Parkinson's disease (PD) is believed to be caused by a deficiency of dopamine. Dopamine is a neurotransmitter, a chemical messenger between nerve cells in the mammalian brain. In this paper I explore how dopamine is exactly related to PD, and how insights about that relation are used to understand and treat PD.
After a general introduction, I first go into the basics of the working of nerve cells and signal transmission between them. Then I go into the basal ganglia, the neural circuitry that partly controls voluntary movement, and how a defect in it causes Parkinsonian symptoms. I close this paper with a short survey of treatments that aim to restore neural communication in the brains of PD patients back to normal
November 22, 1996.
(Bernstein, 1995; Wichmann & DeLong, 1993)
People with Parkinson's Disease (PD) suffer an increasing motor behaviour impairment, usually at an older age. The primary symptoms include: muscular rigidity, resting tremor, difficulty with movement initiation (bradykinesia), slowness of voluntary movement, difficulty with balance, and difficulty with walking. This disease was named after the English MD. James Parkinson, who in 1817 was the first person to describe these symptoms as 'the shaking palsy'.
More than a century later, one believes that the cause of the disease is a dopamine deficiency in the basal ganglia of the brain. Dopamine is a neurotransmitter, a chemical messenger in the nervous system. In PD the neural cells which produce dopamine deteriorate. When these neurons start to disappear, the normal rate of dopamine production decreases. It was discovered that when dopamine supply is abnormally low, Parkinson's symptoms start to appear. Next to PD's primary symptoms mentioned above, a patient may also start to suffer from secondary symptoms which include: depression, senility, postural deformity, and difficulty in speaking.
It is difficult to diagnose PD in an early stage. The earliest symptoms may be non-specific, such as weakness, tiredness, and fatigue. So the disease may be unrecognised for some time. Today there are no conclusive tests for PD, yet there are several methods for evaluating its possible presence. A first diagnosis is based on an evaluation of the presence and severity of the primary symptoms. If this test is significant, a trial test of antiparkinsonian drugs may be used to further diagnose the presence of PD. This test is usually performed with L-DOPA. L-DOPA is a precursor in the biosynthesis of dopamine in nerve cells, and causes the remaining dopaminergic cells to increase the production of dopamine. If the patient fails to benefit from L-DOPA, the diagnosis of PD is questioned.
Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the brain may be helpful in ruling out other diseases whose symptoms resemble PD. These diseases may include other neurological disorders leading to Parkinsonian symptoms. This can be caused by a brain tumour, repeated head trauma, or prolonged use of certain drugs. Such a condition is referred to as Parkinson's syndrome, or Atypical Parkinson's. These kinds of Parkinsonisms should not be confused with Parkinson's disease.
The cause of PD is still unknown. There is one known viral infection that damages the extra pyramidal nervous system and causes PD indirectly. However the majority of sufferers were young people with different symptoms than we usually see in PD. Most of these cases resulted from an epidemic in the 1920's.
More recently it was discovered that several young people who developed Parkinsonian symptoms had used an illegal synthetic drug that was contaminated with the toxic MPTP. It was found out that this toxin damaged the extra pyramidal nervous system, resulting to PD. It is now thought that the brain might, under certain circumstances, produce a substance similar to MPTP. MPTP is now used in animal models to understand how it causes Parkinsonian symptoms, which might lead to a better understanding of PD.
(Kandel, 1991)
Our brains consist of about 1011 interconnected nerve cells, called neurons, which process information from receptors that sense the environment and direct our muscles into coordinated behaviour. Although there are maybe 10.000 subtypes of neurons, all share many common features. For instance, they are all able to detect, process, generate and conduct signals. When we hear a sound, for example, the sensory neurons in our ears transform the sound wave into a nerve signal that is detected by other connecting neurons. The type of connection determines whether a signal is amplified or inhibited. The nervous system as a whole may react to that signal by signaling the motor neurons in your neck to turn your head and look around towards the direction of the sound.
Functionally, the neurons of the nervous system are classified in three groups: afferent or sensory neurons, interneurons, and motor neurons. Afferent neurons are sensitive for sensory stimuli and carry them into the nervous system for conscious perception and motor coordination. The motor neurons conduct signals to muscle fibers and glands which contract or excrete as a reaction, respectively. The largest remaining group, the interneurons, process and carry information, without specific motor or sensory tasks.
The complexity of our behavior is not as much the result of the diversity of neuron types, but is a result of organisation and interconnections. A few principles of organisation can give rise to considerable complexity in behaviour.
