Dopamine and vesicular monoamine transport loss supports incidental Lewy body disease as preclinical idiopathic Parkinson.

Incidental Lewy body disease (ILBD) is a neuropathological diagnosis of brains with Lewy bodies without clinical neuropsychiatric symptoms. Dopaminergic deficits suggest a relationship to preclinical Parkinson's disease (PD). We now report a subregional pattern of striatal dopamine loss in ILBD cases, with dopamine found significantly decreased in the putamen (-52%) and only to a lower extent in the caudate (-38%, not statistically significant); this is similar to the pattern in idiopathic PD in various neurochemical and in vivo imaging studies.

The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters.

(±)-cis-4,4'-Dimethylaminorex (4,4'-DMAR) is a new psychoactive substance (NPS) that has been associated with 31 fatalities and other adverse events in Europe between June 2013 and February 2014. We used in vitro uptake inhibition and transporter release assays to determine the effects of 4,4'-DMAR on human high-affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). In addition, we assessed its binding affinities to monoamine receptors and transporters.

Early Paradoxical Increase of Dopamine: A Neurochemical Study of Olfactory Bulb in Asymptomatic and Symptomatic MPTP Treated Monkeys.

Parkinson's disease (PD) is a neurodegenerative disease with both motor and non-motor manifestations. Hyposmia is one of the early non-motor symptoms, which can precede motor symptoms by several years. The relationship between hyposmia and PD remains elusive.

The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter.

Mephedrone (4-methylmethcathinone, MMC) and 3,4-methylenedioxymethamphetamine (MDMA) are constituents of popular party drugs with psychoactive effects. Structurally they are amphetamine-like substances with monoamine neurotransmitter enhancing actions. We therefore compared their effects on the human monoamine transporters using human cell lines stably expressing the human noradrenaline, dopamine and serotonin transporter (NET, DAT and SERT); preparations of synaptic vesicles from human striatum in uptake experiments; and a superfusion system where releasing effects can be reliably measured.

Is Parkinson's disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum.

The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson's disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles where it is protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals.

The noradrenaline transporter as site of action for the anti-Parkinson drug amantadine.

Amantadine is an established antiparkinsonian drug with a still unclear molecular site of action. In vivo studies on rodents, in vitro studies on tissue of rodents as well as binding studies on post mortem human tissue implicate monoamine transporters and NMDA receptors. In order to re-examine its action at human variants of these proteins on intact cells we established cells stably expressing the human NR1/2A NMDA-receptor, noradrenaline transporter (NAT) or dopamine transporter (DAT) and tested the activity of amantadine in patch-clamp, uptake, release, and cytotoxicity experiments.

Chronic exposure to manganese decreases striatal dopamine turnover in human alpha-synuclein transgenic mice.

Interaction of genetic and environmental factors is likely involved in Parkinson's disease (PD). Mutations and multiplications of alpha-synuclein (α-syn) cause familial PD, and chronic manganese (Mn) exposure can produce an encephalopathy with signs of parkinsonism. We exposed male transgenic C57BL/6J mice expressing human α-syn or the A53T/A30P doubly mutated human α-syn under the tyrosine hydroxylase promoter and non-transgenic littermates to MnCl₂-enriched (1%) or control food, starting at the age of 4 months.

Zinc regulates the dopamine transporter in a membrane potential and chloride dependent manner.

The dopamine transporter (DAT), a membrane protein specifically expressed by dopaminergic neurons and mediating the action of psychostimulants and dopaminergic neurotoxins, is regulated by Zn(2+) which directly interacts with the protein. Herein, we report a host-cell-specific direction of the Zn(2+) effect on wild type DAT. Whereas low mumolar Zn(2+) decreased dopamine uptake by DAT expressing HEK293 cells, it stimulated uptake by DAT expressing SK-N-MC cells.

Pharmacological characterization of ecstasy synthesis byproducts with recombinant human monoamine transporters.

