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PubMed1994

Dopamine D2 and D3 receptor preferring antagonists differentially affect striatal dopamine release and metabolism in conscious rats.

Classical neuroleptic drugs with high affinity for dopamine D2 receptors in comparison to D3 ones (haloperidol, thioproperazine and spiperone) administered i.p. acutely (0.2, 0.2 and 0.07 mg/kg, respectively) induced a pronounced increase in the extracellular level of 3,4-dihydroxyphenylacetic acid (DOPAC) and only a modest rise in that of dopamine in the dorsal striatum of conscious rats studied by transcerebral microdialysis. Atypical neuroleptics, clozapine and thioridazine (both 20 mg/kg), demonstrating relatively higher affinity for dopamine D3 receptor than typical ones, as well as the dopamine D3 receptor and autoreceptor preferring antagonists, cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(di-n- propylamino)tetralin HCl ((+)-UH232) and cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin HCl ((+)-AJ76) (both 14 mg/kg), were equally effective or even more potent in increasing dopamine release than DOPAC. It is concluded that the dopamine D2/D3 receptor relative potencies of typical and atypical neuroleptics appear to correspond to their ability to affect preferentially dopamine metabolism or release in rat dorsal striatum in vivo.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Involvement of dopamine receptors in the anti-immobility effects of dopamine re-uptake inhibitors in the forced swimming test.

The effects of dopamine re-uptake inhibitors, bupropion and nomifensine on immobility in the forced swimming test were studied in mice. Bupropion and nomifensine reduced immobility time dose-dependently. Both drugs significantly displayed anti-immobility effects at doses without altering locomotor activity. Anti-immobility effects of bupropion and nomifensine were inhibited by the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SCH 23390) and the dopamine D2 receptor antagonist sulpiride. These findings suggest that dopamine may be related to depression and dopamine D1 and dopamine D2 receptors play a role in the effects of dopamine re-uptake inhibitors.

Animals↗
PubMed1996

Lineweaver-Burk analysis for the blocking effects of mammalian dopamine receptor antagonists on dopamine-induced currents in Achatina giant neurones.

1. We had demonstrated (Emaduddin et al., 1995) the blocking effects of the three mammalian dopamine receptor antagonists, (+/-)-SKF83566 (mammalian dopamine D1-like receptor antagonist), (+)-UH232 (D2 and D3-like receptor antagonist) and (+/-)-sulpiride (D2-like receptor antagonist) on the dose (pressure duration)-response curves of dopamine in the three giant neurone types, LVMN (left visceral multiple spike neurone), d-RPeAN (dorsal-right pedal anterior neurone) and v-LCDN (ventral-left cerebral distinct neurone), of Achatina fulica Férussac under voltage clamp. In the present study, we analyzed these data by Lineweaver-Burk plot. 2. Dopamine-induced inward currents (Iin) of the two neurone types, LVMN and d-RPeAN, were blocked by (+/-)-SKF83566 and (+)-UH232 in partly noncompetitive and partly uncompetitive manners. (+/-)-Sulpiride had no effect on these currents. 3. In contrast, dopamine-induced outward current (Iout) of v-LCDN was inhibited competitively by (+/-)-sulpiride and noncompetitively by (+)-UH232. (+/-)-SKF83566 had no effect on this current. 4. Therefore, we consider that the pharmacological features of the dopamine receptors of Achatina neurones are not identical in detail to those of the mammalian dopamine receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Endogenous activation of dopamine D2 receptors regulates dopamine release in the fish retina.