A typical nerve cell consist of four morphologically defined regions (see Figure 1.): the cell body; dendrites; axon and presynaptic terminals. Each of these regions have a distinct function in the detection, generation, conduction, and transmission of signals. The cell body is the metabolic centre of the neuron and give rise to branches of usually several dendrites and one axon. The axon ends in a branch of presynaptic terminals. The branched dendrites serve as the main place for receiving signals from the presynaptic terminals of other neurons. The axon is a long tubular extension of the cell with an isolating myelin sheet and can ramify up to one meter. The axon is capable of conveying information great distances by conducting an electrical pulse called the action potential. This signal arises from the axon hillock, a specialised area of the cell body where the action potential is initiated. The presynaptic terminals on the end of the axon transmit the action potential signal to dendrites of other neurons. The cleft between a terminal and a dendrite is called the synaptic gap, or synapse for short.
Figure 1. Model neuron
The nerve cell is able to process signals because of its special electric properties. Neurons, like all cells in the body, maintain a potential difference of about 65 mV between its membrane and the outside of the cell, called the resting membrane potential. This is the result of an unequal distribution of ions, like NA+, K+ and Cl-, in and out the cell. This distribution is caused by ion-pumps in the membrane and the membranes selective ion-permeability. The Na+-K+ pump continuously transports Na+ out of and K+ into the cell. Yet the nerve cell in its resting state only leaks K+ back out of the cell, while Na+ cannot leak back in. This leaves a negative residue charge on the inside of the membrane.
Excitable cells like neurons are different from other cell in the body, because when the membrane potential is reduced by an outside influence it suddenly becomes highly permeable to Na+. This triggers the action potential signal. And after a delay it returns to it resting state, while the excess of Na+ is pumped out again.
Through the different regions of the nerve cell four types of signals can be distinguished. First a neuron is stimulated externally by an input signal, called a receptor potential in sensory neurons and a synaptic potential in inter- and motor neurons. These signals may be excitatory or inhibitory. An excitatory signal hyperpolarises the cell, which means that the signal increases the membrane potential of the cell body. An inhibitory signal decreases the membrane potential, thereby depolarising it. At the axon hillock all input signals are combined into an integration signal. When this signal reaches the polarisation threshold, which is about 10 mV above the resting membrane potential, a long range action potential pulse travels down the axon. When this pulse reaches the presynaptic terminals, an output signal results.
The output can be a chemical messenger or direct electrical influence of a nearby cell. Almost all neurons share these features in the sense that they have an input component, a signal integration component, a conductive component, and an output component. Nerve cells differ most in the way these components work at a molecular level. For example, different chemical compounds are used as transmitters.
(Kandel, Siegelbaum & Schwartz, 1991; Schwartz, 1991)
The signalling between neurons can be electrically by directly inducing a potential difference in the cell membrane of the connecting neurons, or chemically by releasing a neurotransmitter that influences ion pumps in the cell membrane. An electric signal is fast and of short duration, while chemical transmissions are relatively slow and last longer. The manner of signal transmission depends on the way two neurons are connected, with an electrical or a chemical synaps. Those types of connection differ in several aspects.
The electric synaps is a very small gap between two membranes. In the synaptic area the membranes are connected to each other with gap junction channels. These are connected pores in the membranes through which ionic current can flow, usually in both directions. The positive current of an action potential can thereby directly change the membrane potential of the connected cell.
The chemical synaps on the other hand is much wider, and does not consist of direct connections. The presynaptic terminals have special active zones which contain collections of synaptic vesicles (see Figure 2). These are little containers with thousands of neurotransmitter particles in them. These are usually synthesised in the synaptic terminal. When an action potential reaches a synaptic terminal, the membrane of the terminal becomes suddenly more permeable to Ca+ ions. These ions cause the vesicles at the active zones to fuse with the membrane by a process of exocytosis. This breaks open the vesicles, thereby releasing the neurotransmitters in the synaptic gap. The diffused transmitters can now bind with receptors in the membrane of the other cell. These receptors cause ion pumps to close or open, which will change the membrane potential of the postsynaptic cell. This generally depends on the kind of transmitter that is released and the kind of receptors in the synaptic gap. The last step in the chemical transmission is the removal, or destruction by enzymes, of the transmitter chemicals left in the synaptic gap.
