[reverett123]

Just floating a trial balloon for consideration.
We are so dopamine-centered that we tend to forget the other neurotransmitters. Suppose for a moment that when you are going "off" that it is only partly due to low dopamine and that part of the problem is that something you ate is acting as a temporary road block of some sort. Let's call this nefarious substance "X" for now.

"X" is capable of completely blocking the action of ldopa for four hours or so. Then it relinquishes its hold and the missing meds reappear and kick in. They haven't been destroyed or even much reduced, just delayed.

"X" is able to kill neurons over time by means of excitotoxicity. That would account for a part of progression.

Certain drugs are capable of beating "X" at its own game and either halting progression or even completely relieving symptoms temporarily.

Dopamine and "X" are diametrically opposed (i.e. inhibitory and excitatory) and perhaps get in each ther's way at times.

"X" is common in the food supply and exposure is universal but sensitivity varies.

"X" is glutamate as in MSG. When I accidentally eat it I am frozen for four hours then suddenly released. Glutamate acts on NMDA receptors. Ecstacy does too and relieves PD for awhile. Dextromethorphan acts on them as well. Gluten (a protein) is high in glutamate and can cause neuro problems.

Are thesejust disjointed facts or can we weave them into something?

[caldeerster]

The GAD gene trial published a paper, if I remember correctly, which detailed how brain scans showed that when they restored GABA to the subthalamic nucleus, over time the scans showed brain function returning to a more normal state. Since GAD gene therapy is putatively a symptomatic treatment and does nothing directly to the dopamine neurons, one has to wonder if there is some underlying disease modifying effect that is exerted by the action of inhibiting the pathological excitation in the STN. A chicken and egg question, but another piece of evidence that the ultimate answers do not lie solely with restoring dopaminergic neurons.

Cal

Originally Posted by reverett123

Just floating a trial balloon for consideration.
We are so dopamine-centered that we tend to forget the other neurotransmitters. Suppose for a moment that when you are going "off" that it is only partly due to low dopamine and that part of the problem is that something you ate is acting as a temporary road block of some sort. Let's call this nefarious substance "X" for now.

"X" is capable of completely blocking the action of ldopa for four hours or so. Then it relinquishes its hold and the missing meds reappear and kick in. They haven't been destroyed or even much reduced, just delayed.

"X" is able to kill neurons over time by means of excitotoxicity. That would account for a part of progression.

Certain drugs are capable of beating "X" at its own game and either halting progression or even completely relieving symptoms temporarily.

Dopamine and "X" are diametrically opposed (i.e. inhibitory and excitatory) and perhaps get in each ther's way at times.

"X" is common in the food supply and exposure is universal but sensitivity varies.

"X" is glutamate as in MSG. When I accidentally eat it I am frozen for four hours then suddenly released. Glutamate acts on NMDA receptors. Ecstacy does too and relieves PD for awhile. Dextromethorphan acts on them as well. Gluten (a protein) is high in glutamate and can cause neuro problems.

Are thesejust disjointed facts or can we weave them into something?

[JoeM]

If I have understood correctly benzodiazepines, which are GABA agonists should, at least in theory, help the STN when it blocks your muscles due to over-excitation (caused by glutamate?). Am I right? Anybody has tried this?

[caldeerster]

Clonazepam is one of the few things which actually makes me feel almost normal.

Originally Posted by JoeM

If I have understood correctly benzodiazepines, which are GABA agonists should, at least in theory, help the STN when it blocks your muscles due to over-excitation (caused by glutamate?). Am I right? Anybody has tried this?

[paula_w]

Neurologix can't fill their clinical trial, which does what you are discussing I think. iT is non-dominergic and is gene therapy- it is not regenerative, but relieves symptoms and compared to DBS - uses GABA.

paula

[reverett123]

I have long thought there to be a connection between PD and schizophrenia. Consider the following:
From http://www.sciencedaily.com/releases...1105180809.htm <My comments bracketed>

"ScienceDaily (Nov. 6, 2008) — Research from the University of Pittsburgh could expand the options for controlling schizophrenia by identifying a brain region that responds to more than one type of antipsychotic drug.