In the fish retina, horizontal cell electrical coupling and light responsiveness is regulated by activation of dopamine D1 receptors that are located on the horizontal cells themselves. The effects of dopamine and dopamine D2 receptor agonists and antagonists on cone horizontal cell light responses were studied in in vitro superfused goldfish retinas. Horizontal cell light responses and electrical coupling were assessed by monitoring responses to full-field stimuli and to small, centered (0.4 mm diam) spots of light, respectively. Dopamine (0.2-10 microM) application uncoupled horizontal cells and decreased their responses to full-field stimuli. Application of the D2 antagonist eticlopride (10-50 microM) produced similar effects, whereas quinpirole (0.1-10 microM), a D2 agonist, had the opposite effects. The uncoupling effect of eticlopride was blocked by prior application of SCH23390 (10 microM), a D1 receptor antagonist, and was eliminated after destruction of dopaminergic neurons by prior treatment of the retinas with 6-hydroxydopamine. The effects of these D2 drugs were observed following flickering light stimulation, but were not observed following sustained light stimulation. Application of the D2 antagonists sulpiride (0.5-20 microM) and spiperone (0.25-10 microM) uncoupled horizontal cells when the total concentration of divalent cations (Mg2+ and Ca2+) in the Ringer solution was 1.1 mM. However, when the concentration of divalent cations was 0.2 mM, spiperone had no effect on the horizontal cells and sulpiride increased coupling. In contrast, eticlopride uncoupled the cells and decreased their light responsiveness irrespective of the concentration of divalent cations. The effects of quinpirole also depended on the concentration of divalent cations; its coupling effect was reduced when the divalent cation concentration was increased from 0.2 to 1.0 mM. The results suggest that activation of D2 receptors in the fish retina by endogenous dopamine decreases dopamine release and is greater after flickering compared with sustained light stimulation. These D2 receptors thus function as presynaptic autoreceptors that inhibit dopamine release from dopaminergic cells. In addition, the results also indicate that the effectiveness of some D2 drugs at these receptors is dependent on the concentration of divalent cations.

Animals↗
PubMed1987

Dopamine receptors and the dopamine hypothesis of schizophrenia.

The discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked "monoamine receptors" or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)-butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]-dopamine or [3H]-haloperidol. These binding sites, now termed D2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D1 receptors (which stimulate adenylate cyclase). Based on the fact that dopamine-mimetic drugs elicited hallucinations, and that neuroleptics caused rigidity, Van Rossum in 1966 had suggested a hypothesis that dopamine pathways may be overactive in schizophrenia. The D2-selective blockade by all neuroleptics (except the monoamine-depleting reserpine) provided strong support for the dopamine hypothesis. Further support now comes from postmortem data and in vivo positron tomographic data, both of which indicate that the density of D2 receptors are elevated in the schizophrenic brain. The postmortem data indicate a bimodal pattern with half the schizophrenics having striatal D2 densities of 14 pmol/g (control is 13 pmol/g) and the other half having 26 pmol/g. Current positron tomographic data indicate D2 densities of 14 pmol/g in control subjects, but values of 34 pmol/g in drug-naive schizophrenics. Future tests of the dopamine hypothesis of schizophrenia may entail an examination of the amino acid composition and genes for D2 receptors in schizophrenic tissue, an examination of the ability of the D2 receptor to become phosphorylated and to desensitize into the low-affinity state, and an examination of the interaction of D2 receptors with D1 receptors or other neurotransmitters.

Antipsychotic Agents↗
PubMed1985

Is inhibition of striatal synaptosomal tyrosine hydroxylation by dopamine agonists a measure of dopamine autoreceptor function?

