Dopamine uptake system

The selective inhibitor of dopamine uptake GBR 12935 has been [ IJlabelled440,441 as shown in equation 205. The dopamine uptake system has been probed also using nC labelled cocaine, 305, analogues432. 

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. 

Dopamine showed a potent inhibition (IC50 value 15 pM). It was reported that Trp-P-1 is taken up into PC 12 cells through dopamine uptake system (30), and the uptake of Trp-P-1 into immunocytes was also inhibited by dopamine (data not shown). Therefore, the inhibitory mechanism of dopamine is considered to be due to the competitive effects on the uptake of Trp-P-1. 

The atypical tricyclic antidepressant amineptine (Survector) is an indirect dopamine agonist, which selectively inhibits dopamine uptake and induces its release, with additional stimulation of the adrenergic system. Its antidepressant effects are similar to those of other tricyclic antidepressant drugs. However, it acts more rapidly, is better... 

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. 

Stotz EH, Palacios JM, Landwehrmeyer B, Norton J, Ghetti B, Simon JR, Triarhou LC (1994) Alterations in dopamine and serotonin uptake systems in the striatum of the weaver mutant mouse. J Neur Trans Gen 97 51-64. 

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 and the 5-hydroxytryptamine uptake systems are very similar to the noradrenaline uptake... 

The high affinity of the reuptake systems for monoamines, as measured by the Michaelis constant, is on the order of 0.1-0.4 pM the low affinity is about 10-fold higher. Specific uptake inhibitors for each monoamine have apparently been developed. Chlorimipramine and Lilly 110/40 are presumed to be specific for serotonergic uptake systems. Benztropine and amphetamine (an action separate from its ability to enhance catecholamine release) are thought to block specifically dopamine uptake and desmethyl-imipramine and cocaine are believed to inhibit norepinephrine uptake. 

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... 

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. 

In the Type C mechanism, the substrate is first over-oxidized and is subsequently reduced to the hydroxy compound. The overoxidized intermediate may be a hydroperoxide. While a stable phenyl-hydroperoxide has never been prepared, the existence of such a compound as an enzyme-bound intermediate can certainly not be ruled out. All attempts to demonstrate the enzymic formation of an oxygenated derivative of the substrate in either the phenylalanine- of the dopamine-hydroxylating systems have been unsuccessful. Thus, there is no oxygen uptake in either system when only the enzyme and the substrate are incubated, i.e., reaction (32) cannot be detected. Nor can any peroxide formation be demonstrated under these conditions by quite sensitive chemical techniques (Kaufman, unpublished, and Levin, unpublished). Obviously these negative experiments cannot exclude this type of mechanism if one imposes the condition that reaction (32) does not proceed to a large extent either because of an unfavorable equilibrium or due to the enzyme-bound nature of the intermediate. 

Fuxe K, Andersson K, Nilsen OG, et al Toluene and telencephalic dopamine selective reduction of amine mrnover in discrete DA nerve terminal systems of the anterior caudate nucleus by low concentrations of toluene. Toxicol Lett 12 115—123,1982 Cause EM, Mendez V, Geller I Exploratory smdies of a rodent model for inhalant abuse. Neurobehav Toxicol Teratol 7 143—148, 1985 Gentry JR, Hill C, Malcolm R New anticonvulsants a review of applications for the management of substance abuse disorders. Ann Clin Psychiatry 14 233—245, 2002 Gerasimov MR, Ferrieri RA, Schiffer WK, et al Smdy of brain uptake and biodistribution of [llCjtoluene in non-human primates and mice. Life Sci 70 2811 — 2828, 2002... 

Toxins that gain access to a neuron through its uptake process and then destroy it in some way. This approach has been used mainly to destroy monoamine neurons with 5,6 or 5,7-dihydroxytryptamine targeting 5-HT neurons, 6-hydroxydopamine for dopamine (and to a lesser extent noradrenergic) neurons and MPTP for dopamine neurons (see Chapter 7). Only the latter is fully specific and effective systemically. The others need to be administered directly into the appropriate brain areas and while they may only affect the intended NT neurons, the injection may not affect all of them. 

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