Brian, you wrote on the list in reply to Ron Reiner:
<<Hello Ron, This is the Dopamine story as I understand it: The Dopamine
production system is one which is dedicated to providing Dopamine where
it is
needed, when it is needed, and in the right quantities. It is a
constantly
flowing system because when the Dopamine has done its work as a neuro
transmitter, it decomposes and is transported out of the way by the
brain's
clean-up system. So it is a self-regulating system with apparently quite
a
fast reaction time. The best proof that I know is to consider what
happens
to a person with a normal healthy brain if you give them a large dose of
Sinemet - one that would drive a PWP into wild Dyskinesias. The answer
is that
virtually nothing happens! The reason is that a healthy brain can sense
the
invasion of the tablet, and immediately cut-back productionto
compensate.
The brain of a PWP simply doesn't have enough Dopamine -producing cells
to
shut down to compensate for the large intruder, and so an overdose
condition
exists, causing what we know as dyskinesias.
This model (because that is all it is) has worked pretty well for me: it
explains:
Why it gets progressively more difficult to achieve the ideal
dosage of
levodopa.
Why a newly-diagnosed PWP can tolerate a large input of Sinemet,
although
he doesn't need it.
Why a long-term PWP has to take small doses of levodopa, when
ideally he
needs large doses.>>
I must argue differently about a normal person's response to levodopa.
(actually I have not seen such an experiment or read about such.)
My argument is to dispute the assignment of cause for "virtually nothing
happens". Per my understanding, the healthy brain has no shortage of
levodopa or dopamine. The dopamine is in containers (storage) at the
synapses - available to be released to cross the nerve-to-nerve gap
(synapse) when the signal to transmit gets to that locus. There is some
concentration of dopamine in the fluids in equilibrium with levodopa et
cetera in the fluids of the brain (as well as all other fluids in cells,
brain, blood, eural networks, ...
The added levodopa into the stomach->intestines of a normal person may
not enter the blood at the same rate as in you or I - because the
concentration
gradient there at the intestine-blood membrane. Then, what happens at
the brain membrane will also be dependent upon the membrane transport
inhibition mechanisms - may be concentration difference primarily?) -
and reslt in little or none getting into the brain fluids. then, if the
normal storage is full and the normal backup storage is full, the new
levodopa may drift about as increased concentration until usage or
metabolic equilibrating factors use it or destroy it.
Do you know of a report describing the experiment of normal persons
taking Sinemet? Normal persons eating lots of fava beans would not have
the carbidopa or benzarazide. Do we know the causation of dyskinesia?
chorea?
Since the carbidopa and benzaride are both similar in not preventing
chorea, we can assume it comes from large amounts of levodopa when the
brain gets too much. However, the too much may be due to lack of any
significant active synapses number remaining functional in the advanced
Parkinsonian. It may be that high concentration acts to drive the CNS
random walk dance (chorea)? Maybe, the mechanical analogy of the clutch
is pertinent to chorea: the CNS controller is not functioning smoothly
when there is too much dopamine and no storage capacity of significance,
such that the dopamine that is free reaches concentrations that cause
signals by absorption from fluid to the receiving synapse sites ( not
from the sending neuron); id est, there is random application of the
clutch or random releases of the clutch for various muscle controller
neurons.
The blood pressure and blood flow to the brain are also involved in how
much of all things supplied by the blood and removed from the brain
fluids into the blood. The hypotension chemistry, mechanics, physics,
pharmacokinetics may be involved in the transporting and crossing of
barriers - there are pressure and flow rate effects as well as
concentration, thermal and mass transport mechanics as well as
electrochemical effects, hydrophobic, hydrophilic, et cetera
complications as the pipes clog and lack of exercising all the parts is
hard to accomplish when the brady- prefixes more of our functions.
(G) this will clear it all up for you, I imagine (G g ...gad!) tafn, ron
v
--
ron 1936, dz PD 1984 Ridgecrest, California
Ronald F. Vetter <[log in to unmask]>
http://www.ridgecrest.ca.us/~rfvetter