Rat striatal synaptosomal tyrosine hydroxylation was inhibited dose- and pH dependently by a number of dopamine agonists. The catecholic agonists apomorphine and (-)N-n-propylnorapomorphine inhibited synaptosomal tyrosine hydroxylase completely, with IC50 values of around 0.3 mumol/l at pH 6.6. The noncatechol agonists pergolide and bromocriptine and the putative dopamine autoreceptor agonists 3-PPP(-), 3-PPP(+), HW-165 and B-HT 920 produced only partial inhibition of synaptosomal tyrosine hydroxylation at high concentrations. Comparison of the inhibition of synaptosomal and soluble tyrosine hydroxylase indicated that the inhibition produced by apomorphine could be ascribed to a direct effect on the enzyme, whereas this was not the case for the noncatechol agonists. The inhibition produced by pergolide and 3-PPP(-) was not antagonised by either dopamine receptor or alpha-adrenoceptor antagonists. The present results have been compared with results reported in the literature for inhibition of synaptosomal tyrosine hydroxylation and for two other tests of dopamine autoreceptor agonist activity (inhibition of dopamine release from striatal slices in vitro, and inhibition of the gamma-butyrolactone induced increase in dopamine synthesis in vivo). It is concluded that inhibition of striatal synaptosomal tyrosine hydroxylation by dopamine agonists does not fulfil the criteria required for it to be considered as a useful measure of dopamine autoreceptor function.

Adrenergic alpha-Agonists↗
PubMed1997

Chronic administration of the selective dopamine uptake inhibitor GBR 12,909, but not cocaine, produces marked decreases in dopamine transporter density.

The chronic continuous infusion of cocaine produces partial behavioral tolerance to cocaine and tolerance to the inhibition of dopamine uptake by cocaine, without changing dopamine transporter binding. In order to examine more closely the dopaminergic contribution to this effect, the selective dopamine uptake inhibitor GBR 12,909 (30 mg/kg/day), cocaine (50 mg/kg/day), or vehicle, were continuously infused via osmotic minipump, and their effects on the dopamine transporter examined. Drug and vehicle pumps were implanted into male Sprague-Dawley rats and removed after seven days. [3H]WIN 35,428 binding and [3H]dopamine uptake were measured in caudate putamen and nucleus accumbens at varying intervals after pump removal. The Bmax for [3H]WIN 35,428 binding was decreased by approximately 75% in the caudate putamen and by 40% in the nucleus accumbens of GBR 12,909-treated rats both 1 and 4 days after pump removal, and was still significantly decreased after 10 days, but had returned to normal by 20 days post-treatment. In contrast, cocaine did not significantly alter [3H]WIN 35,428 binding. GBR 12,909 produced both tolerance to the inhibition of [3H]dopamine uptake by cocaine, and a decrease in total uptake of dopamine, in the caudate putamen, with no change in the nucleus accumbens. The persistent reduction of [3H]WIN 35,428 binding following continuous GBR 12,909 does not appear to result from residual drug binding. These findings suggest that GBR 12,909 and cocaine may bind to and regulate the dopamine transporter in different ways.

Animals↗
PubMed1977

Characteristics of dopamine and beta-adrenergic sensitive adenylate cyclases in the frontal cerebral cortex of the rat. Comparative effects of neuroleptics on frontal cortex and striatal dopamine sensitive adenylate cyclases.

Homogenates of frontal cerebral cortex of the rat were prepared from microdiscs punched out in areas rich in dopaminergic terminals. Under optimal assay conditions, dopamine (10-4 M) stimulated an adenylate cyclase present in these homogenates by 80-100%. This stimulation reached 200% when microdiscs were punched out from the medial part of the frontal cerebral cortex, adjacent to the forceps minor. Dopamine interacted with an homogeneous population of receptor sites which had an apparent affinity (KD) of 3.8 +/- 0.9 x 10-6 M (N = 4). The dopamine receptor was blocked by fluphenazine and phentolamine but had no affinity for pindolol, propranolol or L-isoproterenol. The affinities of several neuroleptics having different chemical structures were simultaneously determined on striatal and on frontal cerebral cortex dopamine sensitive adenylate cyclases. Fluphenazine was more potent in blocking the striatal than the frontal cerebral cortex dopaminergic receptors. In contrast, in all experiments, haloperidol had an higher affinity for the cerebral frontal cortex than for the striatal dopaminergic receptors. Thus, haloperidol was less effective than fluphenazine in blocking the striatal dopaminergic receptors, and equally potent than fluphenazine in inhibiting the frontal cerebral cortex dopamine sensitive adenylate cyclase. Chlorpromazine, thioridazine and clozapine had the same affinity for the two dopaminergic adenylate cyclase systems. L-isoproterenol interacted with an homogeneous population of beta-adrenergic receptor sites (KD = 3 +/- 2 X 10-7 M; N = 4) coupled with an adenylate cyclase distince from the dopamine sensitive adenylate cyclase. This beta-receptor had no affinity for dopamine or fluphenazine but was blocked by propranolol or pindolol. L-Norepinephrine was shown to stimulate both the dopamine (KD = 1.8 +/- 1 X 10-5 M; N = 4) and the beta-adrenergic (KD = 8 +/- 3 X 10-7 M; N = 4) sensitive adenylate cyclases. Thus, the L-norepinephrine effect was totally blocked in the combined presence of fluphenazine and pindolol.

