Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.107 (DAT)
 1,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular expression of DAT mRNA and VMAT2 mRNA was investigated in sections of the human post-mortem substantia nigra in control and Parkinson's disease tissue using in situ hybridisation techniques. Short synthetic oligodeoxynucleotides were used to detect these gene transcripts at the cellular level. In the control human nigra, high levels of expression were seen in all sub-divisions of the substantia nigra, especially within medial regions. By contrast, the level of expression of both DAT mRNA and VMAT2 mRNA was markedly reduced in Parkinson's disease; these reductions in hybridisation signal were associated with (i) a marked loss of dopamine-containing cells in the substantia nigra, and (ii) a reduction in both DAT and VMAT2 signal per cell in the remaining pigmented neurones. These disease-related decreases in the cellular abundance of both DAT and VMAT2 gene transcripts in the surviving cells of the parkinsonian nigra may reflect compensatory changes in catecholamine signalling or may be a consequence of neuronal dysfunction.
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PMID:Dopamine transporter (Dat) and synaptic vesicle amine transporter (VMAT2) gene expression in the substantia nigra of control and Parkinson's disease. 901 52

Several lines of evidence suggest that monoaminergic systems, especially dopaminergic and serotoninergic systems, modulate ethanol consumption. Humans display significant differences in expression of the vesicular and plasma membrane monoamine transporters important for monoaminergic functions, including the vesicular monoamine transporter (VMAT2, SLC18A2) and dopamine transporter (DAT, SLC6A3). In addition, many ethanol effects differ by sex in both humans and animal models. Therefore, ethanol consumption and preference were compared in male and female wild-type mice, and knockout (KO) mice with deletions of genes for DAT and VMAT2. Voluntary ethanol (2-32% v/v) and water consumption were compared in two-bottle preference tests in wild-type (+/+) vs heterozygous VMAT2 KO mice (+/-) and in wild-type (+/+) vs heterozygous (+/-) or homozygous (-/-) DAT KO mice. Deletions of either the DAT or VMAT2 genes increased ethanol consumption in male KO mice, although these effects were highly dependent on ethanol concentration, while female DAT KO mice had higher ethanol preferences. Thus, lifetime reductions in the expression of either DAT or VMAT2 increase ethanol consumption, dependent on sex.
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PMID:Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice. 1265 6

Autoxidation pathways and redox reactions of dihydroxytryptamines (5,6- and 5,7-DHT) and of 6-hydroxydopamine (6-OH-DA) are illustrated, and their potential role in aminergic neurotoxicity is discussed. It is proposed that certain aspects of the cytotoxicity of 6-OH-DA and of the DHTs, namely redox cycling of their quinone- and quinoneimine-intermediates as a source of free radicals, may also apply to quinoidal reactive intermediates and to glutathionyl- or cysteinyl conjugates ("thioether adducts") of o-dihydroxylated (catechol-like) metabolites of certain substituted amphetamines (of methylenedioxymethamphetamine (MDMA) and of methylenedioxyamphetamine (MDA)). Despite similarities in their primary interaction with the plasmalemmal (serotonergic transporter/dopamine transporter, SERT/DAT) and vesicular monoamine transporters (VMAT2), MDMA and fenfluramine (N-ethyl-meta-trifluoromethamphetamine, Fen) differ substantially in many aspects of their metabolism, pharmacokinetics, pharmacology, and neurotoxicology profile; the consequences of these differences for neuronal response patterns and long-term survival prospects are not yet fully understood. However, sustained hyperthermia appears to be a critical factor in these differences. Methodological requirements for adequate detection and description of pre- and postsynaptic forms of drug-induced neurotoxicity are exemplified using recently published accounts. The inclusion of microglial markers into research strategies has widened contemporary pathogenetic concepts on methamphetamine (MA)-induced neurotoxicity as an example of inflammatory neurodegeneration, thus complementing the traditional ROS and RNS-dependent stress models. Amphetamine-type neurotoxicity studies may assist in elaborating of preventive strategies for human neurodegenerative disorders.
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PMID:Serotonin neurotoxins--past and present. 1563 91

