Dopamine transporter uptake system

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

Although the MPP+ is formed outside the neuron, it is then taken up by the dopamine transporter uptake system (DAT), where it accumulates and may associate with neuromelanin. DAT is located on the membrane of dopaminergic neurons, especially in the substantia nigra, and there is a correlation between the expression of DAT and the loss of the neurons. 

Other functional imaging studies of the DA system have reported decreased Di receptor density (Dagher et al. 2001), increased F-DOPA uptake (a marker for increased DA turnover) (Salokangas et al. 2000), and both decreased (Krause et al. 2002) and no alterations (Staley et al. 2001) in dopamine transporter binding in smokers. 

Noradrenaline is transported by uptake systems that have been extensively studied. On release of noradrenaline from sympathetic nerve varicosities in the peripheral nervous system, it is subject to two uptake systems. Uptake 1 (UJ is a reuptake process where the noradrenaline is recovered by the nerve via a process that has a high affinity but relatively low maximum rate, whereas a second process, uptake 2 (Uj), clears noradrenaline from the tissues into extraneuronal sites by a low affinity, but fast, process (which is inhibited by GLUCOCORTICOIDS, phenoxybenzamine and normetanephrine). The first - the neuronal system - has been studied in detail, and is essentially the same process as used for dopamine and 5-hydroxytryptamine in the CNS. The U transport protein has now been cloned, and is one of a famiiy of transporter proteins which act as co-transporters for Na, Cl and the amine, driven by the ATP-generated electrochemical gradient for Na . This Ui noradrenaline reuptake process is inhibited by cocaine and amphetamine (thus accounting for some of their actions, particularly within the CNS), phenoxybenzamine and the extensive class of tricyclic and related compounds that are used as ANTIDEPRESSANTS (e.g. desipramine). 

The dopamine uptake system - or dopamine transporter system - is inhibited by the following clinically used agents amfonelic acid, bupropion, mazindot or experimental agents, nomifensine, indatraline, p-CFT, p-ClT-FP, GYKl 52895 and LR 5182. 

S5mthesized via tyramine (Fig. 30-26), apparently functions in place of noradrenaline. Note fhe precursor-product relationship between dopamine, noradrenaline, and adrenaline. The synthetic pathways to these neurotransmitters involve decarboxylation and hydroxylahon, types of reacfion imporfanf in formation of other transmitters as well. The most important process for ferminafing fhe acfion of released catecholamine transmitters is reuptake by the neurons. High-affinity uptake systems transport the catecholamine molecules back into the neurons and then into the synaptic vesicles. The uptake is specifically blocked by the drug reserpine (Fig. 25-12).7 The dopamine transporter is a major binding site for cocaine (see Fig. 30-28).7 7-7Si Catecholamine trans-miffers are catabolized by two enzymes. One is the... 

A recently developed pinhole high-resolution SPECT system and a 1.5 T clinical MRI scanner with a specially developed surface coil were used for rats (n = 9) after injection of the dopamine transporter ligand I-FP-CIT. The SPECT images showed clear striatal uptake. On the MR images, cerebral and extra-cerebral structures could be easily delineated. 

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. 

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. 

Storage of norepinephrine in vesicles Dopamine is transported into synaptic vesicles by an amine transporter system that is also involved in the re-uptake of preformed norepinephrine. This carrier system is blocked by reserpine (see p. 78). Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine 3-hydroxylase. Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate and the 3-hydroxylase. Not all of the norepinephrine is packaged in vesicles some exists in a cytoplasmic pool that can be displaced. In the adrenal medulla, norepinephrine is methylated to yield epinephrine both are stored in chromaffin cells. On stimulation, the adrenal medulla releases about 85% epinephrine and 15% norepinephrine. 

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. 

The neurotransmitter phenotype, (i.e., what type of neurotransmitter is stored and ultimately will be released from the synaptic bouton) is determined by the identity of the neurotransmitter transporter that resides on the synaptic vesicle membrane. Although some exceptions to the rule may exist all synaptic vesicles of a given neuron normally will express only one transporter type and thus will have a dehned neurotransmitter phenotype (this concept is enveloped in what is known as Dale s principle see also Reference 19). To date, four major vesicular transporter systems have been characterized that support synaptic vesicle uptake of glutamate (VGLUT 1-3), GABA and glycine (VGAT), acetylcholine (VAChT), and monoamines such as dopamine, norepinephrine, and serotonin (VMAT 1 and 2). Vesicles that store and release neuropeptides do not have specific transporters to load and concentrate the peptides but, instead, are formed with the peptides already contained within. 

Amphetamine blocks the uptake of dopamine, 5-HT, and norepinephrine by presynaptic transporters, increasing the extracellular levels of these monoamines. D-amphetamine acts primarily on the dopaminergic systems, wdiereas L-amphetamine acts primarily on norepinephrinergic neurons. The stimulant effects of D-amphetamine on behavior are linked to enhanced dopaminergic activity, primarily in the mesolim-bic system of neurons. 

The application of R. leads to a reduction in the levels of noradrenaline, dopamine, and serotonin in the synapses R. binds irreversibly to the transport system of noradrenaline (NA) so that the re-uptake of NA in the vesicles of the synapses is inhibited. Thus, transmission of stimuli is reduced, the blood pressure decreases with a concomitant central sedation. R. thus acts as a neuroleptic agent. The side effects of an overdose may include diarrhea, elevated secretion of saliva and gastric juices, depression, and Parkinson s disease. R. is suspected of being carcinogenic since in female patients an increased incidence of breast cancer seems to occur. The roots of R. serpentirm have been used in India for centuries as a sedative they also contain yohimbine. The first total synthesis was achieved by Woodward, for stereospecific synthesis, see Lit.. Deserpidine (11-demethoxyreserpine, canescine, recanescine, CsaHjgNjOg, Mr 578.64, cryst., mp. 228-230°C, [a]o-163° (pyridine) is also aRauvo/-fia alkaloid it exists in polymorphic forms and also lowers the blood pressure. 

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. 

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