Brian Collins wrote:

<<<<For Ron Vetter, copy to Ron Reiner

Hello all, and hello Ron Vetter. Thanks for the long email, which I will
try to answer.

First: How do I know what happens to a normal person taking a large dose
of
Sinemet :- Because my friendly neuroologist at Nottingham U told me so.
He
did not gove me a bunch of references, but I have a high regard for his
knowledge, and if he says it is so, that's good enough for me. (To
expand
on 'virtually nothing' : What he actually said was "They might get a
slight
headache, but apart from that, nothing happens.">>>>>>>>>>

rv response: Depending upon how large, this is quite consistent with the
lack of much response other than nausea or vomiting with the healthy
volunteers in pre-approval testing (no mention of effect) and those who
get no benefit (non-PD per se diseases).

<<Second: I am quite sure that there is no difference between normal
people
and PWPS all the way from the stomach to the brain side of the
blood-brain
barrier. Thus the hypothetical 'large tablet' that I refer to must
arrive
in the brain, in=A0exactly the same quantity and format in either case.
This
is a fundamental point about PD - we are just like everyone else, apart
from
our inability to produce Dopamine.

Third: Your description of the dopamine being held in containers at the
synapses - available to be released to cross the nerve-to-nerve gap is
not
quite right: I refer you to pages 26 to 30 of 'The Parkinson's Handbook'
(McGoon) and especially p.28. The 'message' that is so important to us
is
an electrical charge, not a chemical one. The charge can only cross the
gap
from one axon to the next if the conductive properties of the fluid
bathing
the axon are favourable, and this depends on the quantity and quality of
the
Dopamine which the axon receives.>>>>>>>>>>>>>>>

rv response: As Dr. McGoon states, he is an amateur: "... how it all
functions remains a complex tantalizing puzzle. Even we nonexperts can
appreciate that the effort to understand processes that can take place
only in a living human brain ..."

The doctor mentions the passing of a baton from one runner to the next
on page 28. The figure 4 detail on page 29 shows the synaptic vesicles.
Unfortunately, he does not state well that the electron charge must be
carried across the synapse "on" or "by" the chemical neurotransmitters
stored-available in those vesicles. The recipient dendrite receptors
must accept the charge carrier - which requires that it fit into a
"socket" to transfer the "charge". Then, the dopamine drifts off again
into the fluid - without "charge" ... it may be re-stored to the
vesicle-storage if levo-deprenyl is present to suppress the normal
metabolic destruction.

I recommend the article, Anatomy of the Basal Ganglia by John B. Penney,
Jr.,M.D., stating on page 8 of the United Parkinson Foundation 1994
Newsletter #1, Part 1.

There are also some video documentary illustrations which depict the
artist-conceptions neural signalling processes. There are fast
electronic signals from dendrite to cell to axon-synapse(s) and the
slower chemical transmitting at the synapses via multiple ionized
neurotransmitters typically. Some signals to some neurons produce a
virtual rain of neurotransmitters from many axons to many synapses.
Sometimes to provide a general alert - fight or flight response to
perceived hazard. Gone awry, this is a panic attack. Or, a sudden mood
change.***********

<<<So the nerve cells in the Substantia Nigra manufacture Dopamine,
which
travels down the axon to the next nerve cell, where it bathes the
synapse.>>

rv response: I do not believe the dopamine travels down the
axon.********

<<The Dopamine is not the message, and the time at which this process
occurs
is not necessarily related to the timing of the action represented by
the
electrical impulse. All that matters is that when the electrical charge
passes from the brain to the muscle, the axons which it encounters must
previously have been bathed by the appropriate neurotransmitter.

What follows is my personal speculation, so don't blame Dr McGoon: It
occurs
to me that as the electrical charge zips down the axons, encountering
synapses
along the way ( like points in a railroad track), it may be just as
important
that certain synapses are 'dry' and do not propagate the signal any
further.
This may be how dyskinesias occur: through excess levodopa bathing the
wrong
synapses. Don't forget that in my vision of the whole thing, an excess
of
Dopamine cannot exist in a normal brain.>>>>>

rv response: The electrical monitoring probes recordings during
insertions indicate that dyskinesia is characterized by overload-noise
signalling in the target site(s) for pallidotomy, thalamotomy, or
sib-thalamic locus for stimulator implantatation. The lesioning kills
the axon of these cells transmitting so much static or uncontrolled
signalling (which is the source of the muscle twitching-tremor or the
constant tonus, or the choreic dyskinesia. The dopamine that is missing
is from the substantia nigra cells which shut down these overactive
transmitters - as I understand the process.

Hope this helps.  Best wishes from ron
--
ron      1936, dz PD 1984  Ridgecrest, California
Ronald F. Vetter <[log in to unmask]>
http://www.ridgecrest.ca.us/~rfvetter