Disease relevance of Slc6a3

• The paradoxical hyperdopaminergia in the DAT KO mice despite a marked decrease in TH and dopamine levels suggests a parallel to Parkinson's disease implying that blockade of DAT may be beneficial in this condition [1].
• Deletion of the dopamine transporter (DAT) results in increased dopaminergic tone, anterior pituitary hypoplasia, dwarfism, and an inability to lactate [2].
• We treated C57BL/6 mice with MPTP and followed the expression of the immediate-early gene zif268 in striatum as a marker of DA synaptic activity, determined the pharmacology of its activation during MPTP toxicity, and assayed the time course of MPTP effects on striatal DA transporter (DAT), and D1 and D2 DA receptor-binding sites and their mRNAs [3].
• Taken together, these findings provide direct evidence that mitochondrial impairment and metabolic stress cause striatal DA efflux via the DAT and suggest that disruptions in DA homeostasis resulting from energy impairment may contribute to the pathogenesis of neurodegenerative diseases [4].
• The aim of the present study was to investigate the effects of reserpine administration on the development of orofacial dyskinesia and on plus-maze discriminative avoidance task (DAT-an animal model of associative learning) in male and female mice [5].

Psychiatry related information on Slc6a3

• However, one of these hydroxylated WIN analogues, namely 12b, which possesses nanomolar potency at the DAT and NET and micromolar potency at the SERT, when tested in vivo, was found capable of attenuating cocaine's locomotor activity (AD(50) = 94 mg/kg) [6].
• These results shed light on the degenerative process of dopamine neurons and suggest that individual differences in developing Parkinson's disease in human may be related to differences of uptake through the DAT of a yet unidentified neurotoxin [7].
• Deletion of DAT results in a hyperdopaminergic phenotype and DAT(-/-) mice are characterized by pituitary hypoplasia, impaired maternal behavior, and increased locomotion [8].
• In two experiments we investigated the effects of elevated dopaminergic tone on instrumental learning and performance using dopamine transporter knockdown (DAT KD) mice [9].
• In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects [10].

High impact information on Slc6a3

• The function of dopamine autoreceptors was assessed in mice lacking the dopamine transporter (DAT) [11].
• In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self-administer cocaine [12].
• These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice [12].
• The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse [12].
• The effects of DAT deletion on pituitary function result from elevated DA levels that down-regulate the lactotroph D2 DA receptors and depress hypothalamic growth hormone-releasing hormone content [2].

Chemical compound and disease context of Slc6a3

• In vivo evaluation of three selected compounds indicated that despite their high potency at the DAT, these compounds stimulated locomotor activity (LMA) less than cocaine when tested across similar dose ranges [13].
• OBJECTIVES: These studies characterized the effects of 3,4-methylenedioxy-N-methylamphetamine (MDMA), a serotonin releaser, on the amount and patterns of locomotor activity in DAT (+/+) and (-/-) mice [14].
• OBJECTIVES: The goal of the present study was to investigate the effects of acute and daily administration of d-amphetamine on the locomotor activity of DAT(-/-) mice and examine the development of behavioral sensitization [15].
• METHODS: DAT(+/+), DAT(+/-), and DAT(-/-) mice were injected with acute amphetamine (0, 0.3, 1, 3, or 10 mg/kg, SC), repeated amphetamine (1 mg/kg for 8 days, SC), or with the serotonin reuptake inhibitor fluoxetine (0, 5, 10, or 20 mg/kg, SC) and their locomotor activity was evaluated [15].
• Such agents, when labeled with technetium-99m, might function as imaging agents for the dopamine transporter (DAT) system that would be useful for assessing the onset and severity of Parkinson's disease [16].

Biological context of Slc6a3

• Mice lacking the dopamine transporter (DAT) display biochemical and behavioural dopaminergic hyperactivity despite dramatic alteration in dopamine homeostasis [1].
• In mice lacking the dopamine transporter (DAT), the amplitude of dopamine (DA) release and the kinetics of dopamine elimination were measured in vivo using carbon fibre electrodes combined with amperometry [17].
• The findings presented in this paper reinforce the functional significance of dopamine and more specifically the D2 receptor in olfactory discrimination and may help explain the behavioral phenotype in the DAT and D2 knockout mice [18].
• These results suggested that baicalein may attenuate methamphetamine-induced DAT loss by inhibiting the neutrophil increase and the lipid peroxidation caused by neutrophil-derived reactive oxygen species in striatum [19].
• It is interesting to consider that the switch to a dopamine-deficient, but functionally hyperactive, mode of neurotransmission observed in mice lacking the DAT may represent an extreme example of neuronal plasticity resulting from long-term psychostimulant abuse [20].

