Striatum, dopamine projections

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.

IPD has a characteristic neuropathologic picture that permits differentiation from similar clinical syndromes. In the SNc, loss of neurons and Lewy bodies (a neuronal inclusion body composed of amyloid neurofilaments) is always found. Lewy bodies appear in degenerating neurons in association with adjacent gliosis. The loss of pars compacta neurons is the basis for loss of dopamine projections to the striatum. Small numbers of Lewy bodies can be found in other neurologic disorders and in normal aging. The occurrence of SNc Lewy bodies in patients without parkinsonism indicates that the disease can exist as a pathologic entity with less involvement than necessary for... 

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. 

Muscarinic and dopaminergic pathways in the CNS interact in control of numerous pathways implicated in diseases, especially those controlling involuntary motor systems. Muscarinic effects on dopamine release are mediated in several ways via different mAChR subtypes. Thus mAChR facilitation of DA release appears to involve M4 receptors on GABA projection neurons to the striatum, while M3 receptors on striatal DA neurons are predicted to inhibit striatal DA release [12],... 

Dopamine. Dopamine is present in high concentration in the striatum (Fig. 46-2), in densely aborized terminals of projections that originate in the SNc. Neurons in the... 

Dopamine acts on G-protein-coupled receptors belonging to the D1 -family of receptors (so-called D1-like receptors , or DlLRs, comprised of Dl- and D5-receptors), and the D2-family of receptors ( D2-like receptors , or D2LRs comprised of D2-, D3- and D4-receptors). Dl LRs stimulate adenylate cyclase activity and, possibly, also phosphoinosit-ide hydrolysis, while D2LRs reduce adenylate cyclase activity. In the striatum, DlLRs are predominately associated with medium spiny neurons of the direct pathway, while D2LRs have been found as autoreceptors on dopaminergic terminals, as heteroreceptors on cholinergic interneurons, and on indirect pathway neurons. In the SNr, DlLRs are located on terminals of the direct pathway projection, while D2LRs appear to function as autoreceptors. 

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. 

In contrast to acetylcholine, dopamine has both excitatory (Dl) and inhibitory (D2 and D3) receptors. Dopaminergic neurons occur in two closely connected groups AlO—ventral tegmental area (VTA), and A9—substantia nigra, pars compacta (Fig. 3). While substantia nigra neurons project to the striatum, VTA... 

The brain stem cholinergic neurons are essential for the regulation of sleep-wake cycles via projections to the thalamus. The cholinergic interneurons in the striatum modulate striatal GABAergic neurons by opposing the effects of dopamine. Increased cholinergic tone in Parkinson s disease and decreased cholinergic tone in patients treated with neuroleptics are examples of an imbalance of these two systems in the striatum (Cala-bresi et al., 2000). 

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. 

When transfected in heterologous cell systems, both the D1 and D5 receptors are able to stimulate the production of cAMP (Dearry et al., 1990 Tiberi et al., 1991). Although other signaling pathways have been described, the cAMP pathway stimulated by D1/D5 receptors remains the most extensively studied and, it has been described in a very interesting manner, in detail, at the level of the dorsal and ventral striatum, the main projection areas for mesencephalic dopamine neurons. 

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