Dopamine central nervous system disorders

Siqueira and Moraes 1989). However, the relationship between manganese effects on peripheral versus central dopamine levels has not been clearly defined, and given the lack of change in dopamine content in substantia nigra of humans exposed to manganese, the relevance of the animal studies to central nervous system disorder is questionable. 

Complicated processes govern wakefulness, sleep, and the transitions leading to sleep initiation and maintenance. Although the neurophysiology of sleep is complex, certain neurotransmitters promote sleep and wakefulness in different areas of the central nervous system (CNS). Serotonin is thought to control non-REM sleep, whereas cholinergic and adrenergic transmitters mediate REM sleep. Dopamine, norepinephrine, hypocretin, substance P, and histamine all play a role in wakefulness. Perturbations of various neurotransmitters are responsible for some sleep disorders and explain why various treatment modalities are beneficial. 

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. 

Schizophrenia is a chronic, complex psychiatric disorder affecting approximately 1% of the population worldwide. The chronic nature of the illness, in addition to the early age of onset, results in direct and indirect health care expenditures in the U.S., which amount to approximately 30 to 64 billion dollars per year [4]. It is perhaps the most devastating of psychiatric disorders, with approximately 10% of patients committing suicide. The dopamine hypothesis of schizophrenia postulates that overactivity at dopaminergic synapses in the central nervous system (CNS), particularly the mesolimbic system, causes the psychotic symptoms (hallucinations and delusions) of schizophrenia. Roth and Meltzer [5] have provided a review of the literature and have concluded a role for serotonin as well in the pathophysiology and treatment of schizophrenia. The basic premise of their work stems from the known interaction between the serotonergic and dopaminergic systems. 

In the central nervous system, there are close associations between NT and dopamine systems, and NT may be involved in clinical disorders involving dopamine pathways such as schizophrenia, Parkinson s disease, and drug abuse. Consistent with this, it has been shown that central administration of NT produces effects in rodents similar to those produced by antipsychotic drugs. 

Chlorpromazine Blockade of D2 receptors >> 5 2 receptors .-Receptor blockade (fluphenazine least) muscarinic (M)-receptor blockade (especially chlorpromazine and thioridazine) Hx-receptor blockade (chlorpromazine, thiothixene) t central nervous system (CNS) depression (sedation) t decreased seizure threshold t QT prolongation (thioridazine) Psychiatric schizophrenia (alleviate positive symptoms), bipolar disorder (manic phase) nonpsychiatric antiemesis, preoperative sedation (promethazine) pruritus Oral and parenteral forms, long half-lives with metabolism-dependent elimination Toxicity Extensions of effects on a - and M- receptors blockade of dopamine receptors may result in akathisia, dystonia, parkinsonian symptoms, tardivedyskinesia, and hyperprolactinemia... 

List of Abbreviations Ach, acetylcholine AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid CNS, central nervous system COMT, catechol-O-methyltransferase DA, dopamine DRP-2, dihy-dropyrimidinase-related protein 2 DSM, diagnostic and statistical manual of mental disorders GNAS1, guanine nucleotide-binding protein (G-protein) alpha stimulating activity polypeptide 1 5-HIAA, 5-hydroxyindole acetic acid 5-FIT, serotonin (5-hydroxytryptamine) MAO, monoamine oxidase MHPG, 3-methoxy-4-hydroxyphenylglycol NE, norepinephrine NMDA, N-methyl-D-aspartate PCP, phencyclidine SSRI, selective serotonin reuptake inhibitor SDS, schedule for the deficit syndrome... 

It was named Dopamine because it was a monoamine, and its synthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA). He was awarded Nobel Prize in 2000 along with Eric Kandel and Paul Greengard in Medicine for showing that dopamine is not just a precursor of noradrenaline and adrenaline, but also neurotransmitter as well. DO is a type of neurotransmitter naturally produced in by the human body. It is also a neurohormone released by the hypothalamus. It is a chemical messenger that is similar to adrenaline and affects the brain processes that control movement, emotional response, and the capacity to feel pleasure and pain. It is vital for performing balanced and controlled movements [172,173], In the extra-cellular fluid of the central nervous system, the basal DO concentration is very low (0.01-1 pM). Abnormal levels of DO have been linked with Parkinson s disease, Tourette s syndrome, Schizophrenia, attention deficit hyperactive disorder and generation of pituitary tumours [174-176],... 

Dopamine is a major catecholamine neurotransmitter in the central nervous system that has been implicated in the regulation of locomotor activity, emotion, cognition, and behavior reward and in neuroendocrine regulation [39]. Clinically, dopaminergic drugs (e.g., risperidone) that block or activate dopamine receptors are used to treat neurodegenerative, neuropsychiatric, and neurode-velopmental conditions such as Parkinson s, schizophrenia, bipolar disorder, and autism [40],... 

