TO: Dennis Greene, Brian Collins, Jim Slattery, Phil Gesotti,
Ron Vetter, et als.
FROM: Stephan Schwartz
RE: Models for PD
#What we know:#
1. Brain cells (neurons) signal each other where
they connect (synapse) by releasing chemicals
(neurotransmitters) that stimulate specific receptors
(specially shaped areas of the neuron). The neurotransmitter
is likened to a #key# which usually fits into a specific
receptor, #lock.#
2. During normal brain function neurotransmitters
create information flow which in turn causes the neurons to
either stimulate or inhibit the parts of the body to which they
connect. After they pass on the information,
neurotransmitters are removed from the synapse by
enzymes and reabsorbed into the neurons.
3. Dopamine is a neurotransmitter, so is
acetylcholine and norepinephrine.
4. Drugs can mimic the effects of a neurotransmitter
on a receptor. Amphetamines, such as Dexedrine, are close
to the chemical makeup of dopamine and norepinephrine.
Amphetamines stimulate receptors that accept dopamine,
hence arousal and alertness. However, the receptors being
over-stimulated by the drug, become #tolerant# and require a
higher dose of the drug to respond. As higher doses are
required, side effects begin to show: irritability,
sleeplessness, fatigue, etc.
>From Duvoisin, M.D., #Parkinson#s Disease,# 2nd ed.:
Parkinson#s is caused by the loss of brain cells that
produce dopamine resulting in a deficiency of dopamine in
the brain. The brain cells somehow compensate for the
loss of dopamine until there are too few left [at about 70%
loss] and the symptoms appear.
L-Dopa helps metabolize adrenaline. Through
chemical reactions L-Dopa is changed into dopamine and
then to norepinephrine and then to adrenaline. It is possible
to increase the amount of dopamine in the brain by adding
L-Dopa, thereby relieving the symptoms of Parkinson#s by
restoring brain dopamine to almost normal levels. Levodopa
helps the remaining brain cells make more dopamine.
Since the remaining brain cells have likely
compensated for the loss of dopamine, they have probably
increased the rate at which dopamine was formed and
increased their sensitivity* to dopamine: so that smaller
amounts are needed to activate the receptors. Thus, the
brain cells become hypersensitive* to the action of
dopamine. Then, when levodopa is introduced and the
dopamine levels rise, the receptors produce exaggerated
responses. In addition, other brain cells (not normally
associated with the production of dopamine) begin to
process the levodopa. But, they do not store, nor release
the dopamine gradually, and release it at wrong times and in
wrong places.** The most common side effect of levodopa
treatment is dyskinesias. The compensation
mechanisms which the neurons have developed do not
appear to reverse themselves with levodopa therapy.
*See post of 5/28 from Jim S.
**Flooding?
Researchers have confirmed Dr. Duvoisin#s model. They
believe that when the remaining brain cells fall below
15%-10%, the brain changes the way it #makes# dopamine.
Other brain cells, glial cells, transform the levodopa into
dopamine, but have no way to store or control its release in
the same manner that healthy dopamine neurons can. This
causes high concentrations of dopamine in the synapse.
Thus, abnormally stimulating the D1 and D2 receptors.
Dopamine is believed to increase activity through D1
receptors and decrease activity through D2 receptors. The
D1 receptors are thought to shut down under the
dumping of dopamine and are #taken out of the loop#
[see posts of 5/20 & 5/23 from Brian, 5/22 from Phil &
5/23 from Ron]. Thus all the dopamine is channeled to the
D2 receptors, resulting in dyskinesias.
When apomorphine was substituted for levodopa, peak-dose
dyskinesias remained the same. Because apomorphine
directly stimulates D1 and D2 receptors without the need to
be converted into dopamine. Hence, the hypersensitive
receptors react as if there was too much dopamine in the
synapse, without the need of levodopa [see Dennis# post of
6/3].
Stephan 52/6
