Reserpine, vesicular monoamine

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). 

Erickson JD, Eiden LE, Hoffman BJ (1992) Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc Natl Acad Sci USA 89 10993-10997. 

Naudon L, Raisman-Vozari R, Edwards RH, Leroux-Nicollet I, Peter D, Liu Y, Costentin J (1996) Reserpine affects differentially the density of the vesicular monoamine transporter and dihy-drotetrabenazine binding sites. Eur J Neurosci 8 842-846. 

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). 

Storage Vesicular monoamine transporter Reserpine (j) Tetrabenazine (j)... 

Erickson JD, Eiden LE, Hoffman BJ (1992) Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc Natl Acad Sci USA 89 10993-10997 Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E (1996) Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci USA 93 5166-5171 Faham S, Watanabe A, Besserer GM, Cascio D, Specht A, Hirayama BA, Wright EM, Abramson J (2008) The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science 321 810-814... 

NE secretion can be effectively decreased by administration of reserpine, an alkaloid isolated from a small woody perennial found in India (Rauwolfia), which has a high affinity for the vesicular monoamine transporter-2 (VMAT-2) and as such prevents NE storage. Alternatively, NE secretion can be increased by administration of tyramine (decarboxylated tyrosine), which is a constituent of a variety of foods including red wine, pickled herring and cheese. Amphetamine has a similar effect, which is most prominently manifested in the CNS. The termination of NE effects can be circumvented by the administration of cocaine, which blocks NE transport into presynaptic nerve endings (NET) an effect, which is also shared by some of the first generation antidepressants, such as imipramine. 

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. 

Effects of drug treatment on cytosolic levels of catecholamines and total oxidizable species were also investigated. Reserpine, an inhibitor of the vesicular monoamine transporter (this transporter loads vesicles with catecholamines), had no effect on the amount... 

Experiments of this kind have provided a great deal of evidence in favour of exocytotic release of vesicular noradrenaline. For example, by administering reserpine (which causes noradrenaline to leak out of the vesicles into the cytoplasm) together with an inhibitor of the enzyme monoamine oxidase (which will prevent metabolism of cytoplasmic noradrenaline), it is possible to redistribute the noradrenaline stored within nerve terminals because it leaks from the vesicles but is preserved within the neuronal cytoplasm. Under these conditions, the total amount of transmitter in the terminals is unchanged but impulse-evoked release rapidly diminishes. 

Iproniazid also prevents the reserpine syndrome in rats. Reserpine blocks vesicular uptake of monoamines which, as a consequence, leak from the storage vesicles into the cytosol. Although these monoamines would normally be metabolised by MAO, they are conserved when a MAO inhibitor (MAOI) is present, and so co-administration of reserpine and a MAOI leads to accumulation of monoamines in the neuronal cytosol. It is now known that, when the concentration of cytoplasmic monoamines is increased in this way, they are exported to the synapse on membrane-bound monoamine transporters. The ensuing increase in monoamine transmission, despite the depletion of the vesicular pool, presumably accounts for the effects of iproniazid on the behaviour of reserpine-pretreated rats. 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

Dopamine depleting agents. Reserpine, a natural alkaloid that blocks vesicular transport of monoamines, depletes stored monoamines, including DA. DA depletion is associated with the emergence of parkinsonism. This effect of reserpine was among the first clues that PD is the result of DA deficiency (see above). Generally, the parkinsonism resulting from reserpine is reversible. 

Rauwolfia Antipsychotic Reserpine Monoamine depletion via vesicular reuptake inhibition... 

Reserpine blocks vesicular storage of monoamines, prolonging their presence in cytoplasm. There they are degraded by MAO, leading to a depletion of monoamines in synaptic terminals of central and peripheral neurons, so that little or no neurotransmitter is released when the neuron depolarizes (Oates 1996). Reversal of this process requires synthesis of new vesicles, which occurs over a period of days to weeks after discontinuation of the drug. 

It is possible that antidepressant drugs have other targets in addition to their actions at cell surface monoamine transporters. AI-Damluji and Kopin (107) have described a novel amine uptake process in peptide-containing hypothalamic neurons, which they, named "transport-P." Like the vesicular transporters this process is driven by a proton gradient, but it is distinct from the vesicular transporters in being insensitive to reserpine, but sensitive to a variety of tricyclic antidepressants at micromolar concentrations (108). It is not clear, however, what role if any transport-P plays in the inactivation of the monoamine neurotransmitters. 

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