http://sulcus.berkeley.edu/mcb/165_0...ipts/_572.html
_________________________

The "Cause" of P.D. Symptoms and its Drug Treatments

The effect of dopamine levels on fluidity of movement can be followed by tracing the pathway "upstairs" from the substantia nigra to the motor cortex. In the normal human brain, the substantia nigra (via dopamine) stimulates the corpus striatum, to which it is attached by many thin fibers. The corpus striatum inhibits the globus pallidus which in turn inhibits the motor thalamus, which finally stimulates the motor cortex (at the top of the brain) to initiate muscle action.

This delicate balance of excitatory and inhibitory pathways is disrupted in the patient with a degenerating substantia nigra. Diminished dopamine levels cause the corpus striatum to be less inhibiting on the globus pallidus, which in turn overinhibits the motor thalamus. This means that the motor cortex is hardly stimulated at all, resulting in the bradykinesia characteristic of Parkinson's Disease.

Clearly, treatment should either restore dopamine levels in the brain, involve drugs that imitate dopamine, or modify the brain in some way to compensate for the deficiency in dopamine. With the aim of restoring brain dopamine levels, the administering of levodopa is the prevalent form of treatment today. Levodopa is converted to dopamine in the body via AADC (aromatic amino acid decarboxylase). Levodopa taken orally is absorbed by the small intestine and enters the circulation to all parts of the body, peaking in blood around 2-3 hours after ingestion, and the effects slowly wear off after 4-6 hours. These peaks and valleys in levodopa effects are referred to as "on/off" periods. Only about 10f the levodopa finally penetrates the brain (dopamine being unable to cross the blood-brain barrier), implying that one must take large as well as continuous doses of the drug for it to be effective. Several months of continuous treatment are necessary to fill up dopamine stores in the brain.

Unfortunately, a common side effect to levodopa treatment is nausea and vomiting. Today, levodopa is administered in conjunction with carbidopa (or another enzyme inhibitor) which prevents levodopa from being converted to dopamine except in the brain. This significantly reduces the side effects as well as allowing levodopa to be administered in much lower doses, eliminating the "dilution effect" caused by AADC's converting L-DOPA to dopamine while it is still floating around in the body.

Another side effect of levodopa treatment is chorea, the neurological term for a series of jerky, involuntary movements. The severity of the chorea increases with levodopa levels, but cutting back on the dosage results in the reappearance of parkinsonian symptoms. A compromise must be made, which is a major drawback of levodopa therapy.

Depression is a commonly reported side effect of Parkinson's Disease itself. Most anti-depressants (and other prescription drugs in general) are safe and will not interact negatively with levodopa. However, a group of antidepressants called "monoamine oxidase inhibitors" (MAO inhibitors) must never be administered with levodopa. Monoamine oxidase keeps dopamine, norepinephrine, and epinephrine levels in the body in check; levodopa will quickly be converted to these substances in the presence of MAO inhibitors, leading to an "overdose" and possibility of a heart attack or a cerebral hemorrhage.

The idea behind the second form of treatment is that administering drugs that mimic dopamine will eliminate the possibility of side effects caused by levodopa. The first dopamine receptor agonist to be tested on P.D. patients was apomorphine, a drug that was already used as an emetic (to induce vomiting). It had been reported in the 1950s that apomorphine alleviated the tremors of P.D. However, not only was it half as effective as levodopa, it was also discovered to have a toxic effect on the kidneys. Other drugs were tested but either did not improve the P.D. or else were also toxic to the kidneys. Finally, bromocriptine (or Pardolel) was found to have about the same potency as apomorphine (half that of levodopa) but the main advantage is that it lasts longer. Bromocriptine acts as a prolactin suppresser and in the future may also be used to treat premenstrual syndrome. It is usually co-administered with levodopa, has the same side effects, and is expensive, being very difficult to synthesize. Consequently, although it can help a select few, it is not the treatment of choice. The search for dopamine receptor agonists is exacerbated by the fact that there are several types of dopamine receptors (D-1 and D-2 included here) and drugs such as bromocriptine are agonists of one but antagonists of the other. Drugs that imitate the natural effects of dopamine through fine-tuned interactions with the receptors remain to be found.

The third method of treatment focuses on compensating for reduced brain dopamine levels. Acetylcholine is present in the brain in much larger amounts than dopamine, and levels are normal even in people with P.D. These two hormones have a reciprocal relationship; dopamine has a restraining effect on acetylcholinergic nerve cells and when it is gone, acetylcholine is no longer regulated, resulting in parkinsonian symptoms. Anticholinergic drugs aim to alleviate this problem.

The first anticholinergics were derived from plants and used to treat P.D. at least as far back as the 19th century when Jean Charcot prescribed hyoscine/ scopolamine to his P.D. patients.

The closely-related atropine (from the belladonna) and hyoscyamine, both from the potato family, have also been used medicinally since ancient times. However, anticholinergics only reduce P.D. symptoms about 25% (compared to levodopa). Interestingly, post-encephalitic P.D. patients respond to anticholinergics much more positively than regular P.D. patients.