Interaction of amphetamines and related compounds at the vesicular monoamine transporter

John S. Partilla, Allison G. Dempsey, Ameet S. Nagpal, Bruce E. Blough, Michael H. Baumann, Richard B. Rothman

Research output: Contribution to journalArticlepeer-review


Amphetamine-type agents interact with the vesicular monoamine transporter type 2 (VMAT2), promoting the release of intravesicular neurotransmitter and an increase in cytoplasmic neurotransmitter. Some compounds, such as reserpine, "release" neurotransmitter by inhibiting the ability of VMAT2 to accumulate neurotransmitter in the vesicle, whereas other types of compounds can release neurotransmitter via a carrier-mediated exchange mechanism. The purpose of this study was to determine, for 42 mostly amphetamine-related compounds, their mode of interaction with the VMAT2. We used a crude vesicular fraction prepared from rat caudate to assay VMAT2 activity. Test compounds were assessed in several assays, including 1) inhibition of [3H]dihydrotetrabenazine binding, 2) inhibition of vesicular [3H]dopamine uptake, and 3) release of preloaded [3H]dopamine and [3H]tyramine. Several important findings derive from this comprehensive study. First, our work indicates that most agents are VMAT2 substrates. Second, our data strongly suggest that amphetamine-type agents deplete vesicular neurotransmitter via a carrier-mediated exchange mechanism rather than via a weak base effect, although this conclusion needs to be confirmed via direct measurement of vesicular pH. Third, our data fail to reveal differential VMAT2 interactions among agents that do and do not produce long-term 5-hydroxytryptamine depletion. Fourth, the data reported revealed the presence of two pools of [ 3H]amine within the vesicle, one pool that is free and one pool that is tightly associated with the ATP/protein complex that helps store amine. Finally, the VMAT2 assays we have developed should prove useful for guiding the synthesis and evaluation of novel VMAT2 agents as possible treatment agents for addictive disorders.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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