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PubMed1983

Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and walking in the rat.

Single unit activity of dopamine and non-dopamine neurons in the substantia nigra and ventral tegmental area was recorded across stages of sleep and waking in the rat. These stages consisted of slow wave sleep (SWS), rapid eye movement (REM) sleep, awake-quiet (AQ) and awake-moving (AM). The dopamine neurons showed no change in mean firing rate across the stages of sleep or waking. During REM sleep, however, the dopamine cells fired with a more variable interspike interval than during SWS. In contrast, non-dopamine neurons in the substantia nigra and ventral tegmental area showed large increases in firing rate in REM compared to SWS, and in AM compared to AQ, without showing changes in interspike interval variability. In conclusion, whereas other monoaminergic neurons and various cortical and subcortical neurons exhibit marked changes in firing rate across the stages of sleep and waking, the dopamine neurons are unique in their lack of change in firing rate across stages.

Action Potentials↗
PubMed1986

Release of endogenous dopamine and cholecystokinin from rat striatal slices: effects of amphetamine and dopamine antagonists.

The release of immunoreactive cholecystokinin (CCK) and dopamine was monitored simultaneously from superfused rat striatal slices. Exposure of the tissue to medium containing elevated K+ or veratrine, induced a marked release of both substances. The addition of dopamine (10(-7) and 10(-6) M), the dopamine agonist pergolide (10(-7) M), the D2-antagonist sulpiride (1 microM) or the D1-antagonist (SCH 23390) had no significant effect on basal overflow or on evoked release of CCK. On the other hand, preincubation of striatal slices with D-amphetamine (10(-5) M) enhanced basal and veratrine-stimulated dopamine release but markedly suppressed evoked CCK release. Sulpiride blocked this action of amphetamine whereas SCH 23390 was ineffective. The data suggests that whereas it is difficult to observe any effects of exogenous dopamine agonists or antagonists on evoked CCK release, endogenously released dopamine appears to interact with D2-receptors to suppress evoked CCK release from rat striatal slices.

Animals↗
PubMed1993

In patients receiving dopamine infusions for treatment of shock do free radicals convert dopamine to 6-hydroxydopamine?

Free hydroxyl radicals react with dopamine in vitro to produce the neurotoxin 6-hydroxydopamine (6-OHDA). If 6-OHDA were produced in vivo it could destroy central and/or peripheral neurons. Free radicals are produced in patients with cardiovascular or toxic shock. These patients are often treated with intravenous dopamine infusions. Using a newly developed method for measuring 6-OHDA in biological samples, we have examined blood from 15 patients receiving dopamine infusions for treatment of shock. 6-OHDA neither binds to nor elutes from either alumina or ion-exchange resins; therefore we used ODA-silica (Sep-Pak) to prepare samples for HPLC analysis with electrochemical detection. 6-OHDA disappeared rapidly from whole blood or serum at room temperature but was stable at -70 degrees C in an HClO4 extract. Recovery from Sep-Pak was 95% and detection limit 10 nmol/L. We repeated the experiments that showed in vitro hydroxyl radical conversion of dopamine to 5- and 6-OHDA. We detected neither 5- nor 6-OHDA in plasma samples from patients receiving dopamine infusions at 10-28 micrograms kg-1 min-1. Plasma dopamine in these patients was 1-5 mumol/L. We conclude that any 6-OHDA produced by hydroxyl radical attack in vivo is rapidly scavenged by endogenous substances containing sulfhydryl groups.

Chromatography, High Pressure Liquid↗
PubMed1986

The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment.

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at alpha 2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2-20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1-10 mg/kg s.c.) which elicited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02-2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2-2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5-10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02-1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 micrograms/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 micrograms/kg i.m. It is concluded that the property of B-HT 920 to stimulate the 'denervated' supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.

Animals↗
PubMed1993

Stimulation of dopamine transmission in the dorsal caudate nucleus by pargyline as demonstrated by dopamine and acetylcholine microdialysis and Fos immunohistochemistry.

