Dopamine disease

Ferndndez-Ruiz JJ, Romero J, Garcia-Gil L, Garcia-Palomero E, Ramos JA (1996) Dopaminergic neurons as neurochemical substrates of neurobehavioral effects of marihuana developmental and adult studies. In Beninger RJ, Archer T, Palomo T (eds) Dopamine disease states. CYM Press, Madrid, pp 359-387... 

Neuromelanin, a dark colored pigment and product of the oxidative metabolism of dopamine, is found in the cytoplasm of dopaminergic neurons of the human substantia nigra pars compacta. Neuromelanin deposits increase with age, matching the age distribution of Parkinson s disease. In the absence of significant quantities of iron, neuromelanin can act as an antioxidant in... 

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 immediate metabolic precursor to dopamine, l-DOPA (L-dihydroxphenylalanine) is converted to the active neurotransmitter dopamine by the action of the enzyme aromatic amine acid decarboxylase (AADC). l-DOPA (INN name Levodopa) is the main diug used to treat Parkinson s disease. 

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... 

Hirschsprung s disease have ETB receptor mutations). The lack of ET-3/ETB receptor results in the absence of parasympathic ganglionic neurons in the myenteric plexus (Auerbach). Mice with an ET-3/ETB receptor disruption die within 2 weeks after birth. In transgenic mice, in which the expression of the ETB receptor is driven by the dopamine (3-hydroxylase promoter, normal myenteric plexus are present and no enteric disorder develops. These mice, however, show a salt-sensitive hypertension, which can be efficiently treated with amiloride, indicating that ETB receptors are involved in the regulation of natriuresis via the amilorid-sensitive sodium channel ENaC. 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

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. 

Levodopa is a chemical formulation found in plants and animals that is converted into dopamine by nerve cells in the brain. Levodopa does cross die blood-brain barrier, and a small amount is dien converted to dopamine. This allows the drug to have a pharmacologic effect in patients witii Parkinson s disease (Pig. 29-1). Combining levodopa witii another drug (carbidopa) causes more levodopa to reach die brain. When more levodopa is available, the dosage of levodopa may be reduced. Carbidopa has no effect when given alone. Sinemet is a combination of carbidopa and levodopa and is available in several combinations (eg, Sinemet 10/100 has 10 mg of carbidopa and 100 mg of levodopa Sinemet CR is a time-released version of die combined drugs). 

The dopamine receptor agonists, such as pramipexole (Mirapex) and ropinirole (Requip), are used for die treatment of die signs and symptoms of Parkinson s disease... 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

Those for the D2 receptor (e.g. bromocriptine) have a particular value in the treatment of Parkinson s disease by reproducing the effects of the dopamine lost through degeneration of the nigrostriatal tract (Chapter 15). They are also used to reduce the undesirable effects of prolactinaemia (high plasma prolactin), such as amenorrhoea and galactorrhoea. 

---