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Amino acids, dopamine uptake

Figure 8.5 The synthetic pathway for noradrenaline. The hydroxylation of the amino acid, tyrosine, which forms dihydroxyphenylalanine (DOPA) is the rate-limiting step. Conversion of dopamine to noradrenaline is effected by the vesicular enzyme, dopamine-P-hydroxylase (DpH) after uptake of dopamine into the vesicles from the cell cytosol... Figure 8.5 The synthetic pathway for noradrenaline. The hydroxylation of the amino acid, tyrosine, which forms dihydroxyphenylalanine (DOPA) is the rate-limiting step. Conversion of dopamine to noradrenaline is effected by the vesicular enzyme, dopamine-P-hydroxylase (DpH) after uptake of dopamine into the vesicles from the cell cytosol...
A recent review of the literature on the amino acid structure of DAT stated that uptake of dopamine is dependent on multiple functional groups of amino acids within DAT.26 The authors... [Pg.2]

An alternative delivery strategy for small molecules is based on the presence of the nutrient transporters. Drugs that are structurally similar to substrates of a carrier system can undergo facilitated brain uptake as pseudoneutrients. The best example of this is the therapeutic use of L-DOPA in Parkinson s disease. Unlike the neurotransmitter dopamine itself, which cannot cross the BBB in significant amounts, its precursor L-DOPA is a substrate for LAT, the transporter of large neutral amino acids [56]. Its uptake by the brain is saturable, and subject to competition by the other substrates of the carrier present in plasma. [Pg.37]

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. [Pg.360]

Correct choice = A. Parkinsonian patients show a deficiency of dopaminergic neurons, without a decrease in cholinergic actions. Elevated levels of dopamine can lead to behavorial disorders. Levodopa and large, neutral amino acids share a transport system that is needed to enter the brain thus high protein diets may lead to elevated levels of circulating amino acids, resulting in a decrease in levodopa uptake. Dyskinesia is usually seen with longer-term therapy and is dose-related and reversible. The mechanism of action of deprenyl is not understood. [Pg.99]

Lastly, given the uncertainty about how antidepressants actually work, there is a group of drugs that seem to be of value, but do not readily fit into any of the above categories. These include nomifensine (now withdrawn), which blocks dopamine uptake (see uptake inhibitors), and the amino acid tryptophan, which is sometimes used where other classes of antidepressant have not been effective. [Pg.27]

The presence of a renal dopamine paracrine-autocrine system explains the considerable amounts of free dopamine excreted in the urine. Most derives from renal uptake and decarboxylation of circulating L-dopa and reflects the plasma levels of this amino acid and the function of the renal dopamine paracrine-autocrine system. [Pg.1044]

With the exception of acetylcholine, all the neurotransmitters shown in Figure 7-41 are removed from the synaptic cleft by transport into the axon terminals that released them. Thus these transmitters are recycled Intact, as depicted in Figure 7-42 (step 5]). Transporters for GABA, norepinephrine, dopamine, and serotonin were the first to be cloned and studied. These four transport proteins are all Na -linked symporters. They are 60-70 percent Identical In their amino acid sequences, and each is thought to contain 12 transmembrane a helices. As with other Na symporters, the movement of Na into the cell down Its electrochemical gradient provides the energy for uptake of the neurotransmlt-ter. To maintain electroneutrality, CM often Is transported via an ion channel along with the Na and neurotransmitter. [Pg.290]

Whereas acetylcholine is degraded by a membrane-anchored acetylcholine esterase (ACE) in the synaptic cleft (choline is afterwards taken up presynaptically), the biogenic amines adrenaline, noradrenaline, serotonin, and dopamine are taken up by the presynaptic membrane by transporters (Fig. 3) or by extraneuronal cells in which they are degraded by a catecholamine O-methyltransferase (COMT). These transporter have similar structure and contain 12 transmembrane regions. Once in the presynapse, the neurotransmitters are either degraded by monoamine oxidase (MAO) or taken up by synaptic vesicles. A proton pumping ATPase of the vesicle membrane (V-type ATPase as in plant vacuoles) causes an increase of hydrogen ion concentrations in the vesicles. Uptake of the neurotransmitter serotonin, adrenaline and noradrenaline could be partly achieved either via a diffusion of the free base into the vesicles where they become protonated and concentrated by an "ion trap" mechanism and via specific proton-coupled antiporters. The excitatory amino acids, acetylcholine and ATP cannot diffuse and enter the vesicles via specific transporters. [Pg.17]

It is known that the activity of the rate-limiting enzyme in the biological synthesis of dopamine, tyrosine hydroxylase, can be modulated through a Dj-receptor mediated pathway. To determine whether quinpirole reduces exocytotic quantal size by inhibiting this enzyme or by blocking the vesicular uptake of cytosolic dopamine via inhibition of the vesicular monoamine transporter, VMATl, the tyrosine hydroxylase product l-DOPA has been measured in the presence of an aromatic amino acid decarboxylase inhibitor that blocks the conversion of l-DOPA to dopamine [56]. Interestingly, it has been determined that quinpirole decreases tyrosine hydroxylase activity to approximately 59% of control values, a value close to the percentage of the reduced quantal size reported... [Pg.318]

Specific nutrient transport systems in brain capillaries can be used to facilitate drug entry into the brain. L-dopa (L-3,4-dfiiydroxyphenylalanine), a metabolic precursor of dopamine, is transported across endothelial cells by the neutral amino acid transport system [5], r-dopa permeates through capillaries into the striatal tissue, where it is decarboxylated to form dopamine. Therefore, systemic administration of L-dopa is often beneficial to patients with Parkinson s disease. Certain protein modifications, such as cationization [6] and anionization [7], produce enhanced uptake in the brain. Modification of drugs [8,9] by linkage to an antitransferrin receptor antibody also appears to enhance transport into the brain. This approach depends on receptor-mediated transcytosis of transferrin-receptor complexes by brain endothehal cells substantial uptake also occurs in the Hver. [Pg.171]


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See also in sourсe #XX -- [ Pg.2 ]




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