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(6-OHDA) into the substantia nigra or medial forebrain bundle to destroy the as-
cending dopamine tracts. Depending on the method used, the effects vary and can
be temporary or permanent.
MPTP administration in primates produces three distinct phases of altered motor
activity: acute phase, subacute phase, and chronic phase [12]. In the acute phase af-
ter administration, animals appear to go to sleep and fall slowly from their perches
to the floor of the cage; their eyes remain open, but with a vacant gaze [12]. Oc-
casionally, wild running or exaggerated startle response events are observed [12].
The acute effects of MPTP last approximately 0.5-1.0 h and then disappear until
subsequent administration [12].
During the subacute phase after MPTP administration, persistent motor deficits
develop. Animals become increasingly akinetic and show rigidity of the limbs,
freezing episodes, postural abnormalities, and loss of vocalization and blink re-
flex [12]. Compulsive climbing behavior can also occur at this stage, causing an-
imals to damage their heads and faces [12]. This spectrum of behavioral effects
lasts for some weeks, but the animals slowly recover. In subsequent weeks the mo-
tor deficits stabilize, and the animals enter the chronic phase of MPTP action. They
show less spontaneous movements, although when challenged, they can move freely
in the home cage [12]. Complex movements are poorly coordinated and clumsily
executed. Hesitation prior to movement is apparent, and the range of movements
observed appears limited [12].
Postmortem studies of PD in humans [22] and MPTP-treated rhesus monkeys
[44] have shown that the toxin destroys the cells of the substantia nigra pars com-
pacta, but not of the locus coereleus, dorsal raphe, and substantia nigra innomi-
nata [12]. Within the substantia nigra, the cells in the centrolateral area of the SNc
are damaged more extensively than those in the medial portion of the SNc [32]. Ad-
ministration of MPTP to young primates causes a profound (
90%) persistent loss
of caudate-putamen dopamine content that is irreversible by any form of medication.
The ventral tegmental area (VTA) adjacent to the substantia nigra shows limited
and variable damage to tyrosine hydroxylase-containing cells in MPTP-induced
Parkinsonism [12].
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11.2 Brain Anatomy in Parkinson's Disease
The difficulty in understanding and treating Parkinson's disease is because there are
multiple brain areas and pathways affected from the sites of neuronal degeneration
all the way to the muscles. Figure 11.1 depicts three of these pathways: (1) the
pathway from the substantia nigra pars compacta (SNc) and the ventral tegmental
area (VTA) to the striatum and from there to the thalamic nuclei and the frontal
cortex through the substantia nigra pars reticulata (SNr) and the globus pallidus
internal segment (GPi), (2) the pathway from the SNc and the VTA to the striatum
and from there to the brainstem through the SNr and GPi, and (3) the pathway from
