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At least 577 records · Page 32Linked to original sources

PubMed1984

Effects of dopamine in segmental intestinal ischaemia studied with dopamine receptor blockers.

The influence of dopamine blocking agents, namely pimozide 0.1 mg X kg-1 body weight (b.w.) and metoclopramide 3 mg X kg-1 b.w., on the effects of dopamine on central and regional haemodynamics was studied in rats. The metoclopramide dose was given twice during the experiments. An experimental model involving segmental ischaemia of the small intestine was used. According to earlier investigations administration of dopamine and plasma counteracts the negative haemodynamic effects of such ischaemia. In rats treated with pimozide this drug had some effects per se in the controls, slightly reducing cardiac output and the blood flow in the proximal half of the intestine. On the other hand, in the experimental group the positive effect of dopamine seemed to be unaffected by pimozide treatment. In rats treated with metoclopramide, dopamine did not improve the considerable decrease in intestinal and pancreatic circulation caused by the segmental ischaemia.

Animals↗

PubMed1996

Combining 'caged-dopamine' photolysis with fast-scan cyclic voltammetry to assess dopamine clearance and release autoinhibition in vitro.

We have developed a methodology for inducing a rapid rise in extracellular dopamine concentrations. The clearance of the applied dopamine, as well as its effect on the endogenous dopamine release (i.e., autoinhibition), was then examined using fast scan cyclic voltammetry. In a recording chamber mounted on a Nikon Optiphot epifluorescence microscope, coronal rat brain slices containing either the caudate nucleus or prefrontal cortex were perfused with ACSF containing 100-200 microM 'caged-DA.' UV illumination (100-200 ms) focused at the tip of the recording electrode produced a peak DA concentration of 1-2 microM within 100-200 ms of terminating the illumination. The caudate nucleus exhibited a faster clearance rate for photo-released DA compared to the prefrontal cortex. Cocaine reduced the clearance rates in both the caudate nucleus and prefrontal cortex. In the prefrontal cortex a combination of desipramine/clomipramine also reduced dopamine clearance, suggesting heterologous uptake of the applied DA by noradrenergic and/or serotonergic terminals. Photo-released dopamine inhibited release of endogenous caudate DA release evoked by single electrical stimulation. The advantages of this methodology are discussed.

Animals↗

PubMed1995

Single photon emission tomography (SPET) imaging of dopamine D2 receptors in the course of dopamine replacement therapy in patients with nocturnal myoclonus syndrome (NMS).

Single photon emission tomography (SPET) permits the in vivo measurements of regional cerebral radioactivity in the human brain following the administration of compounds labeled with photon-emitting isotopes. According to our SPET findings of a reduced binding of [123I]labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D2 dopamine receptor ligand) to D2 dopamine receptors in striatal structures in untreated patients with nocturnal myoclonus syndrome (NMS) it seemed to be of interest to investigate whether there are changes in D2 receptor binding under dopamine replacement therapy or not. We studied the uptake and distribution of [123I]IBZM before and in the course of dopamine replacement therapy in four patients with severe insomnia caused by a nocturnal myoclonus syndrome (NMS). We found an increase of the IBZM binding to D2 receptors in the course of treatment, which was associated with an improvement of sleep quality. Reasons for this are discussed. The [123I]IBZM SPET technique in conclusion offers an intersting tool for in vivo investigations of functional changes in the dopaminergic neurotransmitter system in longitudinal studies.

Aged↗

PubMed1996

Dopamine autoreceptor reserve in vitro: possible role of dopamine D3 receptors.

Receptor alkylation in vivo with N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ) decreased the potency, but not the efficacy, of the dopamine D3 receptor-preferring agonist 7-hydroxy-N, N-di-n-propyl-2-aminotetralin (7-OH-DPAT) at synthesis modulating dopamine autoreceptors in striatal and olfactory tubercle slices stimulated by 30 mM K+. In contrast, 7-OH-DPAT was ineffective in slices exposed to forskolin (10 microM). The results support the presence of autoreceptor reserve in vitro, and the partial involvement of dopamine D3 receptors in the autoregulation of dopamine synthesis.

Adenylyl Cyclases↗

PubMed1992

Effects of stimulation of putative dopamine autoreceptors on electroencephalographic power spectrum in comparison with effects produced by blockade of postsynaptic dopamine receptors in rats.