Adenylyl Cyclases↗
PubMed1992

Triazolam blocks the initial rotational effects of quinpirole but permits the later developing reduction of dopamine D2-mediated rotational behavior and dopamine D2 receptors.

Continuous infusion of the dopamine D2 receptor agonist quinpirole into mice with unilateral striatal 6-hydroxydopamine lesions initially produces a supersensitive rotational behavior. This is followed by reductions of dopamine D2-mediated behavior and dopamine D2 receptors. In this study we attempted to determine if it is possible to inhibit the acute increase in D2-mediated behavior while still allowing the reduction of D2-mediated behavioral responses and dopamine D2 receptors to occur. Mice were implanted with Alzet minipumps containing either quinpirole alone or quinpirole combined with the GABA receptor modulator triazolam or the dopamine D2 receptor antagonist sulpiride, and rotational behavior was monitored for the 6 days of infusion. The pumps were then removed, and D2 receptors in striatal membranes were determined. Triazolam completely blocked the initial rotational behavior normally induced by implanting quinpirole. However, the quinpirole-induced reduction of D2-mediated behavioral responses and D2 receptors still occurred. Continuous infusion of sulpiride also inhibited the rotational behavior produced by quinpirole, but it prevented the reduction of dopamine D2 receptors. We conclude that up-regulated dopamine receptors and dopaminergic behaviors can be reversed by the continuous administration of a dopamine receptor agonist and that this reversal can occur without producing an initial exacerbation of dopaminergic responses. These results suggest that this type of treatment regimen might be useful for treating clinical conditions associated with dopaminergic supersensitivity.

Analysis of Variance↗
PubMed1995

Effects of various dopamine uptake inhibitors on striatal extracellular dopamine levels and behaviours in rats.

In vivo central effects of some dopamine uptake inhibitors were evaluated in both brain microdialysis and behavioural studies in rats, and compared with their in vitro affinities to dopamine uptake sites. IC50 values of GBR12909 (1-[2- bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperazine), diclofensine, mazindol, amfonelic acid and nomifensine for inhibiting 1 nM [3H]GBR12935 (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) binding to rat striatal membrane were 7.0, 36, 81, 187 and 290 nM, respectively. In the brain microdialysis study, dopamine levels in the striatal dialysates were increased to 16.3- (GBR12909), 14.1- (nomifensine), 4.8- (diclofensine) and 1.9-fold (amfonelic acid) the respective basal levels 40-60 min after i.p. administration (0.1 mmol/kg) and thereafter decreased slowly but remained at the elevated levels for a further 3 h, while mazindol gradually increased dopamine levels though less pronouncedly than others (1.7-fold 200 min after administration). Remarkable and comparable stereotyped behaviours (licking and forepaw treading) were continuously observed at least for 3 h after administration of GBR12909, nomifensine and amfonelic acid, while stereotypies induced by diclofensine and mazindol were moderate and marginal, respectively. In vivo potencies of dopamine uptake inhibitors to increase the extracellular dopamine levels in the striatum tended to correlate with their in vitro affinities to dopamine uptake sites except in the case of nomifensine, and correlated significantly with their potencies to induce stereotyped behaviours except in the case of amfonelic acid. Based on these findings, pharmacological characteristics of these dopamine uptake inhibitors are discussed.

