How have studies of neuropharmacology helped our

understanding of movement disorders?

With Parkinson's disease becoming ever more common in the modern
world, the appearance of movement disorders in medicine and the media is
gaining popularity. Although this condition accounts for the most frequent
cause of this class of pathology, movement disorders are more generally
defined as either dyskinesia, abornmal involuntary movements, or as akinesia,
a complete lack of movement. Along with Huntingtons disease, Parkinson's
involves a deficit in the basal ganglia. This group produces three
characteristic types of motor disturbances: (1) They cause involuntary
movements and tremor, (2) they produce bradykinesia (slowness of
movement) without paralysis and (3) they cause changes in posture and
muscle tone. An important feature of these diseases is that they both involve
an abnormal production and release of neurotransmitter within the brain.
Hughlings Jackson recognised that the motor disorders can be divided into
two main classes: primary functional deficits and secondary deficits. Primary
functional deficits cause negative signs which result from the loss of specific
capacities normally controlled by the corticospinal system. These negative
signs can be attributed to the loss of function originating from a specific set of
neurons. Secondary deficits show positive signs which consist of abnormal
responses that are attributable to the withdrawal of inhibitory influences
acting on interneuronal networks in motor systems. Secondary deficits may
arise due to malfunctioning of neurons or when a neuron’s controlling input is
dysfunctional or destroyed. The abnormal movements seen in basal ganglia
disease fall into this second category.
The insight that the basal ganglia is involved in the control of movement
initially came from post-mortem examinations of patients who had died of
Parkinsons disease. These examinations revealed pathological changes in the
basal ganglia. Parkinson’s disease is a degenerative motor disorder
characterised by rhythmic tremor at rest, increased muscle tone and rigidity,
postural instability, bradykinesia and in some extreme cases, akinesia. The
symptoms caused by Parkinsons result from a loss of dopaminergic cells in
the pars compacta region of the substantia nigra. These neurons project to the
striatum and their loss leads to changes in activity of the neuronal circuits
within the basal ganglia, the indirect and direct pathways, which ultimately
changes the motor output programmes. In the direct pathway the putamen and
caudate directly inhibit the globus pallidus internus which in turn disinhibits
thalamic neurons which are responsible for excitation of the premotor cortex.
This direct motor loop serves to facilitate movement. The indirect pathway is
involved in the inhibition of unwanted movements. In this pathway the
striatum
inhibits the globus pallidus externus which sends inhibitory output
signals to the subthalamic nucleus. The subthalamic nucleus then projects
back to and excites the internal pallidus. At this point both the indirect and
direct pathways meet. The loss of dopamine in Parkinsons causes decreased
activity of the direct pathway and increased activity of the indirect pathway.
This leads to increased inhibition of the ventral lateral nucleus of the
thalamus, thus causing hypokinesia. Surgical interruption in the outflow from
the basal ganglia either in the globus pallidus or in the VL nucleus decreases
the abnormal neural activity in Parkinsons and alleviates some of the positive
symptoms such as the rhythmic tremor at rest. However, the slowness and
absence of movement does not change providing evidence that these
symptoms are primary deficit symptoms.
The mechanism by which the dopaminergic cells in the substantia nigra are
lost in Parkinsons may be due to abnormal accumulation of the protein alpha-
synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein
ubiquitin complex cannot be directed to the proteosome and therefore it
accumulates to form Lewy bodies. Recent research on the pathogenesis of
Parkinsons has shown that the death of dopaminergic neurons by alpha-
synuclein is due to a defect in the machinery which transports proteins
between the Endoplasmic Reticulum and Golgi.
Parkinsons disease is primarily a disease of ageing and the majority of cases
occur over the age of 60. However in 1982 several relatively young drug
abusers in California developed severe Parkinsonian like symptoms in just a
few days and this phenomenon was illustrated in Oliver Sacks' book
Awakenings. This was very unusual considering that the symptoms of
Parkinsons normally accumulate over several years. Acute medical research
revealed that the drug abusers had taken street versions of a synthetic narcotic
which contained the toxic chemical MPTP. The chemists who had produced
these drugs were trying to produce the opiate MPPP but condensed the
procedure using an alternative method thereby creating a chemical by-product
which kills dopaminergic neurons. MPTP has been used in the research of
Parkinsons Disease and has contributed a great deal to scientists’
understanding of the disease. MPTP is converted to MPP+ in the brain and
then taken up by dopaminergic cells which mistake it for dopamine. Once
inside the cell MPP+ prevents the mitochondria from producing ATP so the
cell can no longer produce energy for its life processes. Experiments which
involved injecting MPTP into squirrel monkeys caused Parkinsonism but the
symptoms were immediately relieved after an injection of L-DOPA, a
precursor for dopamine, currently used in the treatment of Parkinsons disease.
The symptoms caused by MPTP-induced -Parkinsons disease are identical
and indistinguishable to patients with the disease. Based on this observation it
has been suggested that repeated exposure to MPTP through ingestion in
minute amounts (which cannot be detected) may be one of the contributing
factors that cause the disease. Knowledge of MPTP and its use in reliably
recreating Parkinson's disease in experimental models has helped scientists’
understanding of why neurons apoptose. This new insight may enable them in
the future to devise strategies of suicide prevention which halt or avert a
variety of neurological diseases.
Huntingtons Disease is a rare inherited neurodegenerative disorder which,
like Parkinsons, results from pathology within the basal ganglia. Huntingtons
is a syndrome characterized by hyperkinesia and dyskinesia (unlike
Parkinsons which is a hypokinetic disorder). It also causes impaired cognitive
function and personality changes. The disease first manifests itself through
signs of depression and irritability and then gradually as the disease
progresses the patient exhibits chorea, uncontrolled movements and
involuntary movements, until they become so physically disabled that they
are confined to a wheelchair. Mental functions undergo similar deterioration
and eventually the ability to reason disappears. There is no treatment for the
disease and after several years of decreasing capacity, followed by total
disability the afflicted person will inevitably die. Proliferation of the
condition is reinforced by its characteristic appearance after the age of 40.
The defective gene involved in Huntingtons Disease is called the HG gene.
At the end of the HD gene three nucleic acids, cysteine-adenine-guanine, are
found in multiple repeats. CAG is the base sequence for the amino acid
glycine and in healthy individuals up to about 40 trinucleotide repeats are
found at the end of the HG gene. However in Huntingtons more repeats are
found and a mutated form of the encoded protein huntingtin is sequenced
(mHtt). A build up of mHtt in brain cells causes cell death, especially in the
frontal lobes and basal ganglia. There is a loss of specific sets of cholinergic
neurons and neurons within the striatum that synthesise the inhibitory
neurotransmitter, GABA. In the basal ganglia a balance is normally
maintained among the three systems: the nigostriatal dopaminergic system,
the intrastriatal cholinergic system and the GABAergic system. As previously
discussed, in Parkinsons Disease it is the nigostriatal dopaminergic system
which is defective but in Huntingtons there is a profound destruction in the
other two systems. The death of cholinergic interneurons in the striatum and
GABAergic neurons connecting the striatum with the globus pallidus and
substantia nigra result in disinhibition of dopaminergic cells in the substantia
nigra. This disinhibition allows excessive excitation of striatal neurons and an
abnormal output to the thalamus which is the underlying cause of the chorea
movements in Huntingtons disease.
Taking it account the hyperactivity of dopamine-producing neurons in
Huntington's chorea, it seems logical that dopamine receptor blockers would
provide a suitable form of treatment to those affected however the benefits
are not dramatic and offer only mild relief to the patient. Anti-depressants and
sedatives help to control the chorea symptoms as well as keeping the person's