A variety of small molecules, such as glutamate, GABA, and dopamine, can serve as a neurotransmitter. These chemicals do not serve only one function. The same chemical messenger can also be released in the bloodstream to serve as a hormone, e.g. signalling glands. By definition a substance has a function as neurotransmitter when: the chemical is synthesised in the neuron; it is present in the presynaptic terminals and released in the synaptic gap; it has a short distance signalling effect on the postsynaptic neuron; and there is a mechanism to remove it from the synaptic cleft. An extra criterion is also that when the chemical is administered as a drug in comparable concentrations, it exerts the same effect (Schwartz, 1991, p214).
Dopamine is synthesised in the presynaptic terminal by several metabolic pathways (see Figure 2). First tyrosine in the cell is converted to L-DOPA with the help of the enzyme tyrosine hydroxilase (TH). L-DOPA on its turn is converted into dopamine by the enzyme aromatic amino acid decarboxylase (AADC). The synthesised dopamine molecules in the presynaptic terminal are then taken up by synaptic vesicles. After the dopamine is released from the vesicles into the synaptic cleft, the remaining molecules are taken back into the synaptic terminal by transporters in the membrane. There they are transported back into vesicles or broken down to DOPAC by the enzyme monoamine amine oxidase type B (MOA-B) (Vermeulen, 1994) .
Figure 2. Prototypic dopaminergic terminal with cycle of synthesis, storage, release and removal of dopamine. Cf. (Cooper, Bloom & Roth, 1996, pp. 293-351)
The signal to open or close ion-pumps is not determined by the chemical properties of a transmitter alone. The same transmitter chemical, e.g. dopamine, can both inhibit and excite other neurons, depending on the properties of the receptor it stimulates.
Stimulated neurotransmitter receptors influence the membrane potential of a neuron directly or indirectly by several different mechanisms. There are ion channels with special receptor areas that directly bind with a transmitter. When bound to a transmitter these channels undergo a conformational change that opens the channel immediately. The second type of receptors gate ion channels indirectly with a second messenger system. A transmitter bound to such a receptor causes in several steps the release of regulatory proteins within the cell membrane, that act on a family of ion channels.
Both receptors serve different functions. The direct stimulation is relatively fast (though slower than electric stimulation), lasts only milliseconds, and is used in the circuitry that produces behaviour. The second messenger system is slower and often involves lasting changes in connection strength and alterations in excitability of neurons. This makes it possible to learn new behaviour.
(Côté & Crutcher, 1991)
Post mortem examinations of patients with Parkinson's disease revealed that parts of their brain were pathologically changed. This led scientists to believe that this part, called the basal ganglia, plays an important role in controlling voluntary movement. It was shown that signals from the cortex are led through the basal ganglia, to the thalamus, which influences motor control centres in the brain.
The basal ganglia became known as a component of the so-called extrapyramidal motor system, which was first presumed to operate independently of the pyramidal or corticospinal system. However, today it is known that both systems are interconnected, and cooperate. Furthermore, other parts of the brain are shown to play a part in voluntary behaviour as well, and the basal ganglia have also a role in cognitive functioning.
The basal ganglia themselves are a conglomeration of five distinguishable interconnected nuclei. They are called the:
From the cortex there is a direct and an indirect signal pathway through this conglomeration, maintained by circuits that use different neurotransmitters, such as GABA, glutamate, enkaphalin and substance P. There is a delicate balance between these two pathways that is partly maintained by dopamine release from the substantia nigra to the striatum. Dopamine release inhibits the indirect pathway by stimulating dopamine D2 receptors, and excites the direct pathway by stimulating the dopamine D1 receptor (see figure 3A.).
Figure 3. Major neural pathways in normal and Parkinsonian basal ganglia, cf. (Vermeulen, 1994) . The thickness of the arrows represents the strength of the signal. Further explanation, see text.
In postmortem studies it was discovered that the substantia nigra (meaning "black substance"), had lost its pigment in Parkinson patients. Subsequent studies showed that dopamine levels in the striatum were drastically reduced. Because the basal ganglia contains most of the dopaminergic neurons of the brain, these observations suggested that the dopaminergic pathway between the striatum and substantia nigra are degenerated in PD patients. The depletion of dopamine disbalances the direct and indirect pathways from the striatum, which causes the thalamus to be overstimulated. As a result the frontal cortex is less activated which would account for most of the Parkinsonian symptoms (see Figure 3B). Parkinson's disease became the first example of a disorder related to a deficiency of a neurotransmitter, now called a molecular disease.
