Vesicular transporters transport neurotransmitters into vesicles of nerve terminals and neuroendocrine cells and make them available for regulated release. VMAT1 is localized predominantly in the neuroendocrine cells, whereas VMAT2 is widely distributed in monoaminergic terminals and dendrites. In the dopaminergic nerve terminal, VMAT2 transports cytoplasmic dopamine and 1-methyl-4-phenylpyridium (MPP+) into the vesicles (16). Dopamine that is not incorporated into the vesicles gets oxidized spontaneously or by monoamine oxidase type A (MAO-A), leading ultimately to the formation of reactive oxygen species that are neurotoxic. The extent of melanization of midbrain dopamine neurons is directly proportional to the extent of expression of VMAT2, since highly active VMAT2 will incorporate cytoplasmic dopamine more efficiently into the vesicle, thereby reducing the formation of neu-romelanin. Cells that express VMAT2 less intensely are more vulnerable to neuro-toxins (17,18). In concordance with these observations in animals, VMAT2 expression is low in the SNpc and high in the VTA, which corresponds not only to the ratio of melanized to nonmelanized cells in the VTA and SNpc, but also to the loss of an increased number of cells in the SNpc. VMAT2 expression is higher in the VTA than the SNpc and may be an indicator of relatively decreased vulnerability of cell death in the VTA than the SNpc (9,19).
The dopaminergic synaptic transmission is terminated by the transportation of 95% of synaptic dopamine into the nigrostriatal terminals by the dopamine transporter (DAT) molecule (20). DAT also plays a major role in the neurotoxic effects of MPTP by transporting MPP+, the active mitochondrial toxic metabolite of MPTP, into the dopamine neuron terminals. DAT is an important and a specific marker for dopaminergic neurons (20,21). The intensity of expression of DAT mRNA in primate and human nigra is maximal at the caudal, ventral, and lateral group of dopamine neurons and gradually decreases medially in the VTA regions (19-23), corresponding with the pattern of dopaminergic cells that are highly melanized in the SNpc. The SNpc cells that express DAT very densely are the most severely affected in PD, and those VTA neurons expressing DAT less intensely demonstrate a less severe pattern of degeneration. The level of expression of DAT mRNA in the dopaminergic neurons of the arcuate and paraventricular nuclei of the hypothalamus, a group of dopamine neurons that do not degenerate in PD, is very low (20). In PD, the pattern of loss is directly proportional to the intensity of expression of DAT in these cells. The conclusions are supported by the observations that mice that over-express DAT are more vulnerable to neurotoxic effects of MPTP and DAT knockout mice are completely resistant to the neurotoxic effects of MPTP (24). Heptachlor and pyrethyroid pesticides increase the intensity of expression of DAT, which could lead to the transportation of endogenous and exogenous neurotoxins into the dopaminergic nerve terminals and cause toxic degeneration of SNpc neurons (24). These studies suggest that an increased intensity of expression of DAT in the highly melanized dopamine neurons of the SNpc could be an important factor that contributes to the increased vulnerability to neurotoxin-induced neurodegeneration (25).
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