Dopamine Transporter (DAT)
Neurons, or nerve cells, do not generally touch one another; they are separated by gaps known as synapses. In order to process information to run the body, the brain relies on signal molecules called neurotransmitters such as dopamine, serotonin, or norepinephrine to transport the instructions across the synapse. When the electrical impulses that carry information through the nervous system reach the end of the neuron, they release neurotransmitters that are stored in tiny sacs known as vesicles, located at nerve endings. The released neurotransmitter molecules diffuse across the synapse and lock into receptors on the neighboring nerve cell, which sends off a signal to pass the message along. With their message delivered, the neurotransmitter molecules detach from their target and are reabsorbed into the presynaptic neuron via a series of proteins known as transporters that reside on the neuron's outer membrane.
The dendrites of the dopamine neuron receive information from other cells. A signal is then transmitted down the axon to the terminals, where neurotransmitters relay information to target cells.
Enlarged view of a dopamine terminal. Dopamine (purple circles) is created from tyrosine and the molecules packaged into vesicles. In response to a signal, vesicles release their contents into the synapse. Dopamine can then diffuse out of the synapse, interact with receptors, or be returned to the neuron by the dopamine transporter.The number of neurons that utilize dopamine as a neurotransmitter are far fewer than the other types of brain neurons constituting only one out of every one million CNS neurons. Nonetheless, they play a very important role in regulating movement, motivation, cognition and hormone release. (1) Disturbances in the dopaminergic system have been implicated as contributors in the occurence of Parkinson's Disease (PD) and several neuropsychiatric disorders including ADHD.
The Dopamine Transporter (DAT) in Diagnostics and Pharmacological Therapies
Following its release in the synapse of a dopamine neuron and delivery of its message to the corresponding postsynaptic neuron, extracellular dopamine is quickly reabsorbed back into the presynaptic (or sending) neuron by DAT proteins. DATs are located on the membrane of dopamine-producing cells arising from a part of the brain called the substantia nigra. PD, which is caused by a progressive destruction of dopamine producing cells, is associated with a marked decrease in the number of DATs. ADHD may also be linked to an irregularity in the DAT protein in the brain. Therefore, using a DAT-selective molecular imaging agent, imaging techniques can directly evaluate the DAT concentration on the neuron terminals and aid in the diagnosis and differentiation of Parkinson's disease and ADHD. (2)
Preclinical studies using PD models in rodents and non-human primates have demonstrated that blockade of the DAT elevates the dopamine levels at the synapses and provides symptomatic relief in early and advanced PD. Though selective for dopamine, the DAT can also transport other substances back into the cell. There is a large body of evidence from structural, molecular biological and toxicological studies indicating that uptake of endogenous and/or exogenous neurotoxins by the DAT may play a role in the development of PD by interfering with mitochondrial function, which can lead to neuron death. Moreover, uptake and metabolism of dopamine itself, either produced by the cell or that generated from levodopa administration, may contribute to progression of PD. Studies have shown that Wild-type mice treated with a class of compounds called DAT blockers and genetic 'DAT knockout' mice are both resistant to the negative actions of specific neurotoxins (MPTP and 6-OHDA) on dopaminergic neurons. Therefore, as a potential therapeutic, a pharmacological blockade of DAT by potent and selective inhibitors may prevent the onset or slow the progression of PD, and also provide symptomatic benefits associated with increases in CNS dopamine levels.
1 Bannon M, Michelhaugh S, Wang J, Sacchetti P. The human dopamine transporter gene: gene organization, transcriptional regulation, and potential involvement in neuropsychiatric disorders. European Neuropsychopharmacology. 2001; Vol 11, 449-455.
2 Ilgin N, Zubieta J, Reich S.G., Dannals R.F., Ravert H.T., Frost J.J. PET imaging of the dopamine transporter in progressive supranuclear palsy and Parkinson's Disease. NEUROLOGY 1999; 52:1221 - 1226.