Grant Funding Source: Supported by NIH grants DA021325, DA030161, DA006634, DA007246, DA031533, DA031791 and AA007565