The Role of MPTP in Research
Probably the most significant advance in the
research of Parkinson's disease since its connection to
striatal dopamine loss in 1960 is the discovery of the
parkinson-like effects caused by 1-methyl-4-phenyl-
1,2,3,6-tetra-hydropyridine (MPTP). MPTP was implicated
for research after many young narcotic drug abusers in
northern California exhibited parkinson-like symptoms in
the 1980s. An illicit supply of meperidine was tainted
with MPTP, a by-product of the narcotic drug's synthesis.
Immediate research into the mechanism of MPTP's
neurotoxicity produced results that shed much light onto
the study of idiopathic parkinsonism.
MPTP is a lipophilic molecule that easily
crosses the blood-brain barrier. Once inside the brain's
neurons it is rapidly bound by monoamine oxidase (MAO)
receptors in mitochondrial outer membranes. MAO, the
normal role of which is to break down monoamines such as
dopamine, converts MPTP to 1-methyl-4-phenylpyridinium
ion (MPP+- see Figure 1, below) but MPTP does not seem to
significantly interfere with the normal role of MAO.
Figure 1- The Action of MAO on MPTP
For unknown reasons MPP+ tends to
preferentially accumulate in the substantia nigra. MPP+
-induced neuronal death is believed to be caused by
inhibition of oxidative phosphorylation at complex I of
the mitochondrial respiratory chain (and therefore
inhibition of ATP synthesis) (Beal et al. 1993) or by
production of free radicals which cause lipid breakdown
or DNA damage.
A majority of what is currently known about the
pathology of Parkinson's disease is the result of
studying MPTP-induced parkinsonism. In order to draw
conclusions about Parkinson's disease from MPTP studies
it is important to know the similarities and differences
between Parkinson's disease and MPTP
induced-parkinsonism. Most pathological and clinical
aspects of the two diseases are the same but MPTP
patients (meperidine drug abusers) generally have more
cognitive and emotional instabilities. They also have
more difficulty with excess salivation and gait
instabilities. However, MPTP patients usually experience
less tremor.
After the effects of MPTP were discovered,
other similar causative agents were sought. Another
molecule, 6-hydroxydopamine (OHDA), was found to produce
similar clinical characteristics in monkeys. Though both
MPTP and OHDA cause lesions of nigral dopamine neurons,
few studies were carried out on OHDA because it cannot
readily cross the blood-brain barrier. It has to be
directly injected into the brain, and direct physical
manipulation of the brain often causes injuries to
tissue. Because MPTP easily crosses the blood-brain
barrier this problem can be averted by administering MPTP
systemically.
Neuroanatomy of the Extrapyramidal System
The functional neuroanatomy involved in
Parkinson's disease is centered on the extrapyramidal
system. The extrapyramidal tracts control and coordinate
the postural, static, supporting and locomotor
mechanisms. They are also responsible for causing
contractions of muscle groups in sequence or
simultaneously. The principle structures are the
striatum, globus pallidus, substantia nigra, subthalamic
nucleus and the thalamus (see Figure 2).
Two anatomically contiguous nuclei, the putamen
and the caudate nucleus, comprise the striatum. The
caudate nucleus is involved in manifestation or driving
locomotion whereas the putamen is involved in regulation
of tonus in contralateral proximal muscles (Yoshida
1993). The globus pallidus is divided into two segments,
the external and internal nuclei.
Figure 2- Anatomy of the Extrapyramidal System Medial to
the globus pallidus is the thalamus. The subthalamic
nucleus, which is inferior to the thalamus, is referred
to as the gatekeeper of the thalamocortical motor
circuit.
A ventral midbrain nucleus called the
substantia nigra is divided into three functionally
distinct units: the pars reticulata, pars compacta , and
pars lateralis. Although they are parts of the same
anatomical nucleus, they do not all have the same role.
The pars reticulata, along with the internal globus
pallidus, is called the output nucleus. The pars
compacta however, which is made up primarily of
dopaminergic melanin-containing neurons, is the primary
input nucleus. Though believed to be functionally
similar to the pars compacta, the exact function of the
pars lateralis remains unclear. Dopaminergic neuronal
degeneration of the pars compacta defines Parkinson's
disease.
