Dopamine: Synthesis and Application - Research Paper Example

?DOPAMINE: SYNTHESIS AND APPLICATION Introduction Dopamine (DA) belongs to the catecholamine family, and is a neuro-modulator mainly found in the periphery and in the central nervous system (CNS) (Kuchel & Kuchel 709-21). The concentration of DA is largely in the CNS (IBI Biosolutions). Its origin can be traced back to a tiny group of neurons in the mesencephalon (Fellous & Suri 1-6). The following is the chemical structure of dopamine. CHEMICAL STRUCTURE OF DOPAMINE The neural chemical dopamine is chemically represented as C6H3(OH)2-CH2-CH2-NH2. The IUPAC name of dopamine is 4-(2-aminoethyl)benzene-1,2-diol. Externally, as a medicinal agent DA can be synthesized in the presence of hydrogen bromide from demethylation of 2-(3,4-dimethoxyphenyl)ethylamine. Following is the reaction: Importance of Dopamine Dopamine is one of the most important chemicals in the brain. For instance, the sleeping and waking up (Dzirasa et al. 10577-89) is determined by DA, it is known for goal-directed behaviors (Wise 1-12) and reward-learning (Schultz 199-207), and aids in the locomotion by means of the basal ganglia (Graybiel et al. 1826-1831). DA is also essential for cognitive processing. For instance, executive function as well as pre-frontal cortex activities, requires DA. Dopamine roles cannot be ignored in the synaptic plasticity such as the striatum and the pre-frontal cortex in brain regions (Best et al.) When there is a disturbance in the proper functioning of this neuro-modulator in different dopaminergic systems several disorders are known to occur. For example, a reduction in concentration of dopamine in the pre-frontal cortex area as well as in case of disinhibited striatal dopamine release, schizophrenia is known to occur. Parkinson is another disorder that is caused due to the loss of dopamine in the striatum that results in the loss of motor control. Similarly, when there is a variation in or there is abnormal regulation of dopamine discharge and reuptake Tourette's syndrome occurs. There are also studies that link the dopamine and sexual responses. Microdialysis studies suggest addictive drugs boost extra-cellular dopamine concentration. As a result of imbalance several problems may arise in mental stability. Brain imaging has revealed a correspondence among excitement and psycho-stimulant-induced boosts in extra-cellular dopamine. Therefore, it is essential to maintain the required dopamine concentration in different parts of the brain (Best et al.). Biosynthesis of Dopamine The biosynthesis of DA is a complex mechanism and is controlled by enzyme actions. The first step in this mechanism is hydroxylation of the amino acid L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) by the use of the enzyme tyrosine 3-monooxygenase. The common name of this enzyme is tyrosine hydroxylase. In the second step the L-DOPA is further converted to DA by the action of the enzyme DOPA decarboxylase (or generally known as aromatic amino acid decarboxylase). The decarboxylation step takes place in the cytoplasmic region (see figure 1&2). Figure 1: First step in the formation of Dopamine . Figure 2: Second step in the formation of DA In the first step of DA formation the tyrosine has to be taken up through the blood brain barrier by a transporter into the dopaminergic cells (Cooper et al.). DA is also manufactured by neurons in specific parts of the brain such as the ventral tegmental region. This region projects to the prefrontal cortex and the basal forebrain. It also extends to the nucleus accumbens. Additionally, DA pathway can also be found from the substantia nigra pars compacta to the neostriatum (IBI Biosolutions). The second step takes place in the cytoplasm of cells where the DOPA decarboxylase transforms DOPA to DA. Further, dopamine is carried by another active carrier to synaptic vesicles. Here DA molecules are protected from catabolizing enzymes. There are several factors that influence the synthesis rate of the dopamine. For instance, it is dependent on the activity of the tyrosine hydroxylase. This enzyme itself is under the control of many and complex mechanisms (Feldman et al. 277-344). The most important temporary dictatorial factors are end-product inhibition, firing rate of the neuron and auto-receptors situated in the end point of the nerves. The end-product of the dopaminergic neurons, DA, declines the attraction of the enzyme's pteridine co-factor for tyrosine hydroxylase. This further declines the activity of the enzyme. Hence all these factors together with numerous other factors, control the phosphorylation state of tyrosine hydroxylase (Feldman et al. 277-344). Dopamine Metabolism Dopamine is not the end product but it may be further processed into norepinephrine by dopamine beta-hydroxylase in some neurons. Dopamine metabolism to norepinephrine by the enzyme dopamine ?