The Vesicular Monoamine Transporter

The vesicular monoamine transporter (VMAT) is a membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.^1,2 By accumulating both newly synthesized neurotransmitter molecules and freshly returned neurotransmitter molecules from the synapse, VMAT function plays a critical role in the signaling process between monoamine neurons. The VMAT exists in 2 distinct forms: VMAT1 and VMAT2.³

VMAT1, previously known as the chromaffin granule amine transporter, is found in extraneural tissues including the chromaffin cells of the adrenal medulla and endocrine and paracrine cells of the GI tract.^4,5 VMAT2, previously known as the synaptic vesicular monoamine transporter, is primarily located in neuronal cells of the central, peripheral, and enteric nervous system. Although VMAT2 is also present in the chromaffin cells of the adrenal medulla, it is the VMAT form of primary psychiatric interest. However, interesting recent evidence suggests that VMAT1 may also be present in the human brain, perhaps concentrated in the substantia nigra.^6,7

Mechanisms of VMAT2
VMAT2 is the only molecule able to selectively recognize and transport all of the biogenic amine neurotransmitters across biomembranes. In this way, the VMAT2 is distinct from the plasma membrane neurotransmitter transporters (dopamine [DAT], serotonin [SERT], and norepinephrine(Drug information on norepinephrine) [NET]), which selectively move only 1 of the neurotransmitters from the synapse into the cell. It is also distinct from the many monoamine receptors that respond selectively to individual neurotransmitters based on the receptor type's cellular location and the signaling proteins with which it couples. Thus, VMAT2 is not selective; the DAT, SERT, and NET are selective for each neurotransmitter, while numerous receptor subtypes respond to the individual monoamines in highly individualized ways. One would predict the most narrow and specialized effects to occur through receptor activation, and the most widespread effects through VMAT2 function.

Even though monoamine neurons represent a relatively small proportion of neurons in the brain, they are of great psychiatric and neurological significance.⁸ Unfortunately, at this time, the interpretation of VMAT2 function remains complex, and a considerable amount of the available experimental data predate VMAT2 cloning and are based on whole brain experiments rather than simpler systems using complementary DNA expressed in nonneuronal cells or dissected neurons. Thus, many aspects of the VMAT2 function and pharmacology have not been fully determined.

VMAT physiology
Like plasma membrane transporters, such as DAT, SERT, and NET, VMAT2 displays a similar size and molecular topography with 12 transmembrane domains and both tails located in the interior.^9,10 Surprisingly, however, there is limited amino acid homology and the VMAT is more closely related to other transporter families, such as the multi-drugresistant transporter family.^11,12 VMAT physiology is distinct from plasma membrane transporters in several important ways:

• It uses an H⁺ ion (proton) gradient energetically to transport substrates rather than the Na⁺⁺K⁺ gradient used by DAT, SERT, and NET.
• The extracellular environment for VMAT is actually cytoplasmic, and the cytoplasmic face is actually intravesicular.¹³
• The access of substrates and drugs to the VMAT is more complicated, because it requires transport of the substrate or drug molecule across the plasma membrane into the cell as a first step, either via diffusion or coupled to a plasma membrane transporter.

Thus, access of VMAT drugs or substrate sequestration into the intracellular vesicle involves a kinetic interaction between the plasma membrane transporter and VMAT, with complex ramifications that remain to be delineated.

Currently all drugs known to bind to the VMAT inhibit its function, similar to the manner in which antidepressants and stimulants affect SERT, NET, or DAT. Thus, VMAT ligands are best referred to as inhibitors, rather than antagonists, since the existence of direct agonist drugs, which bind to and increase VMAT activity, is not proved. However, indirect agonists, which affect the trafficking of the VMAT into and out of functional position, are likely to be discovered, as has been the case with plasma membrane transporters.^14-18 Although VMAT agonists, direct or indirect, have not been identified, theoretically, this class of drugs has applications as neuroprotective agents, particularly in a dopamine(Drug information on dopamine)rgic condition such as Parkinson disease in which loose dopamine may be neurotoxic, and for substance abuse treatment by modulating dopamine-related reward.^19,20 A recent preliminary experiment has claimed that bupropion may have a VMAT2 stimulatory effect, but confirmation that the apparent effect is mediated solely through a VMAT2 interaction that could be accomplished in intact human participants remains a considerable project.²¹

Recent genetic studies suggest that some regions of the VMAT2 gene might vary in a way that could serve as a genetic substrate for susceptibility to schizophrenia, bipolar disorder, or alcoholism.^6,22-26 Such observations could become of great significance, but remain inconclusive until larger population-based studies support and further illuminate the results.

Therapeutics
Currently, 2 VMAT inhibitors are available in the United States for clinical use: reserpine(Drug information on reserpine) (Figure), available since 1957, and tetrabenazine(Drug information on tetrabenazine), available as an orphan drug and recently recommended for approval by the FDA. Reserpine, the best-known VMAT ligand, has been used in traditional medicine in India for centuries. Reserpine is derived from the Rauwolfia plant species and has one of the most complex structures of all known natural alkaloids.²⁷ It binds to the amine substrate site of the VMAT with high affinity and irreversibly blocks the uptake of monoamines into secretory vesicles.²⁸ Its use in modern Western medicine began in the 1950s as an antihypertensive and an antipsychotic agent. Subsequently, a syndrome of depression and lethargy induced by reserpine, and the nearly simultaneous discovery of the therapeutic efficacy of tricyclic antidepressants, led to the formulation of the biogenic amine hypothesis of depression.⁸

Reserpine is currently used as a second-line antihypertensive agent and is also approved for use in psychotic disorders. Reserpine is rarely used in the United States for hypertension because of its adverse effects and the many alternative therapies. However, it remains common abroad because it is economical. At present, the most likely clinical scenario to be encountered by the North American psychiatrist involving VMAT is an international visitor taking reserpine for hypertension.

Reserpine is still used for the treatment of psychosis in patients with troublesome extrapyramidal effects from dopamine receptor antagonists. In rare instances, a trial of reserpine might be warranted in a younger patient who has psychotic episodes and has serious choreiform or athetotic movements associated with profound tardive dyskinesia. It is more usual to treat elderly patients who have advanced tardive dyskinesia with large doses of antipsychotics, which suppress the abnormal movements, although worsening the underlying pathophysiology (Table 1).

Tetrabenazine has recently been approved in the United States for the treatment of choreiform movements in Huntington disease. Tetrabenazine is also available internationally for the management of other hyperkinetic disorders. It is not clear why tetrabenazine is more effective than reserpine in chorea, but the effect may be related to its greater activity in dopaminergic neurons, which might involve antagonistic activity on dopamine receptors beyond VMAT2 effects (Table 2).²⁹