When in the early 1980's several users of an illegal drug developed Parkinsonian symptoms it was discovered that this was caused by a toxic contamination called MPTP. In later studies animals were shown to develop the same signs after administration of the toxic, which provided researchers an animal model of Parkinson's disease. It was found out that these animals all suffered from a loss of dopaminergic cells in substantia nigra pars compacta, and a subsequent reduction in the levels of dopamine in the striatum. Consequently it was hypothesised that PD is caused by an environmental toxic agent like MPTP. Yet, no toxin that has this effect other then MPTP is found in Parkinson patients.
(Côté & Crutcher, 1991; Vermeulen, 1994)
Given the observations in the basal ganglia in the early1960's Birkmayer and Hornykiewics reasoned that it would possibly help Parkinson patients if the level of dopamine was restored to normal levels. It is not possible to administer dopamine itself as a drug because it will not pass the blood-brain barrier between the blood vessels and neurons. However, L-DOPA, the precursor in the synthesis of dopamine will. So they reasoned they could boost the dopamine production up to higher levels by providing the few remaining healthy dopaminergic neurons with large amounts of extra L-DOPA.
The first tests led to a successful initial remission of the symptoms. Yet this positive effect was countered by serious side effects such as nausea, vomiting, blood pressure changes, and collapse. This could be explained by the fact that the enzyme AADC, which converts L-DOPA to dopamine, is also present in the liver, kidney and many other places in the body. So while the dopamine levels in the striatum became more normal, the extra dopamine production disturbed chemical balances elsewhere in the body.
After further studies it was demonstrated that the efficacy of the L-DOPA treatment enhancement when the dose of L-DOPA is more gradually increased. So the focus of research became the reduction of the side effects. In the early 1970's the first AADC inhibitors were introduced that could not pass the blood-brain barrier. This made it possible to increase dopamine levels in the brain only, because the conversion of the extra L-DOPA in the peripheral organs could be inhibited selectively.
Another way to increase dopamine levels is to block the enzyme MOA-B that is converting dopamine to DOPAC. It is demonstrated by studies that the administration of MAO-B inhibitors slows down the progression of PD, and increases the live expectancy.
It is argued that this slow down can also be explained by the hypothesis that PD is caused by a toxin similar to MPTP. It was shown that MPTP needs to be converted to MPP+ by the enzyme MAO-B to have its destructive effect. So if some toxin like MPTP causes the cell death in the basal ganglia of PD patients, the inhibition of MAO-B would slow down this process. Yet it is also argued that the positive effect of MAO-B inhibition can be (solely) attributed to the effect that it inhibits the break down of dopamine, and hence increases the dopamine level.
While L-DOPA is the best available remedy to ease the lives of Parkinson patients, it is not even near a cure. Treatment that aims to increase dopamine levels turns out not stop the further deterioration of dopaminergic cells, and hence does not work well in the long term. Long term use of L-DOPA frequently results in fading of the therapeutic effect and the development of serious side-effects, such as further motor impairment and psychiatric complications. Furthermore, while the lack of dopamine causes most of the Parkinson symptoms, PD patients also suffer a loss of noradrenergic and serotonergic neurons, which attributes to the disease as well.
To bypass the problem of the side effects of L-DOPA treatment, research started to synthesise compounds that would directly act on the dopamine receptors. These compounds, called receptor agonists, would take over the role of dopamine, so no administration of L-DOPA would be needed. And hence the side effects induced by large amounts of L-DOPA would be countered.
To date this ideal is not reached. While long-term treatment with the available dopamine receptor agonists results to less dyskinesias, the effect is less then that of L-DOPA. And increasing the dose only leads to other serious side effects such as psychotic reactions. Better effects result from a combination of a low doses of L-DOPA with an agonist.
There is another reason that favours the research into dopamine receptor agonists. The hypothesis has been put forward that long term treatment with L-DOPA accelerates the degeneration of dopaminergic cells. This could be caused by the enhanced generation of toxic free OH-radicals through dopamine auto-oxidation (Vermeulen, 1994) . The higher the amount of dopamine in the cell through extra L-DOPA, or MOA-B inhibition, the higher the risk of toxication. If this claim is true, it is more preferable to use receptor agonists.
Furthermore, synthetic agonists have the advantage that they can be made highly selective for a particular receptor. There are now five known types of dopamine receptors, and further knowledge of how they are integrated in neural circuits that regulate motor behaviour may result in an agonist with less side effects.
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