Dopamine in parkinsonism

Levodopa is the amino precursor of dopamine. It is used to replenish depleted dopamine in Parkinson s disease. Levodopa may cause insomnia, reddish discoloration of urine and headache. 

Txvo balanced systems are important in the extrapyramidal control of motor activity at the level of the corpus striatum and substantia nigra in one the neurotransmitter is acetylcholine in the other it is a dopamine. In Parkinson s disease there is degenerative loss of nigrostriatal dopaminergic neurons and the sjunptoms and signs of the disease are due to dopamine depletion. 

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. 

The nigrostriatal system is predominantly involved in motor control, which is particularly evident in Parkinson s disease (PD), where a progressive loss of these neurons results in loss of motor function. In the early stages of the disorder, the motor impairment can be reversed by the administration of the dopamine precursor l-DOPA (L-3,4-dihydroxyphenylalanine), which bypasses the need for TH in dopamine... 

A synthetic neurotoxin that causes parkinsonism in human and nonhuman primates, mice, gold fish, and dogs. MPTP is inert but metabolized by MAO-B to the neurotoxin MPP+ (1,2-dihydropyridine ion). This neurotoxin causes depletion of dopamine and degeneration of nigrostriatal dopamine neurons similar to what is observed in Parkinson s disease. 

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. 

The symptoms of parkinsonism are caused by a depletion of dopamine in the CNS. Dopamine, when given orally, does not cross the blood-brain barrier and therefore is ineffective The body s blood-brain barrier is a mesh-work of tightly packed cells in die walls of the brain s capillaries that screen out certain substances. This unique meshwork of cells in the CNS prohibits large and potentially harmful molecules from crossing into die brain. This ability to screen out certain substances lias important implications for drug dierapy because some drugs are able to pass through die blood-brain barrier more easily dian odiers. 

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson s disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington s Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA agonists (and levodopa) may overcome akinesia but can induce DA overactivity and dyskinesia (peak dose effect) (see Chapter 15)...

The beneficial effect of deprenyl in Parkinson s disease was su ested to be in part due to its effect on increasing the levels of SOD activity in several brain regions (Carrillo et al., 1993). Deprenyl is known to inhibit monoamine oxidase type B, which results in a reduction in hydrogen peroxide formation by blockade of the oxidative deamination of dopamine. That is believed to be the major mechanism of action of this drug in inhibiting the progression of Parkinson s disease. 

FIGURE 29-1. Anatomy of the extrapyramidal system. The extrapyramidal motor system controls muscle movement through a system of pathways and nerve tracts that connect the cerebral cortex, basal ganglia, thalamus, cerebellum, reticular formation, and spinal neurons. Patients with Parkinson s disease have a loss of dopamine neurons in the substantia nigra in the brain stem that leads to depletion of dopamine in the corpus striatum. The corpus striatum is made up of the caudate nucleus and the lentiform nuclei that are made up of the putamen and the globus pallidus. 

Brotsie JM. Adjuncts to dopamine replacement, a pragmatic approach to reducing the problem of dyskinesia in Parkinson s disease. Mot Disord 1998 13 871-876. 

Roth T., Rye D Borchert L. et al. (2003). Assessment of sleepiness and unintended sleep in Parkinson s disease patients taking dopamine agonists. Sleep Med. 4, 275-80. 

Schoemaker, H., Pimoule, C., Arbilla, S., Scatton, B., Javoy-Agid, R, and Langer, S.Z., Sodium dependent pH]cocaine binding associated with dopamine uptake sites in the rat striatum and human putamen decrease after dopamine denervation and in Parkinson s disease, Naunyn-Schmiedeberg s Arch. Pharmacol., 329, 227, 1985. 

Unlike many chemicals in the brain, neurotransmitters are not homogeneously distributed, but concentrated in certain regions. For example, almost two-thirds of the dopamine in the brain is found in the bilateral nigrostriatal (mesostriatal) tract (pathway), where the neuronal cell bodies are located in the substantia nigra and the axons terminate in the corpus striatum. When over 85% of these dopaminergic neurons are lost, the characteristic motor dysfunction of Parkinson s disease is seen. 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

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