The high sequence conservation of the dopamine D4 receptor may reflect its importance to central nervous system function as is also suggested by its wide expression in the brain and relatively high affinity for dopamine. The dopamine Di receptor gene is essentially nonpolymorphic, in its exon-intronic regions [41], A 5 untranslated region (UTR) promoter SNP, however, has been associated with a number of neuropsychiatric disorders and drug response phenotypes. 

Catecholamine neurotransmitters in the central nervous system are synthesized in that location itself because they cannot cross the blood-brain barrier. However, dopa readily crosses the blood-brain barrier, promoting the catecholamine synthesis. Thus, in disorders involving deficiency of catecholamine synthesis, administration of dopa may have beneficial effects. In Parkinson s disease, in which deficiency of dopamine synthesis affects nerve transmission in the substantia nigra of the upper brain stem, administration of dopa leads to some symptomatic relief. Parkinsonism is a chronic, progressive disorder characterized by involuntary tremor, decreased motor power and control, postural instability, and muscular rigidity. 

DOPA decarboxylase, a pyridoxal phosphate-requiring enzyme, catalyzes the synthesis of dopamine from DOPA. Dopamine is produced in neurons found in certain structures in the brain. It is believed to exert an inhibitory action within the central nervous system. Deficiency in dopamine production has been found to be associated with Parkinson s disease, a serious degenerative neurological disorder (Special Interest Box 14.3). The precursor l-DOPA is used to alleviate the symptoms of Parkinson s disease because dopamine cannot penetrate the blood-brain barrier. (The blood-brain barrier protects the brain from toxic substances. Many polar molecules and ions cannot move from blood capillaries, although most lipid-soluble substances readily pass across. The blood-brain barrier consists of connective tissue and specialized cells called astrocytes that envelop the capillaries.) Once l-DOPA is transported into appropriate nerve cells, it is converted to dopamine. 

From a chemical point of view all amphetamine-type stimulants (ATS) are related to S-phenethylamine, which is the basic element of the body neurotransmitters (such as dopamine and adrenaline) that convey the neuronal information of the central and vegetative nervous system. Amphetamine was first synthesized in 1887 but was not used for medical purposes until the early 1930s, when it was found that it increased blood pressure, stimulated the central nervous system, was effective against asthma, and was useful in treating an epileptic seizure disorder. On the illicit drug market amphetamines have been sold in the form of powders, liquids, crystals, tablets, and capsules. 

Nervous system Tetrabenazine inhibits vesicular monoamine transporter 2, leading to depletion of dopamine and other monoamines in the central nervous system. In a retrospective chart review, 448 patients who had used tetrabenazine between 1997 and 2004 (mean age at onset of the movement disorder, 43 years 42% men) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19) [68"]. They took treatment for a mean of 2.3 years and efficacy was sustained in most cases. Common adverse effects included drowsiness (25%), parkinsonism (15%), depression (7.6%), and akathisia (7.6%). Although it has repeatedly been observed that tetrabenazine alleviates hyperkinetic movements, it can worsen parkinsonism [69 ]. 

Parkinsonism is associated with a number of degenerative changes in both the structure and the chemistry of the basal ganglia. The relationship between the symptoms of the disease and these changes is dependent upon what is the normal function in the extrapyramidal motor system of such substances as dopamine, noradrenaline, serotonin, and the melanins, as well as others such as acetylcholine whose levels appear to be normal in Parkinsonism. Nevertheless, normal levels do not exclude disordered function since dynamic systems can involve different rates of turnover with no apparent change in concentrations. Synaptic transmission in the central nervous system has been extensively reviewed [59-61] and only those factors relevant to Parkinsonism will be discussed here. 

This section may be summarized by pointing out that copper deficiency affects the central nervous system, but the primary lesion that produces the symptoms in unknown. A nervous disorder develops in copper-deficient animals that affects locomotor activity. The ataxic condition is accompanied by hypomyelination of the nerve tract, decreased activity of both neural cytochrome oxidase and superoxide dismutase, and decreased levels of dopamine and norepinephrine in the brain. 

Biogenic monoamine neurotransmitters, specifically serotonin, norepinephrine and dopamine, play a crucial role in various central nervous system (CNS) activities, and monoamine deficiency has been implicated in a variety of CNS disorders. One approach to enhance monoaminergic neurotransmission is by inhibiting its reuptake after release into the synaptic cleft. Drugs that block... 

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