Dopamine transporter uptake

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. 

Kunko P.M., Loeloff R.J., Izenwasser S. Chronic administration of the selective dopamine uptake inhibitor GBR 12,909, but not cocaine, produces marked decreases in dopamine transporter density. Naunyn Schmiedeberg s Arch. Pharmacol. 356 562, 1997. 

Daws L., Callaghan P., Morom J. et al. Cocaine increases dopamine uptake and cell surface expression of dopamine transporters. Biochem. Biophys. Res. Commun. 290 1545, 2002. 

Lin, Z., Itokawa, M., and Uhl, G. R. (2000) Dopamine transporter proline mutations influence dopamine uptake, cocaine analog recognition, and expression. FASEB J. 14, 715-728. 

Lin, Z. and Uhl, G. R. (2002) Dopamine transporter mutants with cocaine resistance and normal dopamine uptake provide targets for cocaine antagonism. Mol. Pharmacol. 61,885-891. 

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. 

Dopamine Transporter SLC6A3 Inhibitors will prevent dopamine uptake (cocaine-like drugs). Important effects on locomotor activity, motivation, reward and cognition, dopaminergic hyperactivity, ADHD, depression. Parkinsonism, psychotic disorders, seizure, dystonia, dyskinesia. 

Starting in 1993, reports have appeared that in rat striatum and nucleus accum-bens D2-like autoreceptors, when activated, enhanced removal of dopamine from the extracellular space by means of the dopamine transporter (DAT) as studied by voltammetry (Table2). D2 receptor activation also increased [3H]-dopamine uptake in Xenopus oocytes transfected with both the human D2 receptor and the human DAT (Mayfield and Zahniser 2001), as well as the uptake of a fluorescent DAT substrate in human embryonic kidney cells equally transfected with both the human D2 receptor and the human DAT (Bolan et al. 2007). In accord with this autoreceptor-transporter connection, clearence of dopamine from the striatal extracellular space in vivo was reduced in D2 receptor knockout mice (Dickinson et al. 1999). Unfortunately, however, the data in the literature are by no means consistent. No effect of D2 receptor activation on the DAT was observed in another rat striatum study (Prasad and Amara 2001), in synaptosomes from rat and human neocortex (Feuer-stein, unpublished observations), and in PC 12 cells that possess D2 receptors and the DAT (Pothos et al. 1998). In a second study with D2 receptor knockout mice, uptake of dopamine in the striatum was increased rather than decreased (Schmitz et al. 2002). The reason for these discrepancies is not clear. It has been suggested that the clearance measurements by means of voltammetry were not appropriate for assessment of the function of the DAT (Prasad and Amara 2001). 

Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter evidence from knock-out mouse lines. J Neurosci 2002 22 389-95. 

Synaptic transmission requires the release of neurotransmitters into the extracellular space to bind pre-or postsynaptic receptors, conveying a chemical message to nerve cells (Torres et al 2003a). Termination of this signaling occurs rapidly by uptake of the released neurotransmitter into the presynaptic cell by high-affinity neurotrans-mitter transporters. The clearance of the monoamines dopamine, norepinephrine, and serotonin occurs via the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), respectively (Torres et al., 2003a)... 

Greg Gerhardt pioneered a chronoamperometry method that has been used to observe diffusion and uptake parameters in the rat brain (45). In this technique an exogenous neurotransmitter, such as dopamine, is introduced into the brain by pressure ejection or iontophoresis. The microelectrode is a known distance from the ejection pipette, so the analyte concentration detected at the microelectrode is a function of extracellular diffusion and uptake by the dopamine transporter. Because an exogenous neurotransmitter is introduced, the analyte being detected is known, and selectivity is not a problem. After a dopamine... 

Lobeline is derived from the plant Lobelia inflata (Indian tobacco). It is both an agonist and an antagonist at nicotinic receptors, although it is not structurally related to nicotine (1). It inhibits nicotine- and amphetamine-induced dopamine release by interacting with the tetra-benazine-binding site on the monoamine transporter. It also inhibits dopamine re-uptake. It has been used in smoking cessation, but is ineffective (2). 

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. 

Kitayama S, Shimada S, Uhl GR. 1992. Parkinsonism-inducing neurotoxin MPP+ uptake and toxicity in nonneuronal COS cells expressing dopamine transporter cDNA. Annu. Neurol. 32 109-11... 

The human norepinephrine uptake transporter was first sequenced and then expressed in HeLa cells in 1991 (85) and found to have properties identical to those of the native transporter. The cloning and sequencing of the dopamine transporter (86-88) and the serotonin transporter (89, 90) were reported in the same year. There are a number of excellent review articles written about monoamine transporters (84,91-93). 

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