Ecstasy samples often contain byproducts of the illegal, uncontrolled synthesis of N-methyl-3,4-methylenedioxy-amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). MDMA and eight chemically defined byproducts of MDMA synthesis were investigated for their interaction with the primary sites of action of MDMA, namely the human plasmalemmal monamine transporters for norepinephrine, serotonin, and dopamine [(norepinephrine transporter (NET), serotonin transporter (SERT), and dopamine transporter (DAT)]. SK-N-MC neuroblastoma and human embryonic kidney cells stably transfected with the transporter cDNA were used for uptake and release experiments.

Dopamine inhibits cell growth and cell cycle by blocking ribonucleotide reductase.

Dopamine (DA) is a classical neurotransmitter modulating various brain functions by acting on its specific receptors. In addition, DA is a reactive molecule that has been implicated in neurodegeneration, especially in Parkinson's disease. Here we show that DA inhibited cell growth of dopamine transporter transfected cells by intracellularly blocking cell cycle progression.

alpha-Synuclein selectively increases manganese-induced viability loss in SK-N-MC neuroblastoma cells expressing the human dopamine transporter.

The established or potentially toxic agents implicated in the nigral cell death in Parkinson's disease, dopamine, 1-methyl-4-phenylpyridinium (MPP(+)), iron, and manganese, were examined as to their effects on the viability of cells overexpressing alpha-synuclein. SK-N-MC neuroblastoma cells stably expressing the human dopamine transporter were transfected with human alpha-synuclein and cell clones with and without alpha-synuclein immunoreactivity were obtained. Cells were exposed for 24-72 h to 1-10 microM dopamine, 0.

Zn2+ modulates currents generated by the dopamine transporter: parallel effects on amphetamine-induced charge transfer and release.

The psychostimulant drug amphetamine increases extracellular monamines in the brain acting on neurotransmitter transporters, especially the dopamine transporter. Mediated by this plasmalemmal pump, amphetamine does not only induce release but also charge transfer which might be involved in the release mechanism. To study a potential link between the two phenomena, we used Zn(2+) as an acute regulatory agent which modulates dopamine uptake by a direct interaction with the transporter protein.

Cellular effects of dopamine--beyond oxidative mechanisms.

Cell cycle blockers inhibit growth in dividing cells, but promote survival of differentiated cells, including neurons. Low micromolar dopamine profoundly inhibited cell growth in dopamine transporter transfected SK-N-MC neuroblastoma cells by cell cycle arrest at G(1). This effect was independent of oxy radical formation, antagonized by transporter block, abolished by FeCl(3) and mimicked by the iron chelator deferoxamine.

Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter.

Amphetamine and related substances induce dopamine release. According to a traditional explanation, this dopamine release occurs in exchange for amphetamine by means of the dopamine transporter (DAT). We tested this hypothesis in human embryonic kidney 293 cells stably transfected with the human DAT by measuring the uptake of dopamine, tyramine, and D- and L-amphetamine as well as substrate-induced release of preloaded N-methyl-4-[3H]phenylpyridinium ([3H]MPP+).

Induction by low Na+ or Cl- of cocaine sensitive carrier-mediated efflux of amines from cells transfected with the cloned human catecholamine transporters.

1. COS-7 cells transfected with the cDNA of the human dopamine transporter (DAT cells) or the human noradrenaline transporter (NAT cells) were loaded with [3H]-dopamine or [3H]-noradrenaline and superfused with buffers of different ionic composition. 2.

Mechanism of the dopamine-releasing actions of amphetamine and cocaine: plasmalemmal dopamine transporter versus vesicular monoamine transporter.

The effects of amphetamine and cocaine were studied in [3H]-dopamine-loaded and superfused COS-7 cells transfected with either the cDNA of the plasmalemmal dopamine transporter ("DAT cells") or the cDNA of the vesicular amine transporter ("VAT cells"), or with both transporters ("DAT/VAT cells"). Amphetamine (0.01-100 microM, added for 4 min of superfusion) led to a concentration-dependent increase in dopamine release in DAT cells, as well as in DAT/VAT cells.

