Greetings Brian -
On May 23 you described the "flood" phenomenon for the
dopamine "left over" in the synaptic cleft. . . . interesting
description . . . . however I believe the Doctors blame the
levodopa.
As of the end of 1996 scientists had identified 5
dopamine receptors in brain nerve cells, termed D-1, D-2,
D-3, D-4 and D-5.
Dopamine is normally stored in one end of a nerve cell
and is continuously released at a steady, gradual rate as
needed. The dopamine crosses the synaptic cleft (the tiny
one inch space between the end of one nerve cell and the
beginning of the other) and interacts with the
individually/uniquely shaped receptors, similar to a key fitting
a lock. . . . which allows that specific receptor's "door" to
open and let the dopamine in.
Parkinson's is a result of the nerve cells in the substantia
nigra dying. Thus, a Doctor prescribes Levodopa medication
to replace the lost dopamine. But, as the cells of the
substantia nigra die, other brain cells (Glial, etc.) try to
compensate, but they don't work as well. Their dopamine is
"dumped" into the synapse at too high a level and with the
levodopa causes side-effects: dyskinesias for example.
Apparently no one knows precisely how or why this
"flood" of natural dopamine and medical levodopa causes the
side effects: except that the receptors are incorrectly
stimulated by the overabundance of "dumped" dopamine and
the therapeutic levodopa.
The D-1 and D-2 receptors have been identified as
sensitive to the action of dopamine agonists (Parlodel,
Permax). Agonists mimic the action of the naturally
produced dopamine. The D-1 receptors are blocked and the
D-2 receptors are stimulated by the agonist, leading to a
decrease in motor fluctuations and rigidity. Suggesting that
the "flood" of the combination of glial-cell dopamine and the
dose of levodopa abnormally over stimulates the D-1 and
under stimulates the D-2.
Scientists have not been able to clearly define a function
or functions for the dopamine receptors. The D-1 receptors
are actually grouped with the D-3s and the D-2 receptors with
the D-3s (too?) and D-4s [don't ask me where the D-5s are!].
The "new" agonists, pramipexole and ropinirole interact with
the D-3 receptor.
On the theory that naturally produced (albeit greatly
reduced) quantities of dopamine from the brain's remaining
nerve cells is superior to dopamine replacement therapy -
Levodopa - the scientists have also suggested blocking the
enzymes COMT and MAO that break down the dopamine.
Eldepryl blocks MAO enzyme activity and two experimental
drugs, tolcapone and entacapone, are being tested for COMT
activity. Anything to squeeze the last drop of dopamine from
the brain!
Now as to your dyskinesia - there are two types: Peak
Dose and Wearing Off. As you have speculated, Peak dose
effects are thought to be caused by a maximum brain
concentration of levodopa (interfering with whatever dopamine
has been "dumped") which is acting upon oversensitive
receptors already craving dopamine. The treatment is to
reduce the amount of levodopa per dose and add an agonist
to sustain the natural dopamine. Wearing off describes the
period (usually 2 - 4 hrs after a dose) when the levodopa is
used up. This condition is usually treated with cutting the
time between doses or using timed-release (Sinemet-CR)
levodopa in conjunction with Eldepryl or an agonist.
Diet has been implicated too. Avoid too much protein for
breakfast and lunch (none is best) and take the medication
30 minutes before eating.
You also described your dyskinesias as "excruciating,"
"distressing," and "muscles . . . acting up." It sounds like
you are in pain. The condition of dyskinesias generally refers
to involuntary movements or hyperactive movements.
Whereas, the condition of dystonia generally describes
painful muscle spasms (usually in the a.m.) causing
abnormal muscle tension and postures. Maybe you are
suffering from dystonia? That is treated with timed-release
levodopa and Eldepryl, similar to Wearing-off effects.
A new technique for reducing dyskinesias is described in
"Neurology," vol. 47, pp. 1493-1495, December 1996.
Liquefy the Sinemet tablet by crushing it and dissolving it in
water . . .that way it will be absorbed more quickly.
In "Parkinson's Disease," 2nd ed., by Dr. Roger Duvoisin,
M.D., he describes one of the three major symptoms of
Parkinson's as tremor (the others are rigidity and slowness)
which ". . . disappears during sleep or when the patient is
resting quietly." Dr. Duvoisin attributes this to a patient's
"alertness" or "state of mind." I have never seen an
explanation for this effect.
Regards,
Stephan Schwartz <[log in to unmask]>
