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NEUROPHARMACOLOGY

Interaction of Amphetamines and Related Compounds at the Vesicular Monoamine Transporter

Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland. (J.S.P., A.G.D., A.S.N., M.H.B., R.B.R.); and Chemistry and Life Sciences Group, Research Triangle Institute International, Research Triangle Park, North Carolina (B.E.B.)

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.

Address correspondence to: Dr. Richard B. Rothman, Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Dr., Baltimore, MD 21224. E-mail: rrothman{at}mail.nih.gov

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