Alterations in cortical EEG activity in male rats produced by putative agonists at dopamine (DA) autoreceptors and by antagonists at postsynaptic DA receptors were compared in order to study, whether an impairment in dopaminergic neurotransmission via two different mechanisms might result in similar or different effects. Simultaneously to the EEG recordings, gross behaviour was observed. Putative agonists at DA autoreceptors (apomorphine 0.05 mg/kg, quinpirole 0.05 mg/kg, or talipexole 0.02 mg/kg s.c.) produced increases in the power in all of the frequency bands, except beta-2, with the most pronounced increase in the delta band. These EEG alterations were accompanied by hypokinesia, ptosis and yawning. In contrast, antagonists at DA receptors (haloperidol 0.1 mg/kg i.p., D2 blocker) or SCH 23390 (0.2 mg/kg i.p., D1 blocker) led to little increases in the delta band, but more pronounced increases in the alpha-2 band. Behavioural signs were hypokinesia, but little ptosis and yawning. The combination of both blockers produced, in addition, strong increases in the delta band and behavioural signs of ptosis and yawning. These results suggest that activation of putative dopamine autoreceptors produces EEG patterns and behavioural patterns different from those produced by blockade of either D1 or D2 postsynaptic dopamine receptors. In contrast, the effects following a stimulation of putative DA autoreceptors, which are expected to decrease the release of the agonist and its action at postsynaptic D1 and D2 receptors, were very similar to those found after a combined blockade of both types of postsynaptic dopamine receptors.

Animals↗

PubMed1999

A dopamine D1 agonist elevates self-stimulation thresholds: comparison to other dopamine-selective drugs.

The effects of the high-efficacy D1 receptor agonist SKF 81297 and the D2/3 receptor agonist 7-OH-DPAT on brain stimulation reward thresholds and on response latencies in responding for the stimulation, were compared to the effects of subtype-selective receptor antagonists and a dopamine uptake blocker. SKF 81297 produced dose-dependent elevations in reward thresholds but did not alter response latencies. In contrast, 7-OH-DPAT produced inconsistent reward threshold elevations, yet dose dependently increased response latencies. Both the dopamine D1 receptor antagonist SCH 23390 and the D2 antagonist raclopride elevated reward thresholds, but only raclopride significantly increased response latencies. The dopamine uptake inhibitor GBR 12909 lowered reward thresholds and did not influence response latencies. The present results provide a clear demonstration that a selective, high-efficacy D1 receptor agonist elevates brain stimulation reward thresholds without producing performance deficits. Furthermore, it was observed that the effects upon reward measures of D1-selective compounds, but not D2/D3-selective compounds, are dissociable from their effects upon response latency in this task. These results are discussed with regard to a distinction between the effects of indirect and direct dopamine agonists on reward thresholds, a distinction that does not depend upon the subtype-selectivity of the direct agonists tested.

Animals↗

PubMed1990

Dopamine-1 and dopamine-2 mechanisms in the control of renal function.

Dopamine (DA), a catecholamine produced in the kidney, is a renal vasodilator and natriuretic substance, but its action at dopamine-1 (DA-1), dopamine-2 (DA-2) and alpha- and beta-adrenergic receptors limits its effectiveness as a heuristic tool and pharmacologic agent. We have studied the effects of highly selective DA-1 and DA-2 receptor agonists and antagonists in normal human subjects and experimental animals to determine the precise physiological role of renal dopamine at DA-1 and DA-2 receptors within the kidney. We studied fenoldopam, a selective DA-1 agonist, in normal human subjects in metabolic balances at high (300 mEq/day) and low (10 mEq/day) sodium (Na) intake. Selective DA-1 receptor stimulation during high Na intake resulted in renal vasodilation, natriuresis and diuresis in a sustained manner for 3 hours. The natriuresis was mediated by a reduction in Na reabsorption at both proximal and distal tubular sites. In contrast, during low Na intake, DA-1 receptor stimulation did not engender a natriuretic or diuretic response. Thus, sodium depletion may inhibit the function of renal tubular cells in response to DA-1 stimulation. DA-1 receptors are present in the medial layer of the renal vasculature, proximal tubule and cortical collecting duct; DA-2 receptors are localized to the glomerulus, the renal nerves surrounding renal blood vessels and possibly the renal vascular endothelium. We have performed studies in conscious dogs with indwelling renal arterial catheters to identify the physiological role of renal DA to DA-1 and DA-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMedDate not supplied

Analysis of the effects of dopamine-1 and dopamine-2 receptor agonists on coronary flow.