The effect of pargyline on dopamine neurotransmission was investigated by trans-striatal microdialysis combined with Fos immunohistochemistry. Pargyline, 75 mg/kg i.p., increased dopamine and acetylcholine output while drastically decreased dopamine deaminated metabolites. Administration of pargyline resulted in the appearance of Fos-positive nuclei distributed along a gradient around the dialysis probe. Pretreatment with the D1 antagonist SCH 23390 potentiated the effect of pargyline on dopamine output while preventing that on acetylcholine output and on Fos formation. Similarly, lack of calcium in the perfusion medium abolished the effect of pargyline on dopamine and acetylcholine output and on Fos formation. In rats not implanted with dialysis probes pargyline administration resulted in only rare Fos-positive nuclei in the dorsal caudate. The present study indicates that pargyline stimulates dopamine transmission in the dorsal caudate in the area around the dialysis probe but not distant from the fibre or in unimplanted rats. This effect appears to reflect an interaction between the drug-induced changes and those locally elicited by the probe.

Acetylcholine↗
PubMed1994

The dopamine D2 antagonist remoxipride acts in vivo on a subpopulation of dopamine D2 receptors.

Dopamine D2 receptors were inactivated by N-ethoxycarbonyl-2-ethoxy-1,2,-dihydroxy-quinoline (EEDQ) (6 mg/kg i.p.). The reduction in dopamine receptors was monitored by quantitative receptor autoradiography using [125I]iodosulpiride or [3H]raclopride as radioligands. Pretreatment of male rats with haloperidol (0.3-3 mumol/kg i.p.) produced a dose-related, complete protection against the decrease in [125I]iodosulpiride binding induced by EEDQ in the dorsal and ventral striata and in all cortical areas examined. Raclopride (0.25-10 mumol/kg i.p.) produced the same pattern of effect as haloperidol but had a weaker effect. In contrast, remoxipride (1-40 mumol/kg i.p. or s.c.) only produced a partial protection against the dopamine D2 receptor inactivation by EEDQ. The results in the EEDQ test were related to the potency to block d-amphetamine-induced hyperlocomotion and the ability to induce bar-test catalepsy in the rat. The potencies in the behavioural tests were found to correspond to the in vivo occupancy for dopamine D2 receptors as evaluated by the EEDQ-induced decrease in D2 binding. However, remoxipride differed from both haloperidol and raclopride by showing a much reduced occupancy of dopamine D2 receptors at doses with behaviourally equipotent effects. The results support earlier suggestions that remoxipride in vivo may act on a subpopulation of dopamine D2 receptors.

Animals↗
PubMed1993

Preparation of [1-11C]dopamine, [1-11C]p-tyramine and [1-11C]m-tyramine. Autoradiography and PET examination of [1-11C]dopamine in primates.

A method for no-carrier-added 1-11C-labelling of 3-hydroxy-, 4-hydroxy- and 3,4-dihydroxy-substituted phenethylamines is described. [11C]Dopamine, [11C]p-tyramine and [11C]m-tyramine were prepared from on-line produced [11C]nitromethane. Condensation of [11C]nitromethane with various protected and unprotected benzaldehydes was investigated. A one-pot two-step reduction of the substituted 11C-labelled nitrostyrene intermediates, gave after hydrolysis and reversed-phase semi-preparative HPLC-purification the corresponding labelled amines in a total radiochemical yield of 8-20% (based on [11C]CO2 and decay-corrected). The total synthesis time was 45-50 min with a specific radioactivity of 400-1000 Ci/mmol (15-37 GBq/mumol). The radiochemical purity was higher than 98% [11C]Dopamine was used for in vitro autoradiography on human post-mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. Autoradiographic examination of [11C]dopamine binding on human brain section post-mortem demonstrated specific binding in the caudate putamen and the substantia nigra, regions with a dense dopaminergic innervation. Some binding was also seen in the globus pallidum, nucleus ventralis of the thalamus and in nucleus dentatus of the cerebellum, regions where the dopaminergic innervation is very low. In PET examinations of [11C]dopamine binding in Cynomolgus monkeys there was a high uptake of radioactivity in the pituitary, the kidneys and the heart. Any passage of [11C]dopamine across the blood-brain barrier could not be demonstrated. In human PET studies [11C]dopamine has potential as a radioligand for examination of the myocardium, pituitary and kidneys.

