Nigrostriatal projection

This peptide itself has no selectivity for the two CCK receptors, CCK-A and B, which have so far been established to stimulate IP3/DAG while, like substance P, can close potassium channels to increase neuronal activity. The CCK-B receptor is thought to predominate in the CNS but species differences may make this interpretation difficult. It has a wide distribution in the CNS but is also found in the gut whereas the CCK-A receptor is more restricted but is found in the hypothalamus, hippocampus and in the brainstem. There are high levels of the natural peptide, CCK-8 in cortex, hippocampus, hypothalamus, ventral tegmentum, substantia nigra, brainstem and spinal cord. CCK is one of the most abundant peptides in the brain and CCK co-exists with dopamine, substance P, 5-HT and vasopressin. Interestingly, in the dopamine areas, CCK co-exists in the mesolimbic pathways but in the nigrostriatal projections, the peptide and... 

It is widely accepted that Parkinson s disease primarily results from degeneration of pigmented neurons in the substantia nigra (Gibb 1998). This causes a loss of nigrostriatal projections and lack of dopamine modulation in the striatum. In addition to loss of neurons, many of the remaining neurons contain Lewy bodies. 

The first generation antipsychotics, now known as typical drugs, were all D2 receptor blockers and, as such, very likely to produce Parkinsonian side effects. Because antipsychotic potency was associated with D2 receptor affinity, it was assumed that dopamine overactivity was the essential defect in schizophrenia and that a direct dopamine blockade was the definitive route to treatment. But these drugs affected both the target dopamine pathways of the mesolimbic projection and the uninvolved nigrostriatal projection. Unfortunately, that meant that movement disorders were the price that had to be paid for antipsychosis. 

Subchronic oral administration of lithium causes a time-dependent increase in the substance P level in the striatum, which is prevented by coadministration of haloperidol. In PC 12 pheochromocytoma cells, lithium dramatically increases the intracellular levels of the neuropeptide neurotensin and the mRNA encoding it. An extensive overlap between specific and high-affinity neurotensin binding sites and dopamine perikarya and dendrites has been shown to occur in the mesocorticolimbic and nigrostriatal projection systems. Consistent with this observation are the results of observations showing that cocaine, an indirect sympathomimetic agent that enhances the extrapyramidal dopaminergic activity, increases dramatically the striatal content of neurotensin-like immunoreactivity. 

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). 

Baker SA, Baker KA, Hagg T (2004) Dopaminergic nigrostriatal projections regulate neural precursor proliferation in the adult mouse subventricular zone. Eur J Neurosci 20 575-579. 

Druga R (1989) Nigrostriatal projections in the rat as demonstrated by retrograde transport of horseradish peroxidase. I. Projections to the rostral striatum. J Hirnforsch 7 11-21. 

Consistent with the documented expression of the D3R in nigrostriatal projection neurons, D3R(—/—) mice were shown to have abnormal dopamine neurotransmission. The locomotor hyperactivity was associated with elevated extracellular dopamine levels as measured by in vivo microdialysis (Joseph et al., 2002). Evoked dopamine release studied in striatal brain slices showed that the effect of the D2R/D3R agonist quinpirole in inhibiting dopamine release was mildly reduced in D3R(—/—) mice confirming that this receptor at least participated in D2-like dopamine autoreceptor functionality. 

Hanley JJ, Bolam JP (1997) Synaptology of the nigrostriatal projection in relation to the compartmental organization of the neostriatum in the rat. Neuroscience 81 353-370. 

Pritzel M, Huston JP, Sarter M (1983) Behavioral and neuronal reorganization after unilateral substantia nigra lesions evidence for increased interhemispheric nigrostriatal projections. Neuroscience 9 879-888. 

Langer FL, Graybiel AM (1989) Distinct nigrostriatal projection systems innervate striosomes and matrix in the primate striatum. Brain Res 495 344-350. 

Hedreen JC, DeLong MR (1991) Organization of striatopallidal, striatonigral, and nigrostriatal projections in the macaque. J. Comp. Neurol, 304, 569-595. 

Gibb, W.R.G. (1992) Melanin, tyrosine hydroxylase, cal-bindin and substance P in the human midbrain and substantia nigra in relation to nigrostriatal projections and differential neuronal susceptibility in Parkinson s disease. Brain Res. 581 283-291. 

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. 

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). 

Figure 30-12 Diagram illustrating some of the major interconnections of the "extrapyramidal system" of the brain. Arrows indicate major direction of projections. The nigrostriatal (substantia nigra to striatum) and related neuronal pathways are indicated with dashed lines. After Nohack and Demarest,405 pp. 182 and 183.

FIGURE 11 —4. When dopamine 2 receptors are blocked by dopamine 2 antagonists in the postsynaptic projections of the nigrostriatal pathway, it produces disorders of movement, which can appear very much like those in Parkinson s disease. That is why these movements are sometimes called drug-induced parkinsonism. Since the nigrostriatal pathway projects to the basal ganglia, a part of the so-called extrapyramidal nervous system, side effects associated with blockade of dopamine 2 receptors there are sometimes also called extrapyramidal symptoms (EPS). 

The nigrostriatal system, in which fibres originate from the A9 region of the pars compacta and project rostrally to become widely distributed in the caudate nucleus and the putamen. 

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