emotional state stable. Recent studies include the belief that omega-III fatty
acids can delay the development of the disease and may even reverse its
progression.
Hyperkinesia can also result from other types of lesions in the basal ganglia.
Hemiballismus is a condition characterized by violent flinging movements of
the limbs. It is caused by damage to the subthalamic nucleus which usually
results from an interruption in its blood supply following a
stroke. The damaged neurons in the subthalamic nucleus are no longer able to
provide excitatory stimulation to the globus pallidus internus and therefore
there is decreased disinhibition of the thalamus and consequently involuntary
stimulation of the Motor Cortex. Tardive Dyskinesia is another clinical
disorder that involves the basal ganglia. It causes involuntary movements of
the face and tongue and like Huntingtons is a hyperkinetic disorder. It is a
medically induced disorder connected with long term use of dopamine
antagonists such as antipsychotic drugs which are often used to treat epilepsy.
Long term blockage of the dopaminergic system hypersensitises the
dopamine receptors to dopamine and alters the balance within the
dopaminergic-cholinergic-GABAergic loop which causes the unwanted
involuntary movements.
In conclusion, the study of the various neurotransmitters in the brain such as
dopamine and GABA has provided us with a greater understanding of the
various movement disorders. Diseases such as Parkinsons and Huntingtons
are caused by an imbalance of these chemicals which alter the motor program
systems within the brain. Parkinsons disease enabled the medical community
to realize that the loci for many neurological diseases are at the specific
molecular components of chemical synapses. The causation of the
pathological alterations at these loci, whether genetic, infectious, toxic or
degenerative, is not known in the majority of motor disorders. With
Huntingtons disease, the locus has been identified as the mutant gene HD but
currently there is a lot of uncertainty surrounding how this mutant protein
causes the disorder. For each disease, rational treatments demand a decent
understanding of the various steps which cause changes in synaptic
transmission.