Substantia nigra dopamine-containing neurons

Adult dopamin-containing neurons in the substantia nigra rely on Cavl. 3 channels as pacemaker channels. It appears that the resulting enhanced Ca2+ load renders these channels more susceptible to neurotoxic effects and neurodegeneration as observed in Parkinson s disease. Preclinical evidence suggests that block of these with dihydropyridines causes a switch to a Cavl.3-independent pacemaker and protects these neurons from neurotoxicity. 

M5 AChR represent the predominant muscarinic subtype in dopamine-containing neurons of the pars compacta of the substantia nigra and the ventral tegmental area. 

Parkinson s disease affects about 1 in 200 of the elderly population. In broad terms, it is caused by degeneration of the substantia nigra in the midbrain, and consequent loss of dopamine-containing neurons in the nigrostriatal pathway (see Fig. 19.3, p. 382). There is no known cure but drug treatment can, if properly managed, dramatically improve quality of life in this progressive disease. 

Damier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson s disease. Brain 122 1437-1448. 

Christoph GR, Leonzio RJ, Wilcox KS (1986) Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. / Neurosci., 6, 613-619. 

The basal nuclei are a collection of paired structures that modulate motor pathways from the cerebral cortex and play a role in the fine control of movement. Part of this is a pathway from the substantia nigra in the midbrain to an area called the striatum in the basal nuclei. The neurotransmitter of this pathway is dopamine and loss of dopamine-containing neurons here causes Parkinson s disease (see page 212). 

Butcher, L.L., Talbot, K., and Bilezikjian, L., Localization of acetylcholinesterase within the dopamine-containing neurons in the zona compacta of the substantia nigra, Proc. West. Pharmacol. ScL, 18, 256, 1975. 

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. 

A potentially promising, although very controversial, approach to the treatment of Parkinson s disease is replacement of dopaminergic neurons. The grafting of fetal substantia nigra tissue, which contains the dopamine neurons, into the striatum of parkinsonian patients has been modestly successful. The procedure will remain experimental, however, until the many practical problems and ethical issues associated with the use of fetal tissue are resolved. The discovery of pluripotent stem cells is also being viewed as a possible way of developing dopamine neurons for transplant purposes. 

Trulson ME (1985) Activity of dopamine-containing substantia nigra neurons in freely moving cats. Neurosci... 

Immunohistochemical analyses have provided evidence of D4 receptors in mediumsized spiny neurons in the human striatum (Khan et al., 1998). Using immunohistochem-istry, D4 dopamine receptors were also localized within the GABA-containing cells of the striatum as well as GABAergic cells in the cerebral cortex, hippocampus, globus pallidus, substantia nigra and thalamic reticular nucleus of the nonhuman primate (Mrzljak et al., 1996). Thus, dopaminergic transmission via the D4 dopamine receptor appears to be predominantly inhibitory, so that blockade of D4 dopamine receptors may result in disinhibition of excitatory transmission in intrinsic cortical, thalamocortical and extrapyramidal pathways. 

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