Nigrostriatal tract

The nigrostriatal tract is one of the four main dopaminergic pathways in the central nervous system. About 75% of the dopamine in the brain occurs in the nigrostriatal pathway with its cell bodies in the substantia nigra, whose axons project in the corpus striatum. Degeneration of the dopaminergic neurons in the nigrostriatal system results in Parkinsons disease. 

Nigrostriatal Tract/Pathway Anti-Parkinson Drugs... 

Nicotinic Acetylcholine Receptor Nicotinic Receptors Nigrostriatal Tract/Pathway Nitrates... 

Those for the D2 receptor (e.g. bromocriptine) have a particular value in the treatment of Parkinson s disease by reproducing the effects of the dopamine lost through degeneration of the nigrostriatal tract (Chapter 15). They are also used to reduce the undesirable effects of prolactinaemia (high plasma prolactin), such as amenorrhoea and galactorrhoea. 

Control of motor function Nigrostriatal tract from substantia nigra (A9) Animals Stereotypy. Rotation if one tract is lesioned Humans Induces dyskinesias Effective in Parkinsonism Animals Catalepsy Humans Reduces dyskinesias Induces Parkinsonism Mainly D2 some Di ... 

People with Parkinson s disease show a specific degeneration of the nigrostriatal tract so DA must be linked in some way to the control of motor function. It is also known that an imbalance of DA function on the two sides of the rat brain, either by stimulation or lesion of one SN, causes off-line or rotational movement (Ungerstadt and Arbuthnott 1970). This is best shown some days after 6-OHDA lesion of one substantia nigra and its nigrostriatal pathway when systemic apomorphine (DA agonist) causes animals to turn away from the lesioned side (contraversive), presumably... 

All such animal procedures suffer from the obvious and basic problem that laboratory animals do not behave like humans and that humans cannot reliably interpret their reactions and behaviour. Thus we know that Parkinson s disease is caused by a degeneration of the dopaminergic nigrostriatal tract but its lesion in animals does not produce any condition which resembles human Parkinsonism, except in primates, even though there are functional tests (e.g. rotational movements) which readily establish that loss of dopamine function and also respond to its augmentation (Chapter 15). By contrast, there are many ways, e.g. electrical stimulation and the administration of certain chemicals, to induce convulsions in animals and a number of effective antiepileptic drugs have been introduced as a result of their ability to control such activity. Indeed there are some tests, as well as animals with varied spontaneous seizures, that are even predictive of particular forms of epilepsy. But then convulsions are a very basic form of activity common to most species and epileptic seizures that are characterised by behavioural rather than motor symptoms are more difficult to reproduce in animals. 

Recently PET studies with 6-fluorodopa, which is taken up by DA nerve terminals in the striatum and is therefore presumably a measure of both the number of functional DA neurons in the nigrostriatal tract to it as well as its DA content, show that this is more like 50% of normal at the start of symptoms, not the 80% observed at PM (see... 

The ability of the striatum to apparently function normally until it has lost much of its DA can be ascribed in part to denervation supersensitivity, the degeneration of the DA input resulting in an increase in postsynaptic DA receptors and partly to the remaining neurons producing more DA. This is supported by measurements in humans which show that the HVA DA ratio, a measure of DA turnover, is much greater in Parkinsonism patients and by microdialysis in rats with 6-OHDA lesions of the nigrostriatal tract, when the reduction in perfusate (released) DA is very much less than that of neuronal (stored) DA. 

Thus initially the nigrostriatal tract is able to compensate for the loss of neurons but eventually this fails and the symptoms of PD emerge. 

Since PD is caused by a relatively specific degeneration of the DA nigrostriatal tract and as there are specific toxins, for DA neurons, i.e. 6-OHDA and MPTP, it should be possible to produce appropriate experimental models. Certainly both toxins cause rotational behaviour in rats (Fig. 7.7) but no rodent shows a syndrome suggestive of PD. Tremor and akinesia can be seen, however, in primates after such toxins and these are being more widely used in experimental studies of PD and drug evaluation. Reserpine causes a depletion of all brain monoamines and produces motor defects in rats, which, even if not PD-like, do respond to DA manipulation. 

Second, although typical neuroleptics produce depolarisation block of both A9 and AlO neurons, the atypical neuroleptics only induce it in AlO neurons (Chiodi and Bunney 1983). So after an atypical neuroleptic the A9 neurons of the nigrostriatal tract remain functional, which would explain why EPSs are not seen. Another difference is seen with the expression of an immediate-early gene, c-fos, and although its functional significance is not clear, typical neuroleptics induce its protein production in both the striatum and nucleus accumbens while the atypicals only achieve it in the accumbens. 

Nigrostriatal tract The major dopaminergic neuronal pathway linking midbrain and forebrain basal ganglia. 

As dopamine deficiency of the nigrostriatal tract, resulting in an overactivity of cholinergic interneurons, is considered to be the fundamental pathophysiological mechanism for Parkinson s disease two approaches for pharmacological intervention seem rational. 

Nigrostriatal tract Substantia nigra and striatum. Motor control. Hypoactivity implicated in parkinsonian-like side effects of antipsychotics. 

DA in the nigrostriatal tract helps regulate kinesis by inhibiting GABAergic and cholinergic neurons. The loss of DA neurons in this trad leads to excessive ACh activity and Parkinsonism. DA receptor antagonists cause a reversible pseudo-Parkinsonism agonists may cause dyskinesis. 

Parkinson s disease is a disorder of the basal nuclei in the brain. Post-mortem studies of brains from patients with Parkinson s disease have shown greatly decreased levels of dopamine in the basal nuclei. The main pathology is degeneration of the dopaminergic neurons of the pathway from the substantia nigra in the brain stem to the corpus striatum (the nigrostriatal tract). 

Parkinsonism is due to an imbalance between DA and ACh activity in the nigrostriatal tract. Drugs attempt to restore this balance either by increasing DA or decreasing ACh levels. Figure IV-6-1 illustrates the CNS sites targeted in antiparkinsonism therapy. 

This drug is protective against the selective neurotoxicity of MPTP, a chemical known to cause the destruction of dopaminergic neurons in the nigrostriatal tract... 

MPTP causes parkinson-like extrapjramidal dysfunction by destroying dopaminergic neurons in the nigrostriatal tract. This neurotoxic action requires the formation of toxic metabolites from the metabolism of MPTP by monoamine oxidase type B. Toxicity is prevented by selegiline, a selective inhibitor of MAO type B. MPTP is used as an experimental tool in animal models of parkinsonism. The answer is (E). 

---