The striatal dopaminergic system and Parkinsonism

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The classical studies of Hornykiewicz and colleagues in the early 1960s clearly established that the symptoms of Parkinsonism were correlated with a defect in the dopamine content of the striatum. The pigmented neurons of the substantia nigra contain dopamine as the major neurotransmitter, accounting for 80% of the total dopamine content of the brain, and the principal motor abnormalities of the disease occur when the transmitter has been depleted by about 80%. While it is now established that acetylcholine, gamma-aminobutyric acid (GABA), glutamate and a number of neuropep-tides (e.g. somatostatin, the enkephalins and substance P) also occur in the basal ganglia, so far only dopamine and acetylcholine appear to be of significance with regard to the drug treatment of this disorder. A simple, but useful, model of basal ganglia function suggests that the neostriatum, containing the caudate nucleus and the putamen, normally contains a balance between the inhibitory dopaminergic and the excitatory cholinergic components. As the cholinergic neurons in the basal ganglia do not appear to be damaged in Parkinsonism, it is postulated that the symptoms of the disease arise as a consequence of the lack of inhibitory control of the excitatory cholinergic neurons. This provides a rational basis for the use of L-dopa (levodopa), the precursor amino acid of dopamine, and of anticholinergic drugs for the symptomatic relief of this disorder. The inter-relationship between the numerous transmitters that play a role in the function of the basal ganglia is shown diagrammatically in Figure 13.3.

Patients with Parkinson's disease show changes in the pre- and postsynaptic dopaminergic neurons which try to compensate for the progressive disappearance of the transmitter. Thus the surviving pre-synaptic terminals become hyperactive, while the postsynaptic D2 receptors become hypersensitive in an attempt to compensate for the reduced dopaminergic function. These compensatory changes probably account for the relative lack of symptoms of the disease until the dopamine content has been depleted by more than 80%.

In addition to changes in the basal ganglia, a disruption of the mesocortical limbic dopaminergic system also occurs. Thus in Parkinson-ism the ventral tegmental area, a dopamine-rich region of the mesocortical system, has been shown to have a reduced dopamine content, as have the terminals that project to the cortex from this region. However, there is no evidence to show that the D2 receptors in the limbic region become hypersensitive as a consequence of dopamine cell loss. The impaired dopaminergic transmission in the limbic and cortical regions may play a crucial role in the psychiatric symptoms (e.g. perseveration, slowness of thought) that occur in the advanced stage of the illness. Similarly, the hallucinations which occasionally occur in patients on long-term L-dopa therapy may be a consequence of overstimulation of D2 receptors in these regions of the brain.

Selective degeneration of dopamine neurons in the hypothalamus also occurs, which probably accounts for the rise in the release of prolactin, growth

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Figure 13.3. Relationship between neurotransmitters in the basal ganglia and the cortex.

Figure 13.3. Relationship between neurotransmitters in the basal ganglia and the cortex.

hormone and melanocyte-stimulating hormone; dopamine is known to inhibit the release of these hormones under normal physiological conditions.

In addition to the well-established degenerative changes in the dopaminergic system which are the main neuropathological features of Parkinson's disease, it is now known that aminergic and cholinergic ascending subcortical neurons, and peptidergic pathways, are also affected in this disease. Thus lesions of the locus coeruleus occur, with a loss of noradrenaline and its main synthesizing enzyme, dopamine beta-oxidase, in both cortical and subcortical regions of the brain. It would appear that the dorsal bundle from the locus coeruleus is most severely damaged, while the ascending pathways are largely unaffected. In patients at an advanced stage of the disease, cortical alpha1 and beta adrenoceptors show an increase which may be correlated with the onset of some of the symptoms of dementia in these patients. Similarly, a defect in serotonergic transmission has been reported in Parkinsonism, a change that may contribute to the depressive symptoms that often occur in the advanced stage of the disease.

Regarding the cholinergic system, there is evidence that the pathway from the substantia innominata to the cortex degenerates in Parkinsonism, and that the septohippocampal pathway is also functioning suboptimally. As more than 30% of Parkinsonian patients exhibit intellectual deterioration with deficits in cognitive function and memory, it is possible that these cholinergic deficits may account for at least some of the symptoms of parkinsonian dementia.

The enkephalins, somatostatin and substance P all appear to be depleted in idiopathic Parkinsonism, which may be a consequence of neuronal degeneration rather than a cause of any of the symptoms of the disease. Thus these changes do not correlate with the severity of the motor symptoms, although there is some indication that the loss of somatostatin may be associated with intellectual impairment.

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