In tomorrow's Science, Bjorn Falkenburger, Karen Barstow, and Isabelle Mintz of Boston University Medical Center demonstrate a novel mechanism for dopamine release in the substantia nigra (SN). They suggest that commonly prescribed antidepressants might act via this mechanism to treat early Parkinson's disease.
The classic notion of dopamine release involves exocytosis of this transmitter at the axon terminals of dopaminergic neurons. This happens in the striatum, the target area to which SN neurons project. (Neurons in this projection pathway die in Parkinson's.) Researchers have long known that dendrites on the cell bodies of dopaminergic SN neurons also release dopamine, perhaps in a self-inhibitory way, but were puzzled by how this happens normally.
Falkenburger et al. used patch-clamping (which enables recording from single membrane channels) and other electrophysiological methods in rat brain slices. First they confirmed the previous assumption that dopaminergic neurons in the striatum, when stimulated by glutamate release from projecting subthalamic neurons, release dopamine from their dendrites to inhibit their own excitability. More importantly, however, the authors also showed that the dendrites release dopamine not by fusing dopamine-laden vesicles with the membrane, but by throwing dopamine transporters (DATs) into reverse gear. At faraway axon terminals, the transporter removes excess dopamine from the synaptic cleft and so reduces its effect, yet on dendrites of the same neuron, the transporter dumps dopamine out. It was known that other transporters could reverse themselves under certain pathological conditions, including ischemia, but this research demonstrates that this happens physiologically in a neuronal population central to PD.
This is intriguing because DAT inhibitors are widely used to treat depression, attention-deficit disorder, and addiction. This paper suggests that these drugs work not only by facilitating dopamine's effect at terminal synapses but also by simultaneously inhibiting dopamine release from dendrites. Clinically, this work may be relevant because subthalamic neurons fire excessively in PD, which leads to increased dopamine efflux from niagral dendrites. Since dopamine can be neurotoxic, the authors speculate that dopamine transporter inhibitors might be neuroprotective in early Parkinson's.
"I have for years thought that DAT inhibitors may be useful in the early stages of the disease," comments Bertha Madras of the New England Primate Research Center in Southborough, Massachusetts, who studies DAT inhibitors in a primate model of PD. "The authors' speculation is supported by some of our own data." Madras also points out that late-onset depression frequently precedes the development of PD.
In a Perspective article in Science, Randy Blakely at the Vanderbilt Center for Molecular Neuroscience in Nashville, Tennessee, notes that the drug of abuse "ecstasy" triggers serotonin efflux through its transporter. He predicts that reverse traffic through transporters may soon become a more general phenomenon in neuroscience research.—Gabrielle Strobel
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- Falkenburger BH, Barstow KL, Mintz IM. Dendrodendritic inhibition through reversal of dopamine transport. Science. 2001 Sep 28;293(5539):2465-70. PubMed.
- Blakely RD. Neurobiology. Dopamine's reversal of fortune. Science. 2001 Sep 28;293(5539):2407-9. PubMed.