Functional sensitization of striatal dopamine D1 receptors in the 6-hydroxydopamine-lesioned rat.

Dopamine-stimulated adenylyl cyclase activity was measured in striatal homogenates of rats in which the nigrostriatal pathway was lesioned by 6-hydroxydopamine 20-24 months before the experiments. In the intact (contralateral) striatum the potency and the efficacy of dopamine in stimulating adenylyl cyclase was lower in the presence of high NaCl concentrations (120 mM) compared with the effects of dopamine in an NaCl-poor assay medium (20 mM). The same effect of NaCl was observed in the striatum on the side of a weak, behaviourally ineffective 6-hydroxydopamine lesion resulting in a loss of 57% of striatal dopamine.

Uptake mechanism of technetium-99m-d, 1-HMPAO in cell cultures of the dissociated postnatal rat cerebellum.

The accumulation and retention mechanisms of 99mTc-d, 1-hexamethylpropyleneamine oxime (99mTc-d, 1-HMPAO) were investigated in cultures of the dissociated rat cerebellum. Our experiments indicate a linear dependency of the uptake on incubation time and on the concentration of the radioligand. Upon chloroform extraction and distribution between the lipophilic and the hydrophilic phases, we located 69.

Ornipressin in the treatment of functional renal failure in decompensated liver cirrhosis. Effects on renal hemodynamics and atrial natriuretic factor.

In 11 patients with decompensated cirrhosis and deteriorating renal function, the effect of the vasoconstrictor substance 8-ornithin vasopressin (ornipressin; POR 8; Sandoz, Basel, Switzerland) on renal function, hemodynamic parameters, and humoral mediators was studied. Ornipressin was infused at a dose of 6 IU/h over a period of 4 hours. During ornipressin infusion an improvement of renal function was achieved as indicated by significant increases in inulin clearance (+65%), paraaminohippuric acid clearance (+49%), urine volume (+45%), sodium excretion (+259%), and fractional elimination of sodium (+130%).

Lower efficacy of the dopamine D1 agonist, SKF 38393, to stimulate adenylyl cyclase activity in primate than in rodent striatum.

The selective D1 agonist, SKF 38393, stimulated adenylyl cyclase by about 40% of basal activity in rat striatum but by only about 10% in the striatum of rhesus monkeys. In contrast, dopamine stimulated striatal adenylyl cyclase in both species with equal efficiency (70-80%). SKF 38393 30 microM inhibited the effect of 30 microM dopamine by about 45% in rat and by about 75% in primate tissue.

Cholinergic deficit induced by ethylcholine aziridinium (AF64A) in rat hippocampus: effect on glutamatergic systems.

The reaction of the glutamatergic systems in the rat hippocampus to the withdrawal of cholinergic function after cholinergic degeneration induced by ethylcholine aziridinium (AF64A) was investigated. Furthermore, the question whether blockade of N-methyl-D-aspartate (NMDA) receptors by MK-801 has an impact on the extent of the cholinergic lesion was addressed. After bilateral intracerebroventricular injection of AF64A (2 nmol/ventricle) the activity of choline acetyltransferase (ChAT) started to decline in the hippocampus within 24 h.

Manufacture and use of fused silica cannulas for intracerebral injections in freely moving rats.

This report describes in detail the assembly and use of miniature cannulas for intracerebral injections in freely moving rats. Guide and injection cannulas were prepared from polyimid-coated fused silica capillaries as routinely in use for gas chromatography, in this way avoiding the permanent contact of stainless-steel with brain tissue. The outer diameter of the guide capillary measured 300 microns, that of the injection capillary 170 microns.

Evidence for neuronal localization of histamine-N-methyltransferase in rat brain.

There is evidence that histamine may be a neurotransmitter in mammalian brain. Histamine in neurons of the central nervous system is easily released and rapidly turned over. The cellular localization of histamine-N-methyltransferase, the proposed histamine-inactivating enzyme, was investigated by measuring its activity in rat striatum after applying neurochemical or electrolytic lesions.