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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 11, 2006; DOI: 10.1124/jpet.106.103622

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Received for publication February 27, 2006.
Revised July 7, 2006.
Accepted for publication July 7, 2006.

Interaction of Amphetamines and Related Compounds at the Vesicular Monoamine Transporter

John S. Partilla 1, Allison G. Dempsey 1, Ameet S. Nagpal 1, Bruce E. Blough 2, Michael H. Baumann 3, Richard B. Rothman 3*

1 Clinical Psychopharmacology Section, IRP, NIDA, NIH, DHHS 2 Chemistry and Life Sciences Group, Research Triangle Institute International 3 Clinical Psychopharmacology Section, IRP, NIDA, NIH

* Address correspondence to: E-mail: rrothman{at}intra.nida.nih.gov

Abstract

Amphetamine-type agents interact with the vesicular monoamine transporter (VMAT2), promoting the release of intravesicular neurotransmitter and an increase in cytoplasmic neurotransmitter. Some compounds, like reserpine, "release" neurotransmitter by inhibiting the ability of VMAT2 to accumulate neurotransmitter in the vesicle, while 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: a) inhibition of [3H]dihydrotetrabenazine binding, b) inhibition of vesicular [3H]dopamine uptake, and c) release of pre-loaded [3H]dopamine and [3H]tyramine. Several important findings derive from this comprehensive study. First, our work indicates that most agents are VMAT2 substrates. Two, our data strongly suggest that amphetamine-type agents deplete vesicular neurotransmitter via a carrier-mediated exchange mechanism rather than via a free-base effect, although this conclusion needs to be confirmed via direct measurement of vesicular pH. Three, our data fail to reveal differential VMAT2 interactions among agents which do and do not produce long-term 5-HT depletion. Four, the data reported revealed the presence of two pools of [3H]amine within the vesicle, that which is free, and that which is tightly associated with the ATP/protein complex that helps store amine. Finally, the VMAT2 assays we've developed should prove useful for guiding the synthesis and evaluation of novel VMAT2 agents as possible treatment agents for addictive disorders.


Key words: amphetamine, cocaine, dopamine, seroronin, transporter, vmat


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