Nigrostriatal projection dopamine

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. 

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. 

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 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). 

Fig. 2. A. Forebrain dopamine projection system in rodents and primates. The nigrostriatal pathway projects from the A8 and A9 groups of the substantia nigra (SN) via the medial forebrain bundle (mfb) to the neostriatum (NS). The mesocorticolimbic pathway projects from the more medially located A10 cell group of the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) and olfactory tubercle (OT) of the ventral striatum (VS) and limbic forebrain areas including prefrontal cortex (Ctx), septum (Se) and amygdala (A). B. Striatal projection areas in the rodent brain are divided into the more dorsal neostriatum, and ventral striatum. C. In the primate brain, including human and illustrated for the marmoset, the neostriatum is divided by the fibers of the internal capsule into caudate nucleus (CN) and putamen (Pu). Correspondingly, the neostriatum of rats is sometimes designated the caudate-putamen (CPu) complex.

Treatment with NMDA receptor antagonists leads to a marked, dose-dependent increase of amphetamine-induced dopamine release (Miller and Abercrombie, 1996). In schizophrenics, this amphetamine-induced dopamine release is much higher compared to healthy controls (LarueUe et al., 1996). This observation is in accordance with the view that activation of the nigrostriatal dopamine system can take place by opposing activation of inhibitory striatonigral GABAergic projection neurons (Carlsson et al., 2001). 

The distribution of dopamine in the brain is very non-uniform. There is some in the limbic system, and a large proportion is found in the corpus striatum - a part of the extrapyramidal motor system which is concerned with the coordination of movement. Dopamine-containing nerves are found in three main pathways in the brain. The nigrostriatal pathway contains about 75% Of the dopamine in the brain, and the cell bodies lie in the substantia nigra and the nerves terminate in the corpus striatum. The second important pathway is the mesolimbic pathway, the cell bodies of which lie in the mid-brain and project to parts of the limbic system, particularly the nucleus accumbens. The third, the tubero-infundibular system, consists of short neurons that run from the arcuate nucleus of the hypothalamus to the median eminence and the pituitary gland, the secretions of which they regulate. 

Seiden, L.S. Commins, D.L. Vosmer, G. Axt, K. and Marek, G. Neurotoxicity in dopamine and 5-hydroxytryptamine terminal fields A regional analysis in nigrostriatal and mesolimbic projections. Ann NY Acad Sci 537 161-172, 1988. 

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