Animals↗
PubMed2005

Delivery of sonic hedgehog or glial derived neurotrophic factor to dopamine-rich grafts in a rat model of Parkinson's disease using adenoviral vectors Increased yield of dopamine cells is dependent on embryonic donor age.

The poor survival of dopamine grafts in Parkinson's disease is one of the main obstacles to the widespread application of this therapy. One hypothesis is that implanted neurons, once removed from the embryonic environment, lack the differentiation factors needed to develop the dopaminergic phenotype. In an effort to improve the numbers of dopamine neurons surviving in the grafts, we have investigated the potential of adenoviral vectors to deliver the differentiation factor sonic hedgehog or the glial cell line-derived neurotrophic factor GDNF to dopamine-rich grafts in a rat model of Parkinson's disease. Adenoviral vectors containing sonic hedgehog, GDNF, or the marker gene LacZ were injected into the dopamine depleted striatum of hemiparkinsonian rats. Two weeks later, ventral mesencephalic cell suspensions were prepared from embryos of donor ages E12, E13, E14 or E15 and implanted into the vector-transduced striatum. Pre-treatment with the sonic hedgehog vector produced a three-fold increase in the numbers of tyrosine hydroxylase-positive (presumed dopaminergic) cells in grafts derived from E12 donors, but had no effect on E13-E15 grafts. By contrast, pre-treatment with the GDNF vector increased yields of dopamine cells in grafts derived from E14 and E15 donors but had no effect on grafts from younger donors. The results indicate that provision of both trophic and differentiation factors can enhance the yields of dopamine neurons in ventral mesencephalic grafts, but that the two factors differ in the age and stage of embryonic development at which they have maximal effects.

Adenoviridae↗
PubMed2005

Blueberry- and spirulina-enriched diets enhance striatal dopamine recovery and induce a rapid, transient microglia activation after injury of the rat nigrostriatal dopamine system.

Neuroinflammation plays a critical role in loss of dopamine neurons during brain injury and in neurodegenerative diseases. Diets enriched in foods with antioxidant and anti-inflammatory actions may modulate this neuroinflammation. The model of 6-hydroxydopamine (6-OHDA) injected into the dorsal striatum of normal rats, causes a progressive loss of dopamine neurons in the ventral mesencephalon. In this study, we have investigated the inflammatory response following 6-OHDA injected into the striatum of adult rats treated with diet enriched in blueberry or spirulina. One week after the dopamine lesion, a similar size of dopamine degeneration was found in the striatum and in the globus pallidus in all lesioned animals. At 1 week, a significant increase in OX-6- (MHC class II) positive microglia was found in animals fed with blueberry- and spirulina-enriched diets in both the striatum and the globus pallidus. These OX-6-positive cells were located within the area of tyrosine hydroxylase (TH) -negativity. At 1 month after the lesion, the number of OX-6-positive cells was reduced in diet-treated animals while a significant increase beyond that observed at 1 week was now present in lesioned control animals. Dopamine recovery as revealed by TH-immunohistochemistry was significantly enhanced at 4 weeks postlesion in the striatum while in the globus pallidus the density of TH-positive nerve fibers was not different from control-fed lesioned animals. In conclusion, enhanced striatal dopamine recovery appeared in animals treated with diet enriched in antioxidants and anti-inflammatory phytochemicals and coincided with an early, transient increase in OX-6-positive microglia.

Animals↗
PubMed2004

Synergistic effects of dopamine and Zn2+ on the induction of PC12 cell death and dopamine depletion in the striatum: possible implication in the pathogenesis of Parkinson's disease.

The mechanism that underlies the progressive degeneration of the dopaminergic neurons in Parkinson's disease (PD) is not clear. The Zn(2+) level in the substantia nigra of Parkinson's patients is increased. However, it is unknown whether Zn(2+) has a role in the degeneration of dopaminergic neurons. This study identifies an interaction between dopamine and Zn(2+) that induces cell death. When PC12 cells were pretreated with Zn(2+) before dopamine treatment, dopamine and Zn(2+) synergistically increased cell death, while Zn(2+) and H(2)O(2) had only additive effects on cell death. The synergistic effect appeared to be caused by increased apoptosis rather than necrosis. The synergistic effect was specific for Zn(2+). The synergistic effect was inhibited by thiol antioxidants but was not significantly affected by calcium channel blockers. There is a similar synergistic effect when dopamine and Zn(2+) were coinfused into the striatum, resulting in striatal dopamine content depletion in vivo. Thus, both dopamine oxidation and Zn(2+) are possibly linked to the degeneration of dopaminergic neurons.