The coronary flow (CF) at constant perfusion pressure and other hemodynamic variables were measured in anesthetized open-chest dogs. At the same doses of 20, 100, 500 and 2000 nM, the dopamine-1 receptor agonist, fenoldopam, was much more potent than dopamine-2 receptor agonist, N-n-propyl-N-n-butyl dopamine (PBDA), in increasing CF. Under conditions of constant systemic arterial pressure, fenoldopam produced a dose-related increase in maximal +dp/dt (dp/dt) and CF. After adrenergic blockade (combined alpha- and beta-adrenoceptor blockade), however, both cardiac and coronary effects of fenoldopam were greatly attenuated. The coronary effects of both dopamine agonists under uncontrolled arterial pressure were apparently greater than those under constant arterial pressure. Under conditions of uncontrolled arterial pressure and after adrenergic blockade, fenoldopam induced a dose-related decrease in mean arterial pressure (MAP) and corresponding increase in CF. SCH23390 and domperidone markedly inhibited the coronary effects of fenoldopam and PBDA, respectively. Our data suggest that the coronary effects of fenoldopam are predominantly secondary to the fenoldopam-induced decrease in total peripheral resistance (TPR) at small doses and to its positive inotropic action at large doses, while the primary dopaminergic coronary vasodilation plays only a minor role and therefore cannot be of physiological importance in regulating CF.

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

PubMed1987

Opposing actions of D-1 and D-2 dopamine receptor-mediated alterations of adenosine-3',5'-cyclic monophosphate (cyclic AMP) formation during the amphetamine-induced release of endogenous dopamine in vitro.

Changes in the formation of cyclic AMP following d-amphetamine (0.1 to 20 mumol/l) were examined in vitro in striatal slices of the rat. d-Amphetamine caused a dose-related increase in cyclic AMP content. This action of d-amphetamine was abolished by tissue pretreatment with reserpine (2.5 mg/kg, i.p.) and 3-iodotyrosine (1 mmol/l). By contrast, both clorgyline (0.1 mumol/l) and nomifensine (30 mumol/l) enhanced the d-amphetamine-induced increase in cyclic AMP formation. In superfusion experiments, a strong correlation between endogenous dopamine and cyclic AMP release was observed before, during and after d-amphetamine exposure. Finally, Sch 23390 (10 mumol/l) abolished while (-)sulpiride (10 mumol/l) enhanced the amphetamine-induced increase in cyclic AMP content. These results suggest that d-amphetamine enhances the formation of cyclic AMP through the release of endogenous dopamine into the synapse where it can interact with both D-1 and D-2 dopamine receptors. These results provide direct evidence that the antagonistic properties of D-1 and D-2 receptors on cyclic AMP formation are apparent at striatal synapses during release of endogenous neuronal dopamine.

Animals↗

PubMed1992

Dynorphin A(1-13) preferentially inhibits behaviors induced by the D2 dopamine agonist RU 24213 but not by the D1 dopamine agonist SK&F 38393.

The effects of dynorphin A(1-13) on the D1 dopamine agonist SK&F 38393- and the D2 dopamine agonist RU 24213-induced behavioral alterations in the mouse were determined by using multidimensional behavioral analyses based upon a capacitance system. Although dynorphin A(1-13) (3.0 or 12.5 micrograms) alone did not produce any significant effects on behaviors, the peptide (12.5 micrograms) caused an inhibitory effect on the RU 24213 (3.0 mg/kg)-induced increase in behavioral patterns such as linear locomotion and circling except rearing and grooming behaviors. The antagonistic effects of dynorphin A(1-313) (12.5 micrograms) were fully reversed by the opioid antagonist M(r) 2266 (10.0 mg/kg). However, dynorphin A(1-13) (3.0 or 12.5 micrograms) failed to affect behaviors elicited by SK&F 38393 (10.0 mg/kg). These results suggest that dynorphin A(1-13) plays an inhibitory role in behaviors induced by the D2 dopamine agonist but not by the D1 dopamine agonist, possibly through the mediation of kappa-opioid receptors.

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

PubMed1999

Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine.

Dopamine D(3) receptors are structurally highly homologous to other D(2)-like dopamine receptors, but differ from them pharmacologically. D(3) receptors are notably resistant to alkylation by 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which readily alkylates D(2) receptors. We compared EEDQ with N-(p-isothiocyanatophenethyl)spiperone (NIPS), a selective D(2)-like receptor alkylating agent, for effects on D(3) and D(2) receptors in rat brain using autoradiographic analysis. Neither agent occluded D(3) receptors in vivo at doses that produced substantial blockade of D(2) receptors, even after catecholamine-depleting pretreatments. In vitro, however, D(3) receptors were readily alkylated by both NIPS (IC(50)=40 nM) and EEDQ (IC(50)=12 microM). These effects on D(3) sites were blocked by nM concentrations of dopamine, whereas microM concentrations were required to protect D(2) receptors from the alkylating agents. The findings are consistent with the view that alkylation of D(3) receptors in vivo is prevented by its high affinity for even minor concentrations of endogenous dopamine.

