Reserpine, vesicular monoamine transporter inhibition

Molecular cloning has identified two closely related but distinct vesicular monoamine transporters, VMAT1 and VMAT2 (Liu et al., 1992 Erickson et al., 1992 Liu and Edwards, 1997). Sequence analysis predicts 12 transmembrane domains with N- and C-termini in the cytoplasm, and the proteins show no sequence similarity to plasma membrane monoamine transporters (Nguyen et al., 1983 Neal and Chater, 1987 Neyfakh et al., 1991). Rather, they show similarity to bacterial proteins involved in detoxification (Figure 2). These bacterial proteins all function as H+ exchangers, and several are even inhibited by the same drugs that inhibit VMATs (e.g., reserpine). 

NE molecules are made inside into synaptic vesicles by the vesicular monoamine transporter (VMAT). This transport is an active, adenosine triphosphate (ATP)-requiring process. VMAT also transports DA, epinephrine and serotonin (5-HT). These hormones and transmitters are so-called monoamines (MO). Certain drugs, such as reserpine and tetrabenazine, inhibit the VMAT and suppress vesicular MO storage (Reinhard et al., 1988 Russo et al., 1994). 

In 955yBernard Brodie and colleagues at the NIH discovered that the drug, reserpine, results in a decrease in serotonin in the brain. Reserpine was isolated in 1952 from the dried root of Rauwolfia Serpentina (Indian snakeroot), and introduced into clinical medicine inl954. Reserpine blocks the uptake and storage of NE and DA into synaptic vesicles by inhibiting the vesicular monoamine transporters. 

Reserpine blocks the uptake (and storage) of norepinephrine and dopamine into synaptic vesicles by inhibiting the vesicular monoamine transporters. Brodie and colleagues found that reserpine also depleted serotonin from body tissues, including the brain. Their studies included patients with carcinoid tumors that produce serotonin, after there are metastases to the liver. 

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