The nigrostriatal pathway

The organization of the nigrostriatal projections in the mouse, studied with lectin-conjugated HRP as tracer, was reported to be similar to that of the rat (Mattiace et al., 1989). 

Differences in the crossed projections have been reported between the rat and the mouse, since it has been suggested that in the latter species the VTA and the retrorubral field, but not the SNc, contribute sparse crossed projections to the striatum (Mattiace et al., 1989). In addition, inter-strain differences have been reported in mice for example, crossed projections were documented in the CBA strain, but not in the BALB/c strain (Mattiace et al., 1989). 

The reversal dorsoventral axis on the basis of which the ventral sheet of SNc and VTA cells project dorsally in the forebrain and the dorsal sheet project ventrally in the forebrain (Fig. 17), which led to the subdivision of the dopaminergic cells into dorsal and ventral tiers, has already been dealt with in Section 2.4. 

In terms of the functional subdivisions determined in the striatum by corticostriatal projections, the motor striatum is innervated mainly by the lateral portion of the SNc, the associative striatum mainly by the medial portion of the SNc and VTA, and the limbic striatum mainly by VTA neurons extending into the medial SNc (Joel and Weiner, 2000). 

Nigrostriatal axons are represented by relatively thin fibers, which exhibit a range of calibers thin (0.1-0.4 pm) and smooth fibers, slightly thicker fibers (0.2-0.8 pm) with more frequent varicosities, and a minority of fibers of slightly larger calibre with large bulbous 

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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. 

While the nigrostriatal pathways are ipsilateral some crossing occurs in fibres from the ventral tegmental AlO nucleus. These pathways are shown diagramatically in Fig. 7.1. Further details can be obtained from Moore and Bloom (1978) and Lindvall and Bjorkland (1978). The nuclei provide distinct loci for activating the dopamine systems for electrophysiological, release and behavioural studies and for their destruction by electrolytic lesion or injection of the toxin 6-hydroxydopamine (6-OHDA). 

Jellinger K. (1991). Pathology of Parkinson s disease. Changes other than the nigrostriatal pathway. Mol. Chem. Neuropathol. 14, 153-97. 

Casas M, Ferre S, Cobos A, Grau JM, Jane F (1989) Relationship between rotational behaviour induced by apomorphine and caffeine in rats with unilateral lesion of the nigrostriatal pathway. Neuropharmacology 28 407 09... 

That conclusion is correct and has been known for quite some time. Back in 1960, examination of the brains of parkinsonism victims revealed that a pathway in the brain termed the nigrostriatal pathway had degenerated. This pathway proceeds from a group of cells called the substantia nigra to the striatum and is known to be important for the control of movement. The neurotransmitter employed in this pathway is dopamine. 

Here is one last word about L-dopa. It delivers dopamine to the entire brain, not just the nigrostriatal pathway. We know from our previous discussion that excess dopamine activity is associated with schizophrenia. It should not surprise you then that a rather common side effect of L-dopa is some of the symptoms of schizophrenia, including hallucinations. 

Dopamine agonists are employed to treat parkinsonism, a disease in which there is a deficit of dopamine activity in the nigrostriatal pathway. 

The nigrostriatal pathway participates in the production of smooth physical motion. It is not the brain area that works to initiate movement, which is in the cerebral cortex (pyramidal tract) it is the region that helps one to have fluid motion (extrapyramidal tract). Although many neurotransmitters are found in this latter system, two neurotransmitters—dopamine and acetylcholine—are predominantly involved in this pathway. The brain normally maintains a relatively stable ratio of dopamine and acetylcholine in the pathway. However, when something happens to upset this ratio, problems arise. 

As you might anticipate, dopamine receptor-blocking antipsychotics lower the functional dopamine/acetylcholine ratio in the nigrostriatal pathway. As a resnlt, the antipsychotics have the same effect in this pathway as idiopathic PD. This is how antipsychotics produce their so-called extrapyramidal side effects (EPS). EPS can take the form of parkinsonism (e.g., rigidity, tremor) or acnte dystonic reactions. 

The occurrence of tardive dyskinesia after treatment with conventional antipsychotics for a long term raises some interesting questions. Remember, dyskinesias are a symptom of HD and other neurological disorders in which there is too much dopamine flowing through the nigrostriatal pathway. How can a dopamine-blocking medication produce symptoms similar to HD ... 

The second theory is that some atypicals work by balancing dopamine blockade with serotonin receptor blockade. We know that one of the roles of serotonin is to attenuate (or lessen) dopamine activity. Blocking serotonin action therefore may release just enough dopamine activity in the nigrostriatal pathway to avoid EPS without interfering with the antipsychotic effects in the mesolimbic area. 

Many side effects of antipsychotic drugs can be understood in terms of the drugs receptor-blocking properties. When antipsychotics reduce dopamine activity in the nigrostriatal pathway (via dopamine... 

Dopaminergic neuromodulatory system. The neurons that synthesize dopamine (structural formula in box) are found in the midbrain, from which they project to the limbic system (the mesolimbic pathway), the cerebral cortex (the mesocortical pathway), as well as to the extrapyramidal motor system (the nigrostriatal pathway). 

The nigrostriatal pathway connects the substantia nigra to the striatum, an area important to movement. Substantia nigra damage leads to Parkinsonism, of which the REM sleep behavior disorder is a herald. 

Hyperactivity of dopamine in the nigrostriatal pathway is thought to underlie various hyperkinetic movement disorders, such as chorea, dyskinesias, and tics. Chronic blockade of dopamine 2 receptors in this pathway may result in a hyper-... 

When D2 receptors are blocked in the nigrostriatal DA pathway, it produces disorders of movement that can appear very much like those in Parkinson s disease this is why these movements are sometimes called drug-induced parkinsonism (Fig. 11 —4). Since the nigrostriatal pathway is part of the extrapyramidal nervous system, these motor side effects associated with blocking of D2 receptors in this part of the brain are sometimes also called extrapyramidal symptoms, or EPS. 

Prolonged blockade of dopamine receptors in the nigrostriatal pathway may lead to an increased sensitization of post-synaptic dopamine 2 receptors and a disorder called ... 

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