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Challenging Parkinson's Dogma: Dopamine May Not Be the Only Key Player in This Tragic Neurodegenerative Disease

ScienceDaily (Oct. 24, 2012) — Scientists may have discovered why the standard treatment for Parkinson's disease is often effective for only a limited period of time. Their research could lead to a better understanding of many brain disorders, from drug addiction to depression, that share certain signaling molecules involved in modulating brain activity.

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A team led by Bernardo Sabatini, Takeda Professor of Neurobiology at Harvard Medical School, used mouse models to study dopamine neurons in the striatum, a region of the brain involved in both movement and learning. In people, these neurons release dopamine, a neurotransmitter that allows us to walk, speak and even type on a keyboard. When those cells die, as they do in Parkinson's patients, so does the ability to easily initiate movement. Current Parkinson's drugs are precursors of dopamine that are then converted into dopamine by cells in the brain.

The flip side of dopamine dearth is dopamine hyperactivity. Heroin, cocaine and amphetamines rev up or mimic dopamine neurons, ultimately reinforcing the learned reward of drug-taking. Other conditions such as obsessive-compulsive disorder, Tourette syndrome and even schizophrenia may also be related to the misregulation of dopamine.

In the October 11 issue of Nature, Sabatini and co-authors Nicolas Tritsch and Jun Ding reported that midbrain dopamine neurons release not only dopamine but also another neurotransmitter called GABA, which lowers neuronal activity. The previously unsuspected presence of GABA could explain why restoring only dopamine could cause initial improvements in Parkinson's patients to eventually wane. And if GABA is made by the same cells that produce other neurotransmitters, such as depression-linked serotonin, similar single-focus treatments could be less successful for the same reason.

"If what we found in the mouse applies to the human, then dopamine's only half the story," said Sabatini.

A detailed view of dopamine neurons.

The surprising GABA story began in the Sabatini lab with a series of experiments designed to see what happens when cells release dopamine. The scientists used optogenetics, a powerful technique that relies on genetic manipulation to selectively sensitize cells to light. In laboratory dishes, researchers tested brain tissue from mice engineered to show activity in dopamine neurons. Typically in such experiments, other neurotransmitters would be blocked in order to highlight dopamine, but Tritsch, a postdoctoral fellow in the Sabatini lab, decided instead to keep the cell in as natural a state as possible.

When Tritsch activated the dopamine neurons and examined their effects on striatal neurons, he naturally expected to observe the effects of dopamine release. Instead, he saw rapid inhibition of the striatal neurons, making it clear that another neurotransmitter -- which turned out to be the quick-acting GABA -- was at work. This was so unusual that the team launched a series of experiments to confirm that GABA was being released directly by these dopamine neurons.

A standard way to detect GABA is to look for vesicular GABA transporter, or VGAT, a protein that packages and carries GABA into neurotransmitter vesicles. The scientists silenced the gene that makes VGAT in mice and found that the dopamine neurons released GABA even in the absence of VGAT.

The researchers then tested other transporters, zeroing in on one that ferries dopamine and a variety of other neurotransmitters. For reasons they don't yet understand, this protein -- the vesicular monoamine transporter -- also shuttles GABA.

"What makes this important now is that every manipulation that has targeted dopamine by targeting the vesicular monoamine transporter has altered GABA as well. And nobody's paid any attention to it," said Sabatini. "Every Parkinsonian model that we have in which we've lost dopamine has actually lost GABA, too. So we really have to go back now and think: Which of these effects are due to loss of GABA and which are due to loss of dopamine?"

Anatol Kreitzer, an assistant investigator at the Gladstone Institute of Neurological Disease in San Francisco, who was not involved in the research, called the findings remarkable.

"It was totally unexpected," said Kreitzer, who is also an assistant professor of physiology and neurology at the University of California, San Francisco. "At the molecular level, nobody really expected dopamine neurons to be releasing significant amounts of GABA. At the functional level, it's surprising that this major modulator of plasticity in the brain, which is so critical for Parkinson's, for learning and rewards, and for other psychiatric illnesses, can also release GABA. That raises a question as to what role GABA has."

GABA can very quickly change the electrical state of cells, inhibiting their activity by making them less excitable. Sabatini wonders if the loss of GABA in dopamine neurons could explain why hyperactivity is sometimes seen after chronic loss of these neurons.

The next challenge will be to explore whether other neurons that express the vesicular monoamine transporter also release GABA in addition to neurotransmitters such as serotonin and noradrenaline.

"These findings highlight how little we actually know about the most basic features of cell identity in the brain," said Sabatini.

Tritsch said what started out as a straightforward project to understand dopamine quickly changed direction, with lots of starts and stops on the way to some exciting new findings.

"It can be nice to come up with a hypothesis, test it, verify it, and have everything fall into place," he said. "But biology rarely works that way."

This research was funded by a Nancy Lurie Marks Family Foundation postdoctoral fellowship and by grants from the National Institutes of Health (NS046579 and 4R00NS075136).

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Story Source:

The above story is reprinted from materials provided by Harvard Medical School. The original article was written by Elizabeth Cooney.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

12 Replies

Very interesting, Anthony - thanks for sharing this. If it leads to improved medication then let us hope it is not too long in development.


I once heard that it takes about 10 years from an idea in the lab. to drug being available in the pharmacies - if yo're lucky.


Who has 10 years? Anyone else out there with either neuropathies or fibromyalgia can see a neurologist about Lyrica or the much less expensive other GABA enhancers like neurontin (all in the anti-seizure meds. category). These drugs are also now approved for these other two conditions. Maybe others I don't know about.


Yes, thanks for posting. The Internet too plays a role in providing answers among the scientific community and to us who want and need to be informed.


That was very interesting and thought provoking.


Very interesting, as dopamine alone is no longer working very well for my husband.


thank you for sharing this article!


thanks for sharing. maybe this was the missing piece to the puzzle. so, now hopefully this will lead to better medications, treatment options, or possibly even a cure... wouldn't that be fantastic!! just hope the development doesn't process take too terribly long!


Very interesting


Thanks. It'a encouraging to know what you shared may help us.


How can I get GABA into my diet? any thoughts?

Thanks Anthony I always enjoy your posts...


Lion and tigers and oh my! I've been wondering why my "atypical PK" diagnosis of 7 years ago, plus a few years of why am I so stiff and falling and crashing into doorways, hasn't progressed much at all. Could it be that the neurontin, topomax etc. I've been of for central pain and pareasthesias courtesy of 10 yrs of ME and decades of fibromayalgia, then Lyrica from the time it came out, has been inadvertently helping?


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