Pramipexole (PRX) is a non-ergot dopamine (DA) D2/D3 receptor agonist. Experimental studies have provided evidence that PRX may exert neuroprotective effects on the nigro-striatal system. Recent studies have demonstrated a slower decline of DAT density in Parkinson's disease patients treated with PRX as measured by SPECT. The aim of this study is to determine whether PRX has direct biological effects on DAergic neuron-associated genes expression, including DAT, VMAT2, and Nurr1. The human neuroblastoma SH-SY5Y cells were treated with PRX for various time periods and harvested to measure the mRNA and protein products of these genes. Treatment with PRX at 10 microM significantly increased DAT mRNA levels by 54-130% in 4-8 h, VMAT2 mRNA levels by 34% in 4 h, and Nurr1 mRNA levels by 31-39% in 2-4 h, which was the earliest induction among these three genes. The protein levels of DAT, VMAT2, and Nurr1 were markedly increased after PRX treatment, among which the increase of Nurr1 protein level was the highest at first 2 h treatment of PRX. Nafadotride, a D3 DA receptor antagonist, blocked the increase of Nurr1 gene expression induced by PRX, while eticlopride, a D2 DA receptor antagonist, didn't show this effect. Our findings that PRX has biological regulatory effects on DAergic neuron-associated genes may explain both the slower decline of imaged DAT and the neuroprotective effect of PRX. Furthermore, our results suggest that the induction of Nurr1 gene expression by PRX may be mediated by D3 DA receptor.
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PMID:Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotection. 1574 Aug 46

Idiopathic Parkinson's disease (PD) affects 2% of adults over 50 years of age. PD patients demonstrate a progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc). One model that recapitulates the pathology of PD is the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here we show that exposure to an enriched environment (EE) (a combination of exercise, social interactions and learning) or exercise alone during adulthood, totally protects against MPTP-induced Parkinsonism. Furthermore, changes in mRNA expression would suggest that increases in glia-derived neurotrophic factors, coupled with a decrease of dopamine-related transporters (e.g. dopamine transporter, DAT; vesicular monoamine transporter, VMAT2), contribute to the observed neuroprotection of dopamine neurons in the nigrostriatal system following MPTP exposure. This non-pharmacological approach presents significant implications for the prevention and/or treatment of PD.
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PMID:Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism. 1579 May 41

Membrane and vesicular monoaminergic transporters, responsible for the homeostasis of neurotransmitter pools at nerve endings, are very involved in the physiology and diseases of central nervous system. Recent progresses of cerebral molecular imaging using SPECT and PET methods allow the extend of in vivo exploration of these transporters. For this aim, an increasing number of radiopharmaceuticals labelled with [123I], [99mTc], [11C] or [18F] have been developed such as cocaine derivatives for the DAT, compounds from the diphenyl sulfide family for the SERT, and dihydrotetrabenazine derivatives for the VMAT2. These functional imaging methods can be very useful in several neurological and psychiatric disorders which involve the monoaminergic neurotransmission systems such as Parkinson's disease, ADHD, depression and autism. For example, the DAT is a specific index of the density of dopaminergic endings which progressively degenerate in Parkinson's disease. In vivo exploration of this transporter can therefore be a relevant way (i) to realize an early detection of the loss of dopaminergic neurons, (ii) to assess the progression of the disease, (iii) to validate and improve the efficacy of new therapeutic strategies such as neuroprotection and neuroreparation. In all, the extend of in vivo exploration of monoamine transporters will allow great progress for (1) knowledge of physiopathological mechanisms of brain disorders, (2) early diagnosis of cerebral dysfunctions, allowing early use of new therapies, (3) selection of homogenous classes of subjects for therapeutic assays, (4) objectiveness of drug-molecular target interaction, (5) follow-up of disease evolution and treatment.
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PMID:PET and SPECT exploration of central monoaminergic transporters for the development of new drugs and treatments in brain disorders. 1625 Aug 52