Alkylating Agents↗

PubMed1998

Anxiolytic effects of dopamine receptor ligands: I. Involvement of dopamine autoreceptors.

The anxiolytic-like properties of dopamine agonists and antagonists with different receptor profiles were investigated in the ultrasonic vocalization test in rats after subcutaneous administration. Only dopamine D2 receptor agonists inhibited ultrasonic vocalization with the following ED50 values: apomorphine (0.07 mg/kg), quinelorane (0.01 mg/kg), quinpirole (0.04 mg/kg), pramipexole (0.09 mg/kg), roxindole (0.04 mg/kg), talipexole (0.04 mg/kg), (+/-)-7-OH-DPAT (0.05 mg/kg), (+/-)-PPHT (0.03 mg/kg), (-)-TNPA (0.06 mg/kg), PD128907 (0.13 mg/kg). The D2 antagonists haloperidol, mazapertine, raclopride, remoxipride, L745870, U99194A, U101958 and S(-)-DS121, the partial agonists PD143188 and preclamol, the selective D1 agonist R(+)-SKF38393 and the D1 antagonist SCH23390, and the uptake inhibitors GBR12909, GBR12935 and indatraline lacked significant inhibitory effects on ultrasonic vocalization. Because at least some of the D2 receptor agonists investigated have selectivity for dopamine autoreceptors, it is speculated that the dopamine autoreceptor may be a target for the development of new antianxiety drugs.

Animals↗

PubMedDate not supplied

The effects of dopamine synthesis inhibitors and dopamine antagonists on regeneration in the hydra Hydra attenuata.

The effects of catecholamine synthesis inhibitors (alpha-methyltyrosine, 3-iodotyrosine, and alpha-methyl-DOPA) and dopamine receptor blockers (haloperidol and spiperone) on the regeneration of apical, gastral, and basal fragments of the hydra Hydra attenuata were studied. These experiments showed that alpha-methyltyrosine and 3-iodotyrosine significantly inhibited regeneration but did not produce morphological anomalies. Alpha-Methyl-DOPA produce less inhibition of regeneration, but induced ectopic tentacles and outgrowths in gastral regenerates. Haloperidol and spiperone had no significant effect on the rate of regeneration but induced significant numbers of morphogenetic anomalies in gastral regenerates. Apical and basal regenerates, which retained their natural organizers (the head and base respectively) never yielded morphogenetic anomalies in the presence of either dopamine receptor blockers or dopamine synthesis inhibitors. The possible role of neurotransmitters. particularly dopamine, in morphogenesis in hydras is discussed.

Animals↗

PubMed2000

Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter.

Mice with a genetic disruption of the dopamine transporter (DAT-/-) exhibit locomotor hyperactivity and profound alterations in the homeostasis of the nigrostriatal system, e.g. a dramatic increase in the extracellular dopamine level. Here, we investigated the adaptive changes in dopamine D1, D2 and D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/- mice. We used quantitative in situ hybridization and found that the constitutive hyperdopaminergia results in opposite regulations in the gene expression for the dopamine receptors. In DAT-/- mice, we observed increased mRNA levels encoding the D3 receptor (caudate putamen, +60-85%; nucleus accumbens, +40-107%), and decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, -45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%). Furthermore, we assessed the phenotypical organization of the striatal efferent neurons by using double in situ hybridization. Our results show that in DAT+/+ mice, D1 and D2 receptor mRNAs are segregated in two different main populations corresponding to substance P and preproenkephalin A mRNA-containing neurons, respectively. The phenotype of D1 or D2 mRNA-containing neurons was unchanged in both the caudate putamen and nucleus accumbens of DAT-/- mice. Interestingly, we found an increased density of preproenkephalin A-negative neurons that express the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT-/- mice. Our data further support the critical role for the D3 receptor in the regulation of D1-D2 interactions, an action being restricted to neurons coexpressing D1 and D3 receptors in the nucleus accumbens.

Animals↗

PubMed1998

Dopamine-induced recruitment of dopamine D1 receptors to the plasma membrane.

The recruitment of G protein-coupled receptors from the cytoplasm to the plasma membrane generally is believed to be a constitutive process. We show here by the use of both confocal microscopy and subcellular fractionation that, for at least one such receptor, this recruitment is regulated and not constitutive. Cells from a proximal tubular-like cell line, LLCPK1 cells, were incubated with either a D1 agonist, a dopamine precursor, or an inhibitor of dopamine metabolism to increase dopamine availability in the cell. Each of the three procedures led to a rapid translocation of dopamine D1 receptors from the cytosol to the plasma membrane.

