It should be emphasized that, whereas neuroleptic control of schizophrenic symptoms
has been spectacularly successful since the 1960s, neuroleptic treatment does not cure
the psychotic patient, who will almost certainly relapse if medication is discontinued.
Nor does our molecular insight answer any questions about the nature, etiology, or
possible biochemistry of psychiatric disorders.
4.4.4 The Clinical–Molecular Interface: Parkinson’s Disease
as a Dopaminergic DisorderDeterioration of the dopaminergic neuronal pathways, known under the name of
Parkinson’s disease, is manifested in a collection of neurological movement disorders
of unknown etiology. The symptoms include a resting tremor (sometimes referred to as
a “pill rolling tremor”), difficulty in initiating movement (akinesia), rigidity, stooped
posture, shuffling gait (referred to as a festinating gait), and speech and swallowing dif-
ficulties. This is an incurable and slowly progressing disease, sometimes leading to total
invalidism.
The mechanism of the neurological symptoms in Parkinson’s disease was discovered
from the ability of reserpine to cause akinesia in humans by the depletion of central cat-
echolamine stores. The dopamine levels in patients who died from parkinsonism were
found to be extremely low because of deterioration of the dopaminergic neuronal cell
bodies and the pathways connecting the substantia nigra with the corpus striatum.
Some new light was shed on the molecular cause of Parkinson’s disease by an acci-
dent. In 1982, drug addicts used a “designer” drug (a noncontrolled analog of a known
and illegal narcotic) contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(4.98, MPTP). Its major quaternary metabolite, MPP+(4.99), which is a dopaminergic
neurotoxin, produced a severe and tragically permanent parkinsonism. It did so by
killing dopamine-producing cells in the brain. The effect serves as a model of
Parkinson’s disease, although rats do not seem to be sensitive to MPTP.
Since Parkinson’s disease arises from a deficiency of DA in the brain, the logical
treatment is to replace the DA. Unfortunately, dopamine replacement therapy cannot be
done with DA because it does not cross the blood–brain barrier. However, high doses
(3–8 g/day, orally) of L(−)-DOPA (levodopa), a prodrug of DA, have a remarkable
effect on the akinesia and rigidity. The side effects of such enormous doses are numer-
ous and unpleasant, consisting initially of nausea and vomiting and later of uncontrolled
movements (limb dyskinesias). The simultaneous administration of carbidopa (4.75) or
benserazide (4.76)—peripheral DOPA decarboxylase inhibitors—allows the adminis-
tration of smaller doses, and also prevents the metabolic formation of peripheral DA,
which can act as an emetic at the vomiting center in the brainstem where the
blood–brain barrier is not very effective and can be penetrated by peripheral DA.
NEUROTRANSMITTERS AND THEIR RECEPTORS 247