Animals↗
PubMed2000

Effects of prefrontal cortex microinjection of neurotensin-(8-13) on midbrain dopamine and non-dopamine cell firing.

Effects of prefrontal cortex microinjections of 0.3 and 3 nmol/0.5 microl of neurotensin-(8-13) on the firing rate of midbrain dopamine and non-dopamine cells were studied in urethane-anesthetized rats. Neurotensin produced an increase in firing in 14 of 26 dopamine cells tested, an effect that peaked between 15 and 20 min after the injection at both doses. On the other hand, a majority of non-dopamine cells (7/10) tested with the higher dose of neurotensin showed a statistically significant decrease in firing when compared to saline, an effect that also peaked between 15 and 20 min. These results show that prefrontal cortex neurotensin can modulate both dopamine and non-dopamine neurotransmission in the ventral midbrain.

Action Potentials↗
PubMed1999

Effects of the NMDA receptor antagonist D-CPPene on extracellular levels of dopamine and dopamine and serotonin metabolites in striatum of kindled and non-kindled rats.

Electrical kindling in rats has previously been shown to cause a hypersensitivity to amphetamine-like behavioral effects of competitive NMDA receptor antagonists such as D,L-(E)-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), or 3-(2-carboxypiperazine-4-yl)propenyl-1-phosphonate (SDZ EAA 494; D-CPPene). From this observation, it was concluded that kindling-induced epileptogenesis enhances the potential of competitive NMDA receptor antagonists to induce such unwanted adverse effects, predicting that such drugs may induce more severe side effects in epileptic patients than in healthy volunteers, which was confirmed in clinical trials. In the present study, we thought to examine the biochemical basis for the enhanced susceptibility of kindled rats to amphetamine-like behavioral effects of NMDA receptor antagonists by measuring extracellular levels of dopamine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin (5-hydroxytryptamine, 5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of awake, behaving rats, using in vivo microdialysis. When administered systemically, D-CPPene, 15 mg/kg i.p., caused more intense stereotyped behaviors in kindled than in non-kindled rats. While there was no significant alteration in extracellular dopamine, in both groups of rats HVA and 5-HIAA significantly increased. In kindled rats, basal levels of HVA and the increase in HVA in response to D-CPPene were higher compared to non-kindled animals. When administered intrastriatally via the microdialysis probe, D-CPPene, 10 microM, significantly increased dopamine, HVA and 5-HIAA, which was associated with stereotyped behaviors. Again, these behaviors were more intense in kindled rats. The data indicate that a competitive NMDA receptor antagonist at high, behaviorally active doses induces increases in striatal dopamine and presumably also 5-HT release, which most likely underlie the amphetamine-like behavioral effects of such a drug. Kindling enhances the sensitivity to these behavioral effects, which could be related to a more marked dopamine and 5-HT release. Thus, in order to avoid false predictions for the clinical situation, it is important to study the behavioral and biochemical effects of NMDA receptor antagonists not only in naive, healthy animals but also in animals that mimic the disease for which a drug is developed.

Amygdala↗
PubMed2000

Age-related dopamine deficiency in the mesostriatal dopamine system of zitter mutant rats: regional fiber vulnerability in the striatum and the olfactory tubercle.