Animals↗
PubMed1982

Are presynaptic dopamine autoreceptors and postsynaptic dopamine receptors in the rabbit caudate nucleus pharmacologically different?

Slices of the rabbit caudate nucleus were preincubated with [3H]dopamine or [3H]choline and then superfused and stimulated electrically. Apomorphine reduced the stimulation-evoked overflow of tritium over the same concentration range, independently of whether slices had been pre-incubated with [3H]dopamine or with [3H]choline. Each of three antagonists--molindone, sulpiride and metoclopramide--increased the evoked overflow of tritium over the same concentration range in experiments with [3H]dopamine and those with [3H]choline. For each antagonist, the pA2 values against apomorphine obtained in [3H]dopamine experiments and in [3H]choline experiments were very similar. This study is a functional in vitro approach to receptor characterization, as opposed to radioligand binding studies or in vivo investigations. The results show that the dopamine receptor agonist apomorphine and three antagonists are unable to distinguish between the presynaptic, release-inhibiting dopamine autoreceptors and those postsynaptic dopamine receptors which, when activated, depress the release of acetylcholine. Although there are certainly more dopamine receptors in the caudate nucleus, these two physiologically important groups seem to be closely related.

Acetylcholine↗
PubMed1988

Effects of dopamine on left ventricular afterload and contractile state in heart failure: relation to the activation of beta 1-adrenoceptors and dopamine receptors.

Although long-term therapy with oral beta-adrenoceptor agonists in patients with heart failure is generally associated with the development of diminished pharmacologic efficacy, the ingestion of levodopa, which is decarboxylated endogenously to dopamine, is associated with a sustained improvement in cardiac function. The beneficial hemodynamic actions of dopamine in patients with heart failure have been attributed to a positive inotropic effect that is mediated through activation of beta 1-adrenoceptors. However, a reduction in left ventricular afterload resulting from the activation of dopamine receptors may also lead to an improvement in the performance of the failing heart. To ascertain the relative importance of the positive inotropic and afterload-reducing effects of dopamine in patients with heart failure, dopamine (2, 4, 6 micrograms/kg per min), dobutamine (2, 6, 10 micrograms/kg per min) and nitroprusside (0.125 to 2.0 micrograms/kg per min) were administered to 13 patients with dilated cardiomyopathy while monitoring left ventricular wall thickness and dimensions by echocardiography and left ventricular and aortic pressures with a micromanometer-tipped catheter. Altering left ventricular afterload, quantified as end-systolic circumferential wall stress, with nitroprusside allowed generation of the left ventricular end-systolic circumferential wall stress-velocity of fiber shortening relation that represented the baseline contractile state of the myocardium. Left ventricular velocity of fiber shortening was elevated during the administration of dobutamine and dopamine when compared with measurements obtained with nitroprusside at the same left ventricular end-systolic circumferential wall stress. Furthermore, left ventricular end-systolic wall stress decreased with dopamine but not with dobutamine. Thus, the beta 1-adrenoceptor activity of dopamine and dobutamine augmented the contractile state of the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover.

BACKGROUND: Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors closely associated with dopamine neurotransmission in the central nervous system. Nur77 expression is strongly modulated by antipsychotic and ant-parkinsonian drugs in dopaminoceptive brain areas. However, the role of Nur77 in dopamine neuron activity and turnover remains elusive. METHODS: We compared various behavioral and biochemical parameters between Nur77 knockout -/- and wild-type +/+ mice in basal and haloperidol-challenged conditions. RESULTS: We report here that Nur77-deficient mice display enhanced spontaneous locomotor activity, greater sensitivity to a small dose of the dopamine D2 receptor agonist quinpirole acting mainly at autoreceptor sites, and higher levels of the dopamine metabolite DOPAC relative to wild-type mice. Dopamine turnover disturbances are also found after acute challenge with haloperidol, a dopamine D2 receptor antagonist. These alterations are associated with increased tyrosine hydroxylase expression and activity, and reduced catechol-O-methyltransferase expression. CONCLUSION: Taken together, these results are consistent with the involvement of Nur77 in dopamine neuron biochemical activity and dopamine turnover.