...Bita Moghaddam, a professor in the Department of Neuroscience in Pitt's School of Arts and Sciences and the paper's lead author, found that schizophrenia-like activity in the orbitofrontal cortex—a brain region responsible for cognitive activity such as decision making—could be triggered by the two different neurotransmitters linked to schizophrenia: dopamine and glutamate....<"decision making", in my experience of PD, is what seems to be going on when I am Off and approaching a doorway or trying to turn. The data stream becomes too large and I am overwhelmed and I freeze.>

"Schizophrenia appears to be caused by very diverse and sometimes rare genetic mutations. Diverse mutations can end up causing the same disease if they disrupt the function of a common group of neurons or networks of neurons.... <Different paths to the same door explains a lot about PD's oddities>

Studies within the last few years—including work by Moghaddam at Yale University—have shown that under-functioning glutamate receptors known as NMDA receptors can produce schizophrenia-like symptoms. Moghaddam and Homayoun found that stunting the NMDA receptors resulted in schizophrenia-like effects in the orbitofrontal cortex. The team also used a dose of amphetamine to simulate dopamine-related schizophrenia symptoms in the orbitofrontal cortex; schizophrenia is often linked to an excess of dopamine in the brain....
<So, do "over-functioning" receptors, as might result from glutamate stimulation, produce PD-like actions?>

Moghaddam and Homayoun then tested the currently prescribed medication—a treatment developed more than 50 years ago that targets neural receptors of dopamine—and new experimental drugs that work on the glutamate system. They found that both medications normalized brain activity." <Presumably we are talking about levadopa here.>

[reverett123]

From http://www.sciencedaily.com/releases...1216201414.htm

"ScienceDaily (Dec. 25, 2008) — Rewarding and stressful signals don't seem to have much in common. But researchers studying diseases ranging from drug addiction to anxiety disorders are finding that the brain's reward and stress signaling circuits are intertwined in complex ways....

Vanderbilt University Medical Center investigators have now discovered a functional link between reward and stress. They found that dopamine – the brain's chief reward signal – works through corticotrophin-releasing factor (CRF) – the brain's main stress signal – to increase the activity of a brain region involved in addiction relapse... <Release of CRF is the first thing that happens when the jerk behind you gets impatient..>

Thomas Kash, Ph.D., a research instructor in Winder's laboratory, decided to explore dopamine's actions in the extended amygdala. Using an in vitro brain slice system, he discovered that dopamine increased excitatory glutamate signaling in this brain region. Surprisingly, he found that dopamine required CRF signaling to increase glutamate signaling....
<This last sentence could have said "The sudden increase in CRF combined with dopamine to increase glutamate signaling and the stimulation of NMDA receptors thereby locking Rick up tight..."

[JoeM]

I don't think you can conclude a relationship between PD and schizophrenia from that article. What we have is a set of substances (neurotrasmitters, factors, proteins, etc) which interact with brain cells and, depending on your particular genetic mutation, some specific group of brain cells is extremely sensitive to any unbalance in the quantity of one or more of those substances in your brain. That unbalance can also be triggered by an external environmental agent. Depending on what part of your brain is more affected you have one disease or another. But maybe something's escaping to my understanding and you are right.

With regard to stress, my personal experience makes me believe that there's a relationship between PD and stress. Don't know if it's a cause or an effect.

[reverett123]

Joe-
Sorry I was unclear, but I intended to make that remark in passing. As you say, it would take more than that story to make the case.

Having said that, however, I do suspect PD of being related to the spectrum disorders. My wife is slightly Asperger's, for example, and I see many similarities. If it arises from the ratio of dopamine to glutamate and the area affected, anything is possible.

[jcitron]

Originally Posted by JoeM

I don't think you can conclude a relationship between PD and schizophrenia from that article. What we have is a set of substances (neurotrasmitters, factors, proteins, etc) which interact with brain cells and, depending on your particular genetic mutation, some specific group of brain cells is extremely sensitive to any unbalance in the quantity of one or more of those substances in your brain. That unbalance can also be triggered by an external environmental agent. Depending on what part of your brain is more affected you have one disease or another. But maybe something's escaping to my understanding and you are right.

With regard to stress, my personal experience makes me believe that there's a relationship between PD and stress. Don't know if it's a cause or an effect.

I agree, Joe. Schizophrenia, like many other psychotic conditions is caused by an imbalance in the neurotransmitters. Now that clinical psychologists know this, they can control the symptoms using medications that help reset the balance to the proper levels. Hehe... I learned something from my Psychology class.

When I was working full-time at a company that was diving deeper than the hole in the North Atlantic Rift, I was off most of the time. I had cognitive function problems, fatigued beyond anything I can explain, and I was ill most of the time. There were also those totally bizarre dreams, and many other things happened. Then I lost my job. After the intial panic, I calmed down, and have gone back to school. Well guess what? Many of the symptoms went away. I'm actually sleeping nearly through the night, and I'm even able to memorize music, which was out of the question before for so many years. I do still have gait problems and freeze when going from grass to pavement, and when panically running up stairs. I realize this now, and avoid being in a rush. There's no reason to kill myself, or worse make a fool of myself in public, so if I'm late I arrive late. There's nothing anyone can do about it.

The jist of it is, stress can wreak havoc on the body, mind, and immune system. PD I think is another one of those syndromes or diseases that is exacterbated by stress, and the more we can do to avoid it the better we will be.

John