Oxidant stress has been implicated in the pathogenesis of Parkinson's disease. To test the oxidant stress hypothesis of dopaminergic degeneration, age-related changes in the mesostriatal dopamine neuron system were compared between zitter mutant rats which have abnormal metabolism of oxygen species in the brain and Sprague-Dawley rat as a control using the neurochemistry and immunohistochemistry. Dopamine content in the caudate-putamen, nucleus accumbens and olfactory tubercle of zitter rats decreased significantly with age, and was lower than that found in corresponding age-matched controls. In the zitter rats, the reduction of dopamine was more prominent in the caudate-putamen than in the nucleus accumbens and olfactory tubercle. A characteristic decline of tyrosine hydroxylase-immunoreactive fibers in the caudate-putamen of the zitter rat was also observed. In the dorsolateral caudate-putamen, reduction of tyrosine hydroxylase-immunoreactive fibers was observed in the matrix-like area, whereas in the ventromedial caudate-putamen the reduction occurred in the patch-like areas. Degeneration of tyrosine hydroxylase-immunoreactive fibers which was characterized by swollen varicosities and clustered fibers was observed in the caudate-putamen and nucleus accumbens and preceded loss of normal tyrosine hydroxylase-immunoreactive fibers in the caudate-putamen. Thus, the depletion of dopamine in the terminal areas is related to axonal degeneration. However, there was no degenerative tyrosine hydroxylase-immunoreactive fibers in the olfactory tubercle at any examined age, but reductions of tyrosine hydroxylase-immunoreactive fibers and dopamine contents were noted in the olfactory tubercle after four months-of-age. Since the zitter rats have an abnormal oxygen metabolism, the degeneration of tyrosine hydroxylase-immunoreactive fibers could result from an accumulation of superoxide species. The present results provide support for the oxidant stress hypothesis of dopaminergic neuronal degeneration and further indicate the region-specific vulnerability of the nigrostriatal dopamine system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Effects of endogenous glutamate on extracellular concentrations of GABA, dopamine, and dopamine metabolites in the prefrontal cortex of the freely moving rat: involvement of NMDA and AMPA/KA receptors.

Using microdialysis, interactions between endogenous glutamate, dopamine, and GABA were investigated in the medial prefrontal cortex of the freely moving rat. Interactions between glutamate and other neurotransmitters in the prefrontal cortex had already been studied using pharmacological agonists or antagonists of glutamate receptors. This research investigated whether glutamate itself, through the increase of its endogenous extracellular concentration, is able to modulate the extracellular concentrations of GABA and dopamine in the prefrontal cortex. Intracortical infusions of the selective glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) were used to increase the endogenous extracellular glutamate. PDC (0.5, 2, 8, 16 and 32 mM) produced a dose-related increase in dialysate glutamate in a range of 1-36 microM. At the dose of 16 mM, PDC increased dialysate glutamate from 1.25 to 28 microM. PDC also increased extracellular GABA and taurine, but not dopamine; and decreased extracellular concentrations of the dopamine metabolites DOPAC and HVA. NMDA and AMPA/KA receptor antagonists were used to investigate whether the increases of extracellular glutamate were responsible for the changes in the release of GABA, and dopamine metabolites. The NMDA antagonist had no effect on the increase of extracellular GABA, but blocked the decreases of extracellular DOPAC and HVA, produced by PDC. In contrast, the AMPA/KA antagonist blocked the increases of extracellular GABA without affecting the decreases of extracellular DOPAC and HVA produced by PDC. These results suggest that endogenous glutamate acts preferentially through NMDA receptors to decrease dopamine metabolism, and through AMPA/KA receptors to increase GABAergic activity in the medial prefrontal cortex of the awake rat.

Animals↗
PubMed1983

A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions.

Several mammalian neurotransmitter candidates, for example, serotonin, dopamine and noradrenaline, may exert some of their synaptic effects by regulating protein phosphorylation systems. Comparison of the regional distribution of brain phosphoproteins with neurotransmitter systems may help to identify the specific phosphoproteins involved in the functions of particular neurotransmitters. Here we report the association of one such phosphoprotein with the dopamine pathways in brain. This protein, of apparent molecular weight (MW) 32,000 (32K), seems to be present only in nervous tissue. Its regional distribution within the brain is very similar to the pattern of dopamine-containing nerve terminals; more specifically, the protein appears to be enriched in those dopaminoceptive neurones which possess D-1 receptors (dopamine receptors coupled to adenylate cyclase). The state of phosphorylation of the protein in these dopaminoceptive neurones can be regulated by both dopamine and cyclic AMP. These results suggest that the phosphoprotein may mediate certain of the trans-synaptic effects of dopamine acting on dopaminoceptive neurones.