Methamphetamine (METH) causes release of stored intracellular dopamine (DA). We explored the interactions of METH with the recombinant human vesicular monoamine (hVMAT2) and/or human DA transporters (hDAT) in transfected mammalian (HEK293) cells and compared the findings with those for DA. In 'static' release assays at 37 degrees C, less than 20% of pre-loaded [(3)H]DA was lost after 60 min, while nearly 80% of pre-loaded [(3)H]METH was lost at 37 degrees C under non-stimulated conditions. Results obtained by measuring substrate release using a superfusion apparatus revealed an even greater difference in substrate efflux. At pH 7.4, nearly all of the pre-loaded [(3)H]METH was lost after just 6 min, compared with the loss of 70-80% of pre-loaded [(3)H]DA (depending on cell type) after superfusion for 32 min. Increasing the extracellular pH from 7.4 to 8.6 had opposite effects on [(3)H]DA and [(3)H]METH retention. At pH 8.6, [(3)H]METH was retained more effectively by both hDAT and hDAT-hVMAT2 cells, compared with results obtained at extracellular pH 7.4. [(3)H]DA, however, was more effectively retained at pH 7.4 than at pH 8.6. These data suggest that DA and METH interact differently with the DAT and VMAT2, and require different H(+) concentrations to exert their effects.
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PMID:Hydrogen ion concentration differentiates effects of methamphetamine and dopamine on transporter-mediated efflux. 1641 78

Mechanisms implicated in protective potential of estrogens are poorly understood. Tamoxifen, a selective estrogen receptor modulator (SERM), presents a neuroprotective effect against methamphetamine (MA)- and methoxy-phenyltetrahydropyridine (MPTP)-induced toxicity when used alone but abolishes estrogen's positive effects when combined with this hormone. In order to understand tamoxifen's protective properties, the present study compared it to estradiol on several markers of dopaminergic neurons to achieve a relatively comprehensive comparison between these two agents. Estradiol benzoate (E) or tamoxifen were used at different concentrations (E: 1, 10 or 40 microg; tamoxifen: 12.5, 125 or 500 microg) 24 h prior to a MA injection in ovariectomized CD-1 mice. The effects of the lesion and treatments were studied on striatal dopamine (DA) concentrations, dopamine and monoamine vesicular transporters (DAT and VMAT2), and preproenkephalin (PPE) mRNA levels. Both treatments, at all concentrations, prevented the MA-induced decrease of striatal DA concentrations and VMAT2 binding. Only E was able to prevent loss of DAT binding in the lateral striatum and to attenuate the MA-induced increase in striatal PPE mRNA levels (at 1 or 40 microg). Therefore, in this paradigm, E and tamoxifen differentially modulated MA-induced neuronal damages. While both treatments prevented the DA decrease, E protected more efficiently other dopaminergic parameters suggesting that overall E is more effective than tamoxifen as a neuroprotectant of the nigrostriatal dopaminergic system.
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PMID:Differential protective properties of estradiol and tamoxifen against methamphetamine-induced nigrostriatal dopaminergic toxicity in mice. 1644 47

Early in Parkinson's disease (PD) physical activity becomes difficult resulting in a more sedentary lifestyle. Clinical and experimental studies have found that increased activity following striatal dopamine loss leads to increased motor function. Decreased physical activity early in PD along with findings that increased physical activity results in functional improvement suggested to us that decreased physical activity during the period of nigrostriatal degeneration may not only be a symptom of the injury, but may also act to potentiate the degeneration. Using the bilateral MPTP mouse model of PD, we restricted use of one forelimb for the first 7 days post-injection. This transient behavioral manipulation during the period of dopamine degeneration resulted in a long-lasting deficit of the restricted forelimb. This was manifested as sustained asymmetrical use of the forelimbs during wall exploration, as well as a neurochemical imbalance between striatal hemispheres measured by immunoreactivity of the dopamine terminal markers, DAT, VMAT2 and TH. These results show a significant interaction between behavior and neurochemistry and suggest that a reduction in activity level may further exacerbate degeneration.
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PMID:Use-dependent behavioral and neurochemical asymmetry in MPTP mice. 1746 55

We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < or = 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint) < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p < or = 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluated rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ.
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PMID:A network of dopaminergic gene variations implicated as risk factors for schizophrenia. 1804 77


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