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PubMed1975

The separation and identification of dopamine 3-O-sulfate and dopamine 4-O-sulfate in urine of Parkinsonian patients.

A method is described for the isolation and measurement of dopamine 3-O-sulfate and dopamine 4-O-sulfate. The sulfate isomers of dopamine were synthesized chemically by the reaction of dopamine with sulfuric acid. The isomers were isolated by anion-exchange column chromatography and the identities of the two isomers were confirmed by gas chromatography coupled with mass spectrometry. A method is described for the assay of the two isomers by high-pressure liquid chromatography. When Parkinsonian patients were treated with 4.0 g/day of L-dopa, the amount of dopamine 3-O-sulfate excreted in the urine was 19.6 times that of dopamine 4-O-sulfate. When untreated Parkinsonian patients received tracer quantities of 3H-L-dopa either intravenously or orally, 3H-dopamine 3-O-sulfate was the predominant isomer but the amounts were only 3 times those of the 4-isomer. Greater quantities of both isomers were excreted when 3H-L-dopa was given orally as compared to intravenous administration. Since dopamine 3-O-sulfate is the predominant sulfate isomer, it is concluded that sulfate conjugation of dopamine could possibly compete with 3-O-methylation in determining the resultant conjugated product.

Administration, Oral↗
PubMed1992

Roles of intracellular cAMP and protein kinase A in the actions of dopamine and neurotensin on midbrain dopamine neurons.

The role of intracellular cAMP and protein kinase A in dopamine-induced inhibition of dopamine neurons and the attenuation of this inhibition by neurotensin were studied in rat midbrain slices. Spontaneous activity of dopamine cells was recorded extracellularly from both the ventral tegmental area and the substantia nigra. Perfusion of the slices with 8-bromo-cAMP and forskolin significantly attenuated dopamine-induced inhibition, but neither blocked the inhibition completely. Neither SQ22536, an inhibitor of adenylate cyclase, nor H8, an inhibitor of protein kinase A, mimicked the inhibitory effect of dopamine on dopamine neurons, although they potentiated dopamine's effect. These results indicate that dopamine-induced inhibition of dopamine neurons can be affected by intracellular cAMP levels, but is unlikely to be mediated solely by inhibition of adenylate cyclase. The similarities between the effects of neurotensin and those of 8-bromo-cAMP and forskolin suggest that intracellular cAMP may be involved in the actions of neurotensin. This suggestion is supported by our findings that isobutyl-methylxanthine (an inhibitor of phosphodiesterases) potentiated the effect of neurotensin and SQ22536 and H8 antagonized it. Phorbol-12,13-dibutyrate (an activator of protein kinase C) did not mimic the effect of neurotensin, and H7 (an inhibitor of protein kinase C) did not reduce the effect, suggesting that protein kinase C is unlikely to be involved in the modulatory effect of neurotensin.

Animals↗
PubMed1992

Differential effects of amphetamine and dopamine uptake blockers (cocaine, nomifensine) on caudate and accumbens dialysate dopamine and 3-methoxytyramine.

Evidence suggests that some amphetamine-like stimulants may enhance accumbens dialysate dopamine to the greater extent than caudate dopamine. To test our hypothesis that the difference in transmitter response may derive, in part, from the degree to which released dopamine in the two regions is metabolized to 3-methoxytyramine, we compared the effects of amphetamine with the uptake blockers, nomifensine and cocaine, on caudate and accumbens dialysate concentrations of dopamine, its acid metabolites and 3-methoxytyramine. The percentage increases in accumbens dopamine were significantly greater than in caudate only after the uptake blockers. All three drugs promoted dose-dependent increases in dialysate 3-methoxytyramine which, although temporally delayed, generally paralleled the increases in dopamine. However, after the administration of uptake blockers, the ratio of dialysate 3-methoxytyramine to dopamine was greater in caudate than in accumbens. In addition, the acid metabolite patterns were the same in the two regions after amphetamine, but were qualitatively different after the uptake blockers. These results indicate that the relative degree of metabolism of released dopamine to 3-methoxytyramine in caudate and accumbens may contribute to the regional differences in dopamine response to uptake blockers.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Examinations on contribution of bradykinin in the action of dopamine in circulatory system of rats. II. Influence of bradykinin in the action of dopamine on the vessel perfusion of the isolated hindpaw of rats.