Analysis of Variance↗
PubMed1972

Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain, and its similarity to the "dopamine receptor".

An adenylate cyclase that is activated specifically by low concentrations of dopamine has been demonstrated in homogenates of caudate nucleus of rat brain. A half-maximal increase in the activity of the enzyme occurred in the presence of 4 muM dopamine. Concentrations of dopamine as low as 0.3 muM stimulated the activity of the enzyme. The adenylate cyclase activity of the homogenates was also stimulated by low concentrations of apomorphine, a substance known to mimic the physiological and pharmacological effects of dopamine. The stimulatory effect of dopamine was blocked by low concentrations of either haloperidol or chlorpromazine, agents known to block the actions of dopamine in mammalian brain. The results suggest that dopamine-sensitive adenylate cyclase may be the receptor for dopamine in mammalian brain. The isolation of this enzyme from caudate nucleus should facilitate the search for new therapeutic agents useful in the treatment of extrapyramidal diseases.

Adenylyl Cyclases↗
PubMed2004

Parkin increases dopamine uptake by enhancing the cell surface expression of dopamine transporter.

Mutations of parkin, a protein-ubiquitin E3 ligase, are linked to Parkinson's disease (PD). Although a variety of parkin substrates have been identified, none of these is selectively expressed in dopaminergic neurons, whose degeneration plays a critical role in PD. Here we show that parkin significantly increased dopamine uptake in the human dopaminergic neuroblastoma cell line SH-SY5Y. This effect was accompanied by increased V(max) of dopamine uptake and unchanged K(m). Consistent with this, increased binding sites for dopamine transporter (DAT) ligand were observed in SH-SY5Y cells overexpressing parkin. The results were confirmed when parkin was transfected in HEK293 cells stably expressing DAT. In these cells, parkin enhanced the ubiquitination and degradation of DAT, increased its cell surface expression, and augmented dopamine uptake. The effects of parkin were significantly abrogated by its PD-causing mutations. Because the cell surface expression of functional DAT requires its oligomerization, misfolded DAT, induced either by the protein glycosylation inhibitor tunicamycin or by its C-terminal truncation, significantly attenuated cell surface expression of native DAT and reduced dopamine uptake. Expression of parkin, but not its T240R mutant, significantly alleviated these detrimental effects of misfolded DAT. Thus, our studies suggest that parkin increases dopamine uptake by enhancing the ubiquitination and degradation of misfolded DAT, so as to prevent it from interfering with the oligomerization and cell surface expression of native DAT. This function of parkin would enhance the precision of dopaminergic transmission, increase the efficiency of dopamine utilization, and reduce dopamine toxicity on neighboring cells.

Animals↗
PubMed2000

Propofol decreases stimulated dopamine release in the rat nucleus accumbens by a mechanism independent of dopamine D2, GABAA and NMDA receptors.