There are approximately 7,000 ipsilaterally
projecting dopaminergic neurons in the substantia nigra,
and each neuron gives rise to approximately 250,000
termini (Yurek and Sladek 1990). Dopaminergic neurons
impinge on three different types of neurons: striatal
interneurons, corticostriatal terminals, and striatal
efferents. Striatal interneurons, which make up less
than four percent of the striatal neurons, are of two
morphological types: aspiny I inhibitory interneurons
release the neurotransmitter gamma-aminobutyric acid
(GABA) and the other type, composed of excitatory aspiny
II interneurons, releases acetylcholine (ACh). A
majority of dopamine cells target striatal efferents
which send axons to the globus pallidus and substantia
nigra. They are also composed of two morphologically
distinct cell types; spiny I interneurons release the
neurotransmitter GABA, and excitatory spiny II
interneurons release substance P. A small fraction of
dopamine neurons impinge on the termini of
corticostriatal neurons.
Mesostriatal Circuitry
One of the difficulties in understanding the
relationship between striatal dopamine loss and the
clinical manifestations of parkinsonism is the complexity
of the neurological circuits involved in the
extrapyramidal system. There is some uncertainty about
details of the circuitry but a general model for the
basal ganglia thalamocortical motor circuit is widely
accepted (see Figure 3). Wichmann et al. describe the
circuit as a reentrant pathway for motor influences from
the supplementary motor area, premotor cortex, and
somatosensory cortex (1993). Motor stimuli emanating
from the precentral and postcentral motor areas of the
cerebral cortex, after being processed by the basal
ganglia and thalamus, are returned to the precentral
motor areas (Wichman et al. 1993). Input from the motor
cortices is supplied to the striatum and then to the rest
of the basal ganglia thalamocortical motor circuit (the
details of which are explained later). After being
processed the motor information is returned to the motor
cortices.
Basal ganglia thalamocortical motor activity is
modulated by dopaminergic input from the pars compacta of
the substantia nigra. Dopaminergic activity in this
nigrostriatal pathway is drastically reduced or
eliminated in parkinsonism. Within the striatum are at
least two types of dopamine receptors, termed D1 and D2.
D1 receptors, which are involved in the "direct" pathway,
are stimulated by dopamine, but D2 receptors of the
"indirect" pathway appear to be inhibited by dopamine
(Albin et al. 1989).
There are D1 receptors on striatal neurons of
the "direct" pathway which release a combination of the
neurotransmitters GABA and substance P in their
monosynaptic inhibitory projections to motor portions of
the internal globus pallidus and pars reticulata (output
nucleus). Stimulation of D1 receptors causes direct
inhibition of the output nucleus which prevents excessive
inhibitory output to the ventrolateral thalamic nucleus.
Other striatal neurons which belong to the
"indirect pathway" have D2 receptors. In the absence of
dopamine these neurons emit tonic inhibitory output to
the external globus pallidus (which itself has tonic
inhibitory projections to the subthalamic nucleus).
However, when the D2 receptors bind dopamine these
neurons are inhibited and their release of the
neurotransmitters GABA and enkephalin to the external
globus pallidus is decreased. Normal dopamine release
prevents excessive inhibition of the external globus
pallidus while allowing moderate tonic inhibition of the
subthalamic nucleus. The subthalamic nucleus has
stimulatory glutamatergic projections to the output
nucleus which causes partial inhibition of the
ventrolateral thalamic nucleus. Reciprocal inhibitory
pathways between the output nucleus and the external
globus pallidus act as a negative feedback mechanism to
regulate inhibition of the ventrolateral thalamic nucleus
(Wichmann and DeLong 1993).
Moderate inhibition of the ventrolateral
thalamic nucleus allows smooth motor control, but
excessive inhibition of the ventrolateral thalamic
nucleus greatly reduces its ability to stimulate the
motor cortex (as in parkinsonism). However, excessive
disinhibition of the ventrolateral thalamic nucleus
causes hyperstimulation of the motor cortex, therefore a
delicate balance of D1 and D2 activity is required for
normal motor control. Striatal dopamine loss results in
enhancement of the indirect D2 pathway and inhibition of
the direct D1 pathway, so the direct pathway no longer
keeps the indirect pathway in check (DeLong 1990).
There is no consensus on the exact relationship
between cerebral cortex hypostimulation and movement
disorders. DeLong suggests that increased feedback by
proprioceptors causes the basal ganglia to falsely
perceive excessive movement or velocity and the basal
ganglia then act to slow them down (1990). He also
suggests that inhibition of tonic ventrolateral thalamic
nuclear activity could decrease the responsiveness of
precentral motor fields (1990). The complexities of the
basal ganglia thalamocortical motor circuit make
verification or refutation of these hypotheses very
difficult.