-hydroxylase mainly takes place in neurons containing this enzyme (IBI Biosolutions). DA can also under go different metabolic pathways. For instance, there are also chances that DA is absorbed by the neurons soon after their release by the use of the DA transporter. It can also be metabolized by monoamine oxidase (MAO) that can give rise to 3,4,-dihydroxyphenylacetic acid. If DA is metabolized by catechol-O-methyltransferase it give rise to 3-methoxytyramine. The action of MAO and COMT results in the deactivation of DA and forms a common metabolite known as homovanillic acid or 3-methoxy-4hydroxy-phenylacetic acid (see figure 3) (IBI Biosolutions). The metabolism of DA occurs in the dopaminergic nerve terminals. The DA metabolized intra-neuronally to their respective aldehyde by the action of the enzyme MAO is subsequently oxidised to DOPAC (Wood and Altar 163-187). Following disseminating out of the neurons, DOPAC further gets metabolised to HVA by the action of the enzyme COMT (Westerink 221-227). The metabolism of dopamine can also take place at various locations such as synaptic cleft, cytoplasm of nerve terminal and in glial cells. The enzymes that are involved in the metabolism process are also differently localized in brain cells. For example, catechol-O-methyltransferase can be located both in membrane bound form in post-synaptic neurons as well as in the extra-neuronal tissue in glial cells in cytoplasmic soluble type (Mannisto et al. 291-348). On the other hand the Monoamine oxidase is situated equally in intra- as well as extra-neuronally (Cooper et al.). The inactivation of dopamine that is released into the synaptic cleft results from re-absorption or uptake into the dopaminergic nerve endings and also by extra-cellular inactivation. Figure 4 shows a schematic representation of dopamine in the brain cells. Researchers study the tissue contents, and the extracellular concentration of 3-MT to measure the amount of dopamine release (Airio 13-48). Figure 3: Metabolic pathways of Dopamine (Source: Airio J. Role of cerebral dopamine and noradrenaline in Locomotor sensitization to morphine in mice) Figure 4: Schematic representation of Dopamine synthesis and its metabolism (Source: Youdim et al. Nature Reviews Neuroscience 7, 295–309 (April 2006). Dopamine Functions Dopamine is one of the most important chemicals that are produced in the brain. It is a chemical that is necessary for the movement. The sensation of pleasure, concentration power, processing of sight and hearing is determined by the concentration of DA in the brain. Additionally it also influences the immunity, sleeping and waking up time, and the temperature of the body. It is concerned in movement instigation. In fact it is the concentration of this chemical in different parts of the brain and its chemical reactions that determine all the above mentioned functions accurately. The neurotransmitter Dopamine is essential in activating the dopamine receptors in the brain. It is released as a neurohormone by the hypothalamus with the main intention to prohibit the prolactin release from the anterior pituitary lobe (iscid.org). There are several disorders that are caused due to the imbalance of DA in different parts of the brain. One of the most common and the most researched dopamine related disease is the Parkinson's disease. Schizophrenia is also a result of overload of DA in the brain particularly in the central part. The overload and deficiency of DA are linked with manic and depressive periods, respectively, of bipolar disorder (pdrecovery.org 115-138). Additionally the imbalance of this chemical is linked with declines in neuro-cognitive tasks such as recollection, concentration, and problem-solving (iscid.org). Tourette’s syndrome, Huntington’s disease, drug addiction or depression are also a result of DA concentration and its malfunction (Fellous & Suri 1-6). In conclusion, it can be said that any imbalance in dopamaine in different parts of the brain causes mental and physical disorders. Besides, if the dopamine path is altered due to the addiction it may further damage the normal functioning of individual’s decision-making. Though medical science has tracked dopamine zones of the brain, there are still uncertainties. Complex interactions and possible cross reactivity with other neurotransmitter circuits calls for further research in this area. BIBLIOGRAPHY Airio Juha. “Review Of The Literature” Role of cerebral dopamine and noradrenaline in Locomotor sensitization to morphine in mice. ISBN 951-45-8733-2 (PDF version) Helsinki 1999. 7 May 2011. Best Janet A. Nijhout H Frederik, Reed Michael C. “Homeostatic mechanisms in dopamine synthesis and release: a mathematical model”. Theoretical Biology and Medical Modelling 2009, 6:21. . Cooper JR, Bloom FE, Roth RH: The biochemical basis of neuropharmacology, 5 edn. Oxford Univesity Press, New York. (1986) Dzirasa K, Ribiero S, Costa R, Santos L, Lin S, Grossmark A, Sotnikova T, Gainet-dinov R, Caron M, Nicolelis M: “Dopaminergic control of sleep-wake states”. J Neurosci 2006, 26:10577-89. Feldman RS, Meyer JS, Quenzer LF “Catecholamines”. Principles of Neuropsychopharmacology. Sinauer Associates, Inc., Publishers, Sunderland, (1997) 277-344. Fellous Jean-Marc, and Suri Roland E. “The Roles of Dopamine”. The Handbook of Brain Theory and Neural Networks, Second edition, (M.A. Arbib, Ed.), Cambridge, MA: The MIT Press, 2002. Graybiel A, Flaherty TA, Kimura M: “The basal ganglia in adaptive motor control”. Science 1994, 265:1826-1831. IBI Biosolutions. “The DB-DRD4 Database Project”. 7 May 2011. iscid.org. “Dopamine” ISCID Encyclopedia of Science and Philosophy. 7 May 2011. Kuchel, O. and Kuchel G. “Peripheral dopamine in pathophysiology of hypertension. Interaction with aging and lifestyle”. Hypertension 1991, 18:709-721. Mannisto PT, Ulmanen I, Lundstrom K, Taskinen J, Tenhunen J, Tilgman C, Kaakkola S “Characteristics of catechol-O-methyltransferase (COMT) and properties of selective COMT inhibitors”. Prog Drug Res 39: (1992) 291-348. pdrecovery.org. “Chapter 7: Dopamine distribution” pp 115-138. 7 May 2011. Schultz W: “Multiple reward signals in the brain”. Nat Rev Neurosci 2000, 1:199-207. Westerink BHC. “Sequence and significance of dopamine metabolism in the rat brain”. Neurochem Int 2: (1985) 221-227. Wise R: “Dopamine, learning and motivation”. Nature Rev Neurosci 2004, 5:1-12. Wood PL, Altar AC “Dopamine release in vivo from nigrostriatal mesolimbic and mesocortical neurons: utility of 3-methoxytyramine measurements”. Pharmacol Rev 40: (1988) 163-187. Read More