The influence of different doses of bradykinin (0.1 micrograms, 1.0 micrograms/0.1 ml) and dopamine (0.1, 0.25, 0.5 micrograms/0.1 ml) on the flow through vessels of the isolated hindpaw of rat was estimated. Dopamine in small doses did not change and in the highest doses decreased the vascular flow. Bradykinin decreased the vascular flow and the effect was dose-dependent. This peptide administered together with dopamine in the smallest dose, evoked the same effect as dopamine itself in the highest dose and decreased the effect of dopamine introduced into the organism in the highest dose. Administration of phentolamine and propranolol decreased the vascular flow. The vasodilating effect of dopamine was seen after administration of drugs blocking the adrenergic receptors and the vaso-constricting effect of dopamine administered in the highest dose was not observed. Bradykinin decreased the vascular flow and when administered together with dopamine evoked effect similar to that after administration of the peptide with phentolamine and propranolol. The authors suppose that except the modifying influence of bradykinin on the action of dopamine, the role of the peptide receptor in this action cannot be excluded.

Animals↗
PubMed1993

Time course of extracellular dopamine and behavioral sensitization to cocaine. II. Dopamine perikarya.

Cocaine was administered daily (15 mg/kg, i.p. x 1 d followed by 30 mg/kg, i.p. x 5 d) to produce behavioral sensitization. Using microdialysis in the ventral tegmental area and medial substantia nigra, the effect of repeated cocaine was examined on the extracellular levels of dopamine. One day after discontinuing repeated cocaine injections, an acute challenge with cocaine (15 mg/kg, i.p.) produced a significant elevation in extracellular dopamine compared to rats pretreated with daily saline (x6 d). The augmentation in extracellular dopamine persisted longer than the sensitized behavioral response. In contrast, 14 d after discontinuing daily cocaine, the increase in extracellular dopamine produced by an acute cocaine challenge was not augmented, although behavioral sensitization was present. In separate animals, the basal concentration of dopamine in the ventral tegmental area/medial substantia nigra was measured by determining the concentration of dopamine at which no net flux occurred across the dialysis membrane in vivo. One day after discontinuing daily treatments, the basal level of extracellular dopamine in the cocaine pretreated rats was significantly elevated over the level in saline-pretreated animals (1.3 nM vs. 0.8 nM). By 14 d after the last daily injection, the basal levels of dopamine were equivalent in cocaine- and saline-pretreated animals. It is concluded that daily cocaine injections produce a transient alteration in the regulation of somatodendritic dopamine release. While such changes are not responsible for the long-term behavioral sensitization produced by repeated cocaine administration, they may be involved in the initiation of behavioral sensitization.

Animals↗
PubMed1997

On the involvement of a tonic dopamine D2-autoinhibition in the regulation of pulse-to-pulse-evoked dopamine release in the rat striatum in vivo.

The dopamine overflow evoked by trains of electrical stimulation pulses applied to the ascending dopaminergic pathway was measured with continuous amperometry in the striatum of anesthetised rats. As previously observed in in vitro studies, a pulse by pulse analysis showed a fall in dopamine overflow evoked by pulses 2 to 6, compared to the response evoked by pulse 1. However, in contrast with in vitro findings, the present in vivo data showed that the dopamine receptor antagonist haloperidol i) completely reverses the fall in dopamine overflow between pulse 1 and subsequent pulses, ii) enhances the dopamine overflow elicited by pulse 1. These results suggest that in vivo, both basal and pulse-evoked dopamine overflow results in stimulation of dopamine D2-type autoreceptors and therefore in regulation of dopamine release.

Animals↗
PubMed1999

Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals.