Although propofol (2,6-di-isopropylphenol) is a popular i.v. general anaesthetic, it has been suggested to have abuse potential. As many drugs of abuse act preferentially via release of dopamine in the limbic system, we investigated the action of propofol on stimulated dopamine release in the rat nucleus accumbens. Nucleus accumbens slices were superfused (1.6 ml min-1) with artificial cerebrospinal fluid at 32 degrees C. Dopamine release was evoked by electrical stimulation (10 pulses, 0.1 ms, 10 mA, 10 Hz, every 10 min) and monitored by fast cyclic voltammetry. Propofol 100 mumol litre-1 reduced stimulated dopamine release over the 2 h after administration, relative to intralipid controls, to mean 30 (SEM 2)% (P < 0.01). The dopamine D2 receptor antagonist metoclopramide 0.3 mumol litre-1 increased dopamine release but did not block the effect of propofol (38 (3)%). The selective GABAA antagonist bicuculline 24 mumol litre-1 also failed to antagonize the action of propofol (45 (3)%). The NMDA receptor antagonist dextromethorphan 10 mumol litre-1 decreased dopamine release to 57 (6)% (P < 0.01) but failed to block the inhibitory effect of propofol (46 (6)%). Although propofol has been reported to bind to D2, GABAA and NMDA receptors, failure of metoclopramide and bicuculline to block its effects suggests that an agonist action at D2 or GABAA receptors does not mediate the effects of propofol on dopamine release in the rat nucleus accumbens. The lack of effect of dextromethorphan makes an NMDA receptor antagonist action unlikely.

Anesthetics, Intravenous↗
PubMed1988

Actions of dopamine antagonists on stimulated striatal and limbic dopamine release: an in vivo voltammetric study.

1. Fast cyclic voltammetry at carbon fibre microelectrodes was used to study the effects of several dopamine antagonists upon stimulated dopamine release in the rat striatum and nucleus accumbens. 2. In both nuclei, stimulated dopamine release was increased by D2-receptor-selective and mixed D1/D2-receptor antagonists. The D1-selective antagonist SCH 23390 had no effect. 3. Striatal and limbic dopamine release were elevated by cis- but not trans-flupenthixol. 4. The 'atypical' neuroleptics (clozapine and thioridazine) did not cause a selective elevation of dopamine release in the limbic terminal region, whereas the non-antipsychotic drug metoclopramide increased dopamine release more in striatum than nucleus accumbens. 5. We conclude from this study that striatal and limbic dopamine release are under the control of a stereoselective dopamine D2-autoreceptor on the nerve terminal and that atypical neuroleptics do not show a limbic-selective effect at this receptor after acute administration.

Animals↗
PubMed1991

Differential effects of dopamine agonists upon stimulated limbic and striatal dopamine release: in vivo voltammetric data.

1. Fast cyclic voltammetry at carbon fibre microelectrodes was used in rats anaesthetized with chloral hydrate to monitor dopamine release in the caudate and nucleus accumbens evoked by electrical stimulation of the median forebrain bundle. Stimulation trains (50 Hz sinusoidal current, 100 +/- 10 microA r.m.s., 2s duration) were repeated every 5 min throughout the experiment. 2. The actions of the dopamine agonists quinpirole, pergolide, SKF 38393, bromocriptine, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3PPP) and (-)-3PPP were compared in the two nuclei. 3. Bromocriptine (10 mg kg-1, i.p.) did not affect release in either nucleus while SKF 38393 caused a fleeting decrease in limbic but not striatal dopamine release at a high dose (20 mg kg-1, i.p.). 4. Quinpirole and pergolide (both 1 mg kg-1, i.p.) decreased stimulated dopamine release in the nucleus accumbens while in the caudate the drugs each caused a transient, though not quite significant, elevation of stimulated dopamine release followed by decrease in release of the same magnitude as that seen in the nucleus accumbens. 5. The (-)-enantiomer of 3PPP (20 mg kg-1, i.p.), a partial agonist at the dopamine autoreceptor, increased stimulated dopamine release in both nuclei although the action in the caudate was larger and more prolonged. (+)-3PPP (20 mg kg-1, i.p.), a full agonist, decreased release in the nucleus accumbens. A small, transient and not significant increase in the caudate was followed by decreased release. 6. The results are interpreted as being evidence for differences in the dopamine autoreceptor in the two nuclei, possibly in the affinity state of the receptor in each nucleus.

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