Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine

PLoS One. 2013 May 3;8(5):e60763. doi: 10.1371/journal.pone.0060763. Print 2013.

Abstract

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Action Potentials
  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology*
  • Corpus Striatum / drug effects*
  • Corpus Striatum / physiology
  • Dextroamphetamine / pharmacology*
  • Dopamine / metabolism*
  • Dopamine / physiology
  • Dopamine Uptake Inhibitors / pharmacology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / physiology
  • Electric Stimulation
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Secretory Vesicles / metabolism
  • Synaptic Transmission / drug effects

Substances

  • Central Nervous System Stimulants
  • Dopamine Uptake Inhibitors
  • Cocaine
  • Dextroamphetamine
  • Dopamine