The aim of the present study was to investigate the locomotor stimulant effects of the atypical antipsychotic agent, olanzapine, in mice depleted of their dopamine by reserpine and alpha-methyl-DL-p-tyrosine pretreatment. Olanzapine (0.5, 1 and 2 mg/kg) dose-dependently increased locomotor activity, which was completely blocked by the selective dopamine D2 receptor antagonist, pimozide (0.5 mg/kg) but not by selective dopamine D1 receptor antagonist, SCH 23390 (0.5 and 1 mg/kg). Unlike olanzapine, the selective dopamine D2 receptor antagonists such as haloperidol (0.25 and 0.5 mg/kg) and pimozide (0.5 and 1 mg/kg), the selective 5-HT2A receptor antagonist, ritanserin (0.5 and 1 mg/kg) or the antimuscarinic agent scopolamine (0.5 and 1 mg/kg) failed to produce any locomotor stimulant effect. Olanzapine (1 and 2 mg/kg) and SCH 23390 (0.5 and 1 mg/kg) blocked hyperlocomotion and stereotypy induced by the selective dopamine D1 receptor agonist, SKF 38393 (10 and 25 mg/kg). Olanzapine (1 and 2 mg/kg) blocked hyperlocomotion and stereotypy induced by B-HT 920 (1 and 2 mg/kg), a selective dopamine D2 receptor agonist, whereas it blocked the hyperlocomotion but not stereotypy induced by the non-selective dopamine receptor agonist, apomorphine (0.5 and 1 mg/kg). The higher dose (4 mg/kg) of olanzapine blocked both stereotypy and hyperlocomotion induced by apomorphine. Olanzapine, in mice depleted of their dopamine stores, exhibited properties consistent with those of a D2 partial agonist having strong D1 antagonist property. The atypical nature of its clinical effect may be explained by a dual effect, partial agonistic-like action at D2 receptors and antagonist-like activity at D1 receptors, respectively.

Adrenergic Uptake Inhibitors↗
PubMed1993

Dopamine D1 receptor stimulation but not dopamine D2 receptor stimulation attenuates haloperidol-induced behavioral supersensitivity and receptor up-regulation.

The effect of selective dopamine D1 and D2 receptor agonists on chronic haloperidol-treated rats was studied. Haloperidol treatment produced a 77% increase in apomorphine-induced sterotypy. The administration of the selective dopamine D1 receptor agonist SKF38393 alone or in combination with the selective dopamine D2 receptor agonist quinpirole attenuated the effect of haloperidol. Treatment with quinpirole alone did not have a significant effect on the response to haloperidol. Haloperidol did not modify the number of dopamine D1 receptors but increased that of dopamine D2 receptors. SKF38393 reversed the effect of haloperidol on dopamine D2 receptor binding. Co-administration of SKF38393 and quinpirole did not modify the increase in the number of dopamine D2 receptors induced by chronic treatment haloperidol. The results confirm a dissociation between behavioral supersensitivity and dopamine receptor up-regulation, suggesting that other mechanisms may be involved in the expression of behavioral supersensitivity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Dopamine transporter binding in rat striatum and nucleus accumbens is unaltered following chronic changes in dopamine levels.

The effects of chronic treatment with the tyrosine hydroxylase inhibitor alpha-methyltyrosine or the dopamine precursor 1-3,4-dihydroxyphenylalanine on radioligand binding to the dopamine transporter in homogenates of rat striatum and nucleus accumbens were assessed. Chronic alpha-methyltyrosine administration decreased dopamine levels in both the striatum and nucleus accumbens without a resulting change in [3H]mazindol binding to the dopamine transporter in either brain region. In a second experiment, chronic administration of alpha-methyltyrosine or L-3,4-dihydroxyphenylalanine produced significant decreases and increases, respectively, in striatal dopamine levels without altering the binding of [3H]WIN 35,428, a chemically distinct dopamine transporter radioligand. These data suggest that even dramatic fluctuations in brain dopamine levels do not modulate the abundance of the dopamine transporter.