Benzazepines↗

PubMed2000

Dopamine depresses excitatory synaptic transmission onto rat subicular neurons via presynaptic D1-like dopamine receptors.

Schizophrenia is considered to be associated with an abnormal functioning of the hippocampal output. The high clinical potency of antipsychotics that act as antagonists at dopamine (DA) receptors indicate a hyperfunction of the dopaminergic system. The subiculum obtains information from area CA1 and the entorhinal cortex and represents the major output region of the hippocampal complex. To clarify whether an enhanced dopaminergic activity alters the hippocampal output, the effect of DA on alveus- and perforant path-evoked excitatory postsynaptic currents (EPSCs) in subicular neurons was examined using conventional intracellular and whole cell voltage-clamp recordings. Dopamine (100 microM) depressed alveus-elicited (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated EPSCs to 56 +/- 8% of control while perforant path-evoked EPSCs were attenuated to only 76 +/- 7% of control. Dopamine had no effect on the EPSC kinetics. Dopamine reduced the frequency of spontaneous miniature EPSCs without affecting their amplitudes. The sensitivity of subicular neurons to the glutamate receptor agonist (S)-alpha-amino-3-hydoxy-5-methyl-4-isoxazolepropionic acid was unchanged by DA pretreatment, excluding a postsynaptic mechanism for the observed reduction of excitatory synaptic transmission. The effect of DA on evoked EPSCs was mimicked by the D1 receptor agonist SFK 38393 and partially antagonized by the D1 receptor antagonist SCH 23390. While the D2 receptor agonist quinelorane failed to reduce the EPSCs, the D2 receptor antagonist sulpiride did not block the action of DA. The results indicate that DA strongly depresses the hippocampal and the entorhinal excitatory input onto subicular neurons by decreasing the glutamate release following activation of presynaptic D1-like DA receptors.

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

PubMed1997

Dopamine as a novel antimigration and antiproliferative factor of vascular smooth muscle cells through dopamine D1-like receptors.

Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine and specific D1-like agonists SKF 38,393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration and proliferation were studied. We observed that cells stimulated by PDGF-BB (5 ng/mL), showed increased migration and proliferation. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 (1 to 10 mumol/L), and this prevention was reversed by Sch 23,390 (1 to 10 mumol/l), a specific D1-like antagonist. These actions are mimicked by forskolin (1 to 10 mumol/L), a direct activator of adenylate cyclase and 8-bromo-cAMP at 0.1 to 1 mmol/L and are blocked by a specific protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H 89), but not blocked by its negative control, N-[2-(N-formyl)-p-chlorociannamylamino)ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/mL)-mediated activation of phospholipase D, protein kinase C, and mitogen activated protein kinase activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration and proliferation of VSMC, possibly through protein kinase A activation and suppression of activated phospholipase D, protein kinase C, and mitogen-activated protein kinase activity.

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

PubMed2000

Dopamine as a novel antioxidative agent for rat vascular smooth muscle cells through dopamine D(1)-like receptors.

BACKGROUND: To elucidate the roles of vascular D(1)-like receptors in atherosclerosis, the effects of the specific D(1)-like agonists on platelet-derived growth factor (PDGF)-BB-mediated oxidative stress in vascular smooth muscle cells (VSMCs) were studied. METHODS AND RESULTS: Immunohistochemical studies demonstrated the coexistence of D(1A) and D(1B) dopamine receptors in VSMCs. Western blotting revealed a band of approximately 70 kDa for D(1A) and D(1B) dopamine receptors. VSMCs stimulated by PDGF-BB exhibited increased oxidative stress directly measured by flow cytometry. These effects were prevented by dopamine, SKF 38393, or YM 435, and this prevention was reversed by Sch 23390. These effects were blocked by a specific protein kinase A (PKA) inhibitor, N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H 89). The PDGF-BB-mediated increase in oxidative stress of VSMCs was significantly suppressed by the indirect phospholipase D (PLD) inhibitor suramin or the specific protein kinase C (PKC) inhibitor calphostin C. Both antisense but neither sense nor scrambled oligonucleotides to D(1A) and D(1B) receptors inhibited dopamine-induced suppression of increase in oxidative stress of VSMCs induced by PDGF-BB. CONCLUSIONS: These findings suggest that vascular D(1)-like receptors (D(1A) and D(1B) receptors) inhibit any increase in oxidative stress of VSMCs, possibly through activation of PKA and suppression of PLD and PKC.

Animals↗