Anatomical context of Slc6a3

• These results taken together indicate that DAT expression is one of the first targets in the ventral mesencephalon of the wv mutation, inducing a specific decrease of DA uptake in the striatum and the nucleus accumbens [21].
• The dopamine transporter (DAT) is believed to control the temporal and spatial activity of released DA by rapid uptake of the neurotransmitter into presynaptic terminals [22].
• DAT (-/-) vertebrae have lower cancellous bone volume as a consequence of increased trabecular spacing and reduced trabecular number, and cortical thickness and bone area in the femoral diaphysis are reduced [22].
• TH, DA, and DAT immunoreactivities were coincident in subsets of neurons (submucosal > myenteric) in guinea pig and mouse intestines in situ and in cultured guinea pig enteric ganglia [23].
• The dopamine transporter (DAT) plays an important role in calibrating the duration and intensity of dopamine neurotransmission in the central nervous system [20].

Associations of Slc6a3 with chemical compounds

• Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.Neuropsychopharmacology (2006) 31, 2132-2139. doi:10.1038/sj.npp.1301009; published online 11 January 2006 [24].
• Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice [24].
• By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so [24].
• In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice [24].
• The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role [24].

Physical interactions of Slc6a3

• The extent of the lesion was measured by striatal DA transporter binding and stereological estimation of the number of tyrosine hydroxylase immunoreactive neurones in the substantia nigra pars compacta (SNc) [25].
• Importantly, both the locomotor activity and the cocaine discrimination ED(50)values were correlated with the DAT binding but not 5-HTT and NET binding [26].

Regulatory relationships of Slc6a3

• Last, dopamine activation of TAAR1 could induce c-FOS-luciferase expression but only in the presence of DAT, whereas dopamine activation of D1 resulted in equivalent c-FOS expression in the presence or absence of DAT [27].
• The increased DA uptake after pharmacological inactivation or gene deletion highlights the plasticity of mesoaccumbal DA neurons and suggests that loss of KOR-1 and the resultant disinhibition of DA neurons trigger short- and long-term DA transporter adaptations that maintain normal DA levels, despite enhanced release [28].

Other interactions of Slc6a3

• For this purpose, anti-tyrosine hydroxylase (TH) antibody, anti-dopamine transporter (DAT) antibody, anti-Cu/Zn-SOD antibody, anti-Mn-SOD antibody, anti-nNOS antibody, anti-eNOS antibody and anti-iNOS antibody were used [29].
• To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14 [30].
• Furthermore, pretreatment and the subsequent administration of minocycline (40 mg/kg, i.p.) significantly attenuated the reduction of 5-HT and dopamine as well as the density of 5-HTT and DAT in the mouse brain by the repeated administration of MDMA [31].
• Pretreatment with the D1R antagonist SCH-23390 (0.25 mg/kg) 30 min before the first and fourth injections of METH conferred partial protection on DAT sites of the CPu [32].
• Pretreatment with the nonpeptide NK-1R antagonist WIN-51,708 (10 mg/kg) 30 min prior to the first and fourth injections of METH prevented the loss of DAT sites of the CPu [32].

Analytical, diagnostic and therapeutic context of Slc6a3

• At 15 weeks after transplantation, immunoreactivities for tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum were significantly recovered in rats grafted with ES or ES-N cells compared to vehicle-injected rats [33].
• Results from Western blotting showed that repeated METH administration (5mg/kg, i.p., four injections at 2-h interval) caused 40% decrease of DAT level in mouse striatum measured at 72h after the last injection [19].
• We describe the development of a novel animal model of acute severe dopamine (DA) deficiency by using genetically altered mice lacking the DA transporter (DAT-KO mice) [34].
• Surgical ablation of sympathetic nerves by extrinsic denervation of loops of the bowel did not affect DAT immunoreactivity but actually increased numbers of TH-immunoreactive neurons, expression of mRNA encoding TH and DAT, and enteric DOPAC (the specific dopamine metabolite) [23].
• High DAT affinity and selectivity, increased locomotor activity with slow onset and long duration of action, and generalization to cocaine shown by the 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol-5-yl)tropanes are properties thought necessary for a pharmacotherapy for treating cocaine abuse [26].

References