Animals↗
PubMed1999

Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers.

The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. This variability might be due to genetic or environmental factors. In the present analysis we searched for relationships between dopamine D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density in vivo, as measured by positron emission tomography and [11C]raclopride in 56 healthy subjects. There was a significant association between presence of a putative functional DRD2 promoter allele (-141C Del) and high striatal dopamine receptor density (t= 2.32, P= 0.02). In agreement with some previous studies the presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t=2.58, P=0.01). Also the DRD2 TaqIB1 allele was associated with low dopamine receptor density (t= 2.58, P= 0.01) wheras there was no significant relationship between another common silent intronic DRD2 short tandem repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results suggest that DRD2 genotypes may participate differentially in the regulation of striatal dopamine D2 receptor density in healthy human subjects. The results should be interpreted with caution because of the limited sample size.

Adult↗
PubMed2003

Evidence for distinct sodium-, dopamine-, and cocaine-dependent conformational changes in transmembrane segments 7 and 8 of the dopamine transporter.

Previously we obtained evidence based on engineering of Zn2+ binding sites that the extracellular parts of transmembrane segment 7 (TM7) and TM8 in the human dopamine transporter are important for transporter function. To further evaluate the role of this domain, we have employed the substituted cysteine accessibility method and performed 10 single cysteine substitutions at the extracellular ends of TM7 and TM8. The mutants were made in background mutants of the human dopamine transporter with either two (E2C) or five endogenous cysteines substituted (X5C) that render the transporter largely insensitive to cysteine modification. In two mutants (M371C and A399C), treatment with the sulfhydryl-reactive reagent [2-(trimethylammonium)-ethyl]methanethiosulfonate (MTSET) led to a substantial inhibition of [3H]dopamine uptake. In M371C this inactivation was enhanced by Na+ and blocked by dopamine. Inhibitors such as cocaine did not alter the effect of MTSET in M371C. The protection of M371C inactivation by dopamine required Na+. Because dopamine binding is believed to be Na+-independent, this suggests that dopamine induces a transport-associated conformational change that decreases the reactivity of M371C with MTSET. In contrast to M371C, cocaine decreased the reaction rate of A399C with MTSET, whereas dopamine had no effect. The protection by cocaine can either reflect that Ala-399 lines the cocaine binding crevice or that cocaine induces a conformational change that decreases the reactivity of A399C. The present findings add new functionality to the TM7/8 region by providing evidence for the occurrence of distinct Na+-, substrate-, and perhaps inhibitor-induced conformational changes critical for the proper function of the transporter.

Amino Acid Sequence↗
PubMedDate not supplied

Dopamine transporter blockade increases LTP in the CA1 region of the rat hippocampus via activation of the D3 dopamine receptor.

Dopamine has been demonstrated to be involved in the modulation of long-term potentiation (LTP) in the CA1 region of the hippocampus. As monoamine transporter blockade will increase the actions of endogenous monoamine neurotransmitters, the effect of a dopamine transporter (DAT) antagonist on LTP was assessed using field excitatory postsynaptic potentials recorded in the CA1 region of the rat hippocampal slice preparation. Application of the DAT-specific blocker GBR 12,935 produced a significant enhancement in LTP of Schaffer collateral synapses in the CA1 at concentrations as low as 100 nM. A selective D1/D5 dopamine receptor antagonist (SCH 23,390, 1 microM) did not affect the ability of GBR 12,935 to enhance LTP, whereas application of the D3 dopamine receptor antagonist U 99,194 (1 microM) blocked the GBR 12,935-induced enhancement in LTP. In addition, a D3 dopamine receptor agonist (7-OH-DPAT, 1 microM) caused a significant increase in LTP, an effect that was also blocked by U 99,194 (3 microM). These results suggest that either endogenously released dopamine (facilitated by DAT blockade) or exogenously applied dopamine agonist can act to increase LTP in the CA1 of the hippocampus via activation of the D3 subtype of dopamine receptor.

Animals↗
PubMed1999

Dopamine transporter: transmembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition.

