Just a few things inspired by another thread...

We are so fixated on dopamine (DA) and alpa-syn we overlook some important things. Dopamine loss as cause of PD is still only a theory that leaves out norepinephrine (NE). We lose both in PD. When we research Alpha-syn it stands to reason that it must also have the same impact on our forgotten neurotransmitter, right? If you want to say that loss of NE is consequence to loss of DA, that is unlikely as researchers think that NE neurons are hit first.

It is theorized that PD begins in gut, olfactory bulb hit next. then the brain stem. I will stop here for a minute. There are holes in this. First not all of us have gastrointestinal stasis or loss of smell. Next, Alpha-syn is thought to help neurotransmission so it is throughout our system. If they mean Alpha-synuclein clumps are found in the intestine, well that too tells us little. Those clumps, are damaging again only in theory, they are found in normal brains with the person showing no evidence of PD.

Reality is dopamine loss as cause of PD is still just a 50 year old hypothesis. There is actually recent autopsy results showing that we lose more norepinehrine cells than dopamine!?! What if we are treating the primary cause of our disorder inadvertently by treating dopamine and were not even aware of it? Dopamine and Norepinephrine are formed from the common amino acid L-Tyrosine and L-Dopa synthesis - it forms dopamine first then is turned into norepinephrine, so ldopa treats loss of both; how could we know?


Here is link to references
http://www.ncbi.nlm.nih.gov/sites/my...tHMVbO1FnYTQ4/.

Further there is accumulating evidence that our motor symptoms are related to loss of norepephrine, not dopamine. Again you might say wait, we respond to it, but really in essence we are treating both. Research models of PD can help us by isolating the two; looking like NE is responsible. In the MPTP model of PD, they can invoke cell loss of dopamine; lots of it like 80% - two key differences: the animals recover and they do not have motor symptoms. Upset their supply of NE, and they look Parkinsonian and do not compensate for the cell loss. This occurs independent of dopamine loss.

Think of how vulnerable we are to stress. Well, norepinephirine connects directly to adrenals and hypothalamus to manage our stress response. Its home is the locus coeruleus in the brain stem. It regulates our fight or flight response, factors into blood pressure and heart rate, it increases oxygen flow to muscles and brain, sends signals to our spinal chord, and initiates glucose release to our cells. In other words, it makes dopamine look more like a sidekick. Norepinephrine in fact has its own system and here is a list of what it communicates with:

Noradrenergic neurons in the brain form a neurotransmitter system, that, when activated, exerts effects on large areas of the brain. The effects are alertness and arousal, and influences on the reward system.
The noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The axons of the neurons in the locus coeruleus act on adrenergic receptors in:
Amygdala, Cingulate gyrus
Cingulum, Hippocampus
Hypothalamus, Neocortex
Spinal cord, Striatum
Thalamus, Some Brainstem nuclei
Cerebellum


We might never know otherwise in supplying ldopa we are restoring lost NE as well. This might explain why people turn out not to have a loss of dopamine in a brain scan yet look Parkinsonian and respond to Sinemet. It also explains how in autopsies, there are brains with lots of alpha-syn clumps but person never expressed any PD symptoms.

It also explains why a reading cerebro-spinal fluid for checking brain dopamine levels are all over the place with us. Animal models also support this. In

Animal models of PD now also implicate NE in dyskinesisa,

It is looking to me like we have been researching and treating the wrong neurotransmitter?!?! for over 50 years. Think this is crazy? It is entirely possible given that AD researchers thought for sure that misfolding protein was the be and end all. A recent trial on a treatment to disrupt that protein was an epic fail. I hate to see dogmatic thinking lead us down one narrow path.

I think we would find more answers as to why the two areas of our brain that produce neuromelanin are so sensitive and easily disrupted. The locus coeruleus and substantia nigra are both packed rich with neuromelanin. Why are both hit in PD? I hope that finding alpha-syn in our intestines shed some light on that. We are 50 years behind when it comes to NE which has been essentially ignored.

On a positive note there are antidepressents and dugs that work on NE receptors (noradrenergic antagonists) already approved by FDA for other conditions that may better treat us than ldopa alone.