Reduce Dopamine? Yes.*

The major theme of this blog is that dopamine reduction therapy is rational to test in clinical trials for people with Parkinson's. Today I'll review the data showing that dopamine is elevated inside the brain cells controlling movement in people with Parkinson's.

Doctors and people with PD know that dopaminergic therapy helps them move and function, so it probably doesn't make sense at first to try to reduce dopamine levels. (As an aside, this is not the same as lowering levodopa dose, which will be discussed in a future post.) What do the data say about the amount of dopamine in these brain cells that control movement, known as dopaminergic neurons?

We were the first to publish data showing that in people with PD, these neurons have elevated amounts of dopamine inside them, even though the total amount of dopamine in the brain tissue is low. Brain cells die in Parkinson's, and even before that, the cells lose some of their connections (axons), which is where dopamine works to allow neurons to communicate, necessary for movement, and where dopamine can be toxic to these neurons. There was some complex math involved in the paper we published, but here's how the math works. We can divide the total amount of dopamine by the amount of axon terminals to determine the amount per axon. While total amount of dopamine in brains of people who died with PD is very low, the loss of axons is even more profound, so that the calculation shows that the levels inside these neurons is higher in PD than in those without PD. Then we can divide that number by the amount of vesicles inside the axons. Vesicles are little balls that store dopamine and prevent it from forming toxic breakdown products. Think of vesicles as sequestering dopamine from the triggers for it to be metabolized. This calculation estimates how much of the dopamine in an average axon is in the cytosol where it forms toxins, rather than in the vesicles where it does not form toxins.

Especially when a scientific finding is reported that goes against convention, as was our report in 2021, corroborating data is critically important. In 1988, Mogi and colleagues used a direct test to show that the enzyme responsible for making dopamine had higher activity in PD than in those without PD. In 1990, Zigmond recalculated Hornykiewicz's 1973 findings to show that an indirect test also showed increased synthesis of dopamine.

Another way to show that elevations in neuronal dopamine is a problem (beyond that it is merely present) is to test what happens when dopamine levels are lowered. In 8 different laboratory models of disease, some focused on dopamine overload, some on synuclein overexpression and others studying genetic or toxin induced pathology, reducing dopamine reversed pathology - in all 8 models. The consistency of these laboratory data are impressive, but the real test will be when we treat people with Parkinson's.

When I discuss these data and ideas, the topic generally skips to the perspective that people need their dopaminergic drugs to function. And certainly that is true in many situations. But most of us realize that dopaminergic drugs don't fix the disease, they palliate symptoms. And if you ever wondered why increasing dopamine amount or effect doesn't fix the disease, one that is taught to be caused by dopamine deficiency, perhaps it is because the dopaminergic neurons experience Parkinson's as a disease of dopamine excess. So why would we expect more to work?

* Dopamine reduction is rational to test in a clinical trial but not in clinical practice, owing to the need to confirm the dose and how to manage any risks.