Cocaine blocks the normal role of the dopamine transporter (DAT) in terminating dopamine signaling through molecular interactions that are only partially understood. Cocaine analog structure-activity studies have suggested roles for both cationic and aromatic interactions among DAT, dopamine, and cocaine. We hypothesized that phenylalanine residues lying in putative DAT transmembrane (TM) domains were good candidates to contribute to aromatic and/or cationic interactions among DAT, dopamine, and cocaine. To test this idea, we characterized the influences of alanine substitution for each of 29 phenylalanine residues lying in or near a putative DAT TM domain. Cells express 22 mutants at near wild-type levels, manifest by DAT immunohistochemistry and binding of the radiolabeled cocaine analog [(3)H](-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (CFT). Seven mutants fail to express at normal levels. Four mutations selectively reduce cocaine analog affinities. Alanine substitutions at Phe(76), Phe(98), Phe(390), and Phe(361) located in TM domains 1 and 2, the fourth extracellular loop near TM 4 and in TM 7, displayed normal affinities for dopamine but 3- to 8-fold reductions in affinities for CFT. One TM 3 mutation, F(155)A, selectively decreased dopamine affinity to less than 3% of wild-type levels while reducing CFT affinity less than 3-fold. In a current DAT structural model, each of the residues at which alanine substitution selectively reduces cocaine analog or dopamine affinities faces a central transporter cavity, whereas mutations that influence expression levels are more likely to lie at potential helix/helix interfaces. Specific, overlapping sets of phenylalanine residues contribute selectively to DAT recognition of dopamine and cocaine.

Alanine↗
PubMed1989

Selective blockade of dopamine D-1 receptor by SCH 23390 affects dopamine agonist binding to 3H-spiperone labeled D-2 receptors in rat striatum.

This study investigated the effects of selective blockade of dopamine D-1 receptors by SCH 23390 and selective stimulation of the receptors by SKF 38393 on the binding characteristics of 3H-spiperone labeled D-2 receptors in rat striatum. Selective blockade of D-1 receptors by 50 nM SCH 23390 significantly decreased the affinity of dopamine agonist for 3H-spiperone labeled D-2 receptors, but did not influence dopamine antagonist binding to D-2 receptors. Selective stimulation of D-1 receptors by SKF 38393 (100 nM) did not affect either dopamine agonist or antagonist binding to D-2 receptors. The characteristics of the effect of SCH 23390 on dopamine agonist binding to D-2 receptors was similar to those of GTP, but different from those of sodium ion. This effect could not be due to a direct modification of D-2 receptors by SCH 23390. Pertussis toxin (IAP) treatment significantly decreased the affinity of dopamine agonist for D-2 receptors and reduced the abilities of both SCH 23390 and GTP to decrease the affinity of dopamine agonist for D-2 receptors. These results suggest, therefore, putative interregulatory mechanism between dopamine D-1 and D-2 receptors and the possible involvement of a pertussis toxin sensitive protein in this mechanism.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

6-hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding.