Animals↗
PubMed2004

Dopamine neurons in culture express VGLUT2 explaining their capacity to release glutamate at synapses in addition to dopamine.

Dopamine neurons have been suggested to use glutamate as a cotransmitter. To identify the basis of such a phenotype, we have examined the expression of the three recently identified vesicular glutamate transporters (VGLUT1-3) in postnatal rat dopamine neurons in culture. We found that the majority of isolated dopamine neurons express VGLUT2, but not VGLUT1 or 3. In comparison, serotonin neurons express only VGLUT3. Single-cell RT-PCR experiments confirmed the presence of VGLUT2 mRNA in dopamine neurons. Arguing for phenotypic heterogeneity among axon terminals, we find that only a proportion of terminals established by dopamine neurons are VGLUT2-positive. Taken together, our results provide a basis for the ability of dopamine neurons to release glutamate as a cotransmitter. A detailed analysis of the conditions under which DA neurons gain or loose a glutamatergic phenotype may provide novel insight into pathophysiological processes that underlie diseases such as schizophrenia, Parkinson's disease and drug dependence.

Amino Acid Transport Systems, Acidic↗
PubMed2000

Manganese administration induces the increased production of dopamine sulfate and depletion of dopamine in Sprague-Dawley rats.

Sprague-Dawley rats were used as an experimental model for investigating the effects of manganese poisoning on the serum levels of unsulfated and sulfated forms of dopamine and its biosynthetic precursors, L-Dopa and L-p-tyrosine. Groups of rats were treated daily with Mn(2+) (20 mg or 40 mg; in the form of MnSO(4)) or Na(+) (20 mg; in the form of Na(2)SO(4)). High performance liquid chromatography (HPLC) analysis of the serum samples taken after a 50-day experimental period revealed that the serum level of dopamine sulfate increased by more than 10 times compared with untreated control rats or rats treated with sodium sulfate. In contrast, there was a dramatic decrease (by as much as 4.8 times) in the serum level of unsulfated dopamine in manganese-treated rats. The serum levels of L-Dopa sulfate and L-p-tyrosine sulfate were also markedly elevated, although not as much as those of dopamine sulfate. Meanwhile, the serum levels of unsulfated L-Dopa and L-p-tyrosine showed no dramatic changes. Atomic absorption spectrophotometric analysis revealed in general an accumulation of manganese in the four organ samples taken from manganese-treated rats. Compared with liver, heart, and kidney, the highest degree of manganese accumulation in manganese-treated rats appeared to be in brain. These results together suggested a role for manganese in stimulating the dopamine-sulfating sulfotransferases in brain, thereby leading to the depletion of dopamine in vivo.

Administration, Oral↗
PubMed1989

A novel orally active dopamine prodrug TA-870. I. Renal and cardiovascular effects and plasma levels of free dopamine in dogs and rats.

Intraduodenal administration of N-(N-acetyl-L-methionyl)-O, O-bis(ethoxycarbonyl)dopamine (TA-870), a newly synthesized dopamine derivative, increased the renal blood flow (RBF) and mesenteric blood flow in anesthetized dogs, while blood pressure and heart rate were less affected. It also increased the glomerular filtration rate, urine volume, and urinary sodium excretion in saline-loaded anesthetized dogs. In conscious dogs, TA-870 and dopamine hydrochloride (DA-HCl) increased RBF in parallel with increases in plasma free dopamine (free-DA) concentration. At an equimolar dose of 71 mumols/kg, p.o., the effect of TA-870 continued for greater than 4 h, while that of DA-HCl lasted for only 2 h: the peak free-DA concentration and maximum increase in RBF were 155 +/- 57 ng/ml and 56 +/- 15%, respectively, for TA-870, and those for DA-HCl were 32 +/- 13 ng/ml and 36 +/- 10%. Similarly, TA-870 showed greater increases in both RBF and plasma free-DA concentration than DA-HCl in anesthetized rats. In contrast to enteral administration, intravenously administered TA-870 exhibited weaker effects than intravenous DA-HCl in anesthetized dogs. In conclusion, TA-870 is an orally effective dopamine prodrug capable of producing higher and more sustained plasma concentrations of dopamine than DA-HCl when administered by the enteral route.

Administration, Oral↗