Behavioral responses to D1 and D2-dopamine agonists are enhanced when these agonists are administered systemically to 6-hydroxydopamine (6-OHDA)-lesioned rats. In the present investigation, microinjection of SKF-38393, a D1-dopamine agonist, into the nucleus accumbens of adult rats lesioned as neonates with 6-OHDA produced a dose-related increase in locomotor activity that was enhanced markedly compared to control. LY-171555, a D2-agonist, elicited less locomotor activity than did SKF-38393 after microinjection into this site. Administration of SKF-38393 or LY-171555 into the nucleus accumbens did not increase locomotion in unlesioned rats at the doses administered to lesioned animals. In adult-6-OHDA-lesioned rats, microinjection of SKF-38393 into the nucleus accumbens also increased locomotion more than did LY-171555. As described previously, systemic administration of SKF-38393 produced little locomotion in adult-6-OHDA-lesioned rats, whereas LY-171555 produced a markedly enhanced response. Administration of SKF-38393 or LY-171555 into the caudate nucleus of neonatally and adult-6-OHDA-lesioned rats produced negligible locomotor activity, but did induce stereotypic behaviors similar to those observed after systemic treatment with these drugs. Stereotypic behaviors occurred to a greater degree in the 6-OHDA-lesioned rats than in unlesioned controls. A regional specificity for certain behaviors induced by dopamine agonist administration was observed. In spite of the enhanced behavioral responses of D1 and D2-dopamine agonists after microinjection into the brain of 6-OHDA-lesioned rats, binding of [3H]spiperone (D2-receptor antagonist ligand) and [3H]SCH 23390 (D1-receptor antagonist ligand) to tissue from striatum and nucleus accumbens was not altered significantly. In contrast to this lack of change in binding characteristics in 6-OHDA-lesioned rats, blockade of dopaminergic transmission with haloperidol treatment caused an elevation of [3H]spiperone binding sites in striatum without affecting affinity for the site. However, chronic haloperidol treatment did not alter significantly [3H]SCH 23390 binding to striatal membranes. These latter findings suggest that chronic dopamine receptor blockade need not produce the same adaptive mechanisms as destruction of dopamine-containing neurons. Thus, a change in receptor characteristics as measured by dopamine antagonist binding does not account for the behavioral supersensitivity observed after D1- and D2-dopamine agonist administration to neonatally or adult-6-OHDA-treated rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1984

Studies on the role of dopamine and dopamine blockers in gastroduodenal motility.

In vitro studies on an intact gastroduodenal preparation of the guinea-pig indicated that dopamine inhibited motor activity via a direct action on the gastrointestinal wall. Dopamine-induced relaxations were prevented by dopamine antagonists, which also exerted intrinsic stimulatory effects and improved gastroduodenal coordination. These effects were confirmed in vivo on conscious dogs. The results cannot be explained by an interaction with alpha- receptors, since alpha-adrenergic blocking concentrations of prazosin were inactive against dopamine, and dopamine-blocking concentrations of domperidone did not interfere with noradrenaline-induced relaxations. Pharmacological evidence confirmed the presence of dopamine receptors in the stomach of conscious dogs. The presence of specific dopamine receptors in the gastrointestinal tract is strongly indicated, and an important role for endogenous dopamine as an inhibitory neuromodulator of gastroduodenal motility is suggested.

Animals↗
PubMed1997

Dopamine induces apoptosis in cultured rat striatal neurons; possible mechanism of D2-dopamine receptor neuron loss during aging.

We examined D2-dopamine receptor containing neurons in cultures of neonatal rat striatum for apoptosis following dopamine treatment. Exposure to cultures to micromolar concentrations of dopamine resulted in 60-70% killing of D2-dopamine receptor neurons within 24 hr. We also utilized a double labeling procedure to determine that treatment with dopamine induced apoptosis in D2-dopamine receptor containing neurons. These results suggest that loss of D2-dopamine receptor containing neurons during aging could be due to an apoptotic effect of dopamine.

Animals↗
PubMed1994

Differential effects of dopamine agonists on evoked dopamine release from slices of striatum and nucleus accumbens in rats.

The effects of dopamine receptor agonists on electrically evoked dopamine release from slices of nucleus accumbens were compared with the effects on release from striatal slices in rats. Apomorphine, which has equal potency at the dopamine D2 and D3 receptors, reduced the evoked dopamine release from both regions to the same extent (ED50, 0.42 microM for nucleus accumbens; ED50, 0.46 microM for striatum). Quinpirole or 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT), which are much more potent at the D3 receptor than at the D2 receptor, reduced the evoked dopamine release from the nucleus accumbens (ED50, 0.12 microM for quinpirole; 0.02 microM for 7-OHDPAT) much more than the release from the striatum (ED50, 1.6 microM for quinpirole; 0.55 microM for 7-OHDPAT). These results suggest that the contribution of D3 receptors in nucleus accumbens to regulate dopamine release from dopamine nerve terminals is much greater than in striatum.

Animals↗