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PubMed1984

The metabolism of dopamine, NN-dialkylated dopamines and derivatives of the dopamine agonist 2-amino-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) by catechol-O-methyltransferase.

A variety of dopamine derivatives and analogues were investigated to assess their potential to act as catechol-O-methyltransferase (COMT) substrates using purified, homogeneous pig liver enzyme. This enabled accurate kinetic constants to be determined as opposed to previous in-vivo studies (Rollema et al 1980; Horn et al 1981; Costall et al 1982; Feenstra et al 1983). 2-Amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN) proved to be a far better substrate (Km = 0.082 mM; Vmax = 300 mu mg-1 protein) than its 5,6-dihydroxy isomer (Km = 2.60 mM; Vmax = 113.9 mu mg-1 protein). This result supports evidence suggesting that differences in brain concentration of these isomers are due to their differential susceptibility to O-methylation by COMT (Rollema et al 1980). A similar result was obtained with a series of NN-di-n-alkyl substituted ADTN derivatives: the same pattern of preferential O-methylation of A-6,7-DTN derivatives over the corresponding A-5,6-DTN isomers was observed. However, increasing the length of the alkyl chain increased the susceptibility of both isomers to metabolism by COMT as shown by a decline in Km. An homologous series of NN-di-n-alkylated dopamines showed a similar trend implying that more hydrophobic compounds are better COMT substrates.

Adenosine Deaminase↗

PubMed1989

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems.

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.

Animals↗

PubMed1991

Differential response of striatal dopamine and muscarinic cholinergic receptor subtypes to the loss of dopamine. I. Effects of intranigral or intracerebroventricular 6-hydroxydopamine lesions of the mesostriatal dopamine system.

Quantitative autoradiography was utilized to examine the response of the dopamine (DA) and muscarinic cholinergic system within the striatum to lesions of the mesostriatal DA system following intranigral 6-hydroxydopamine (6-OHDA) injections. In addition, the response of DA system was examined in the striatum of animals treated with low, medium, or high doses of 6-OHDA made intracerebroventricularly (icv). Three weeks following removal of the mesostriatal DA fibers with intranigral 6-OHDA, there was an almost complete depletion of DA and [3H]mazindol binding throughout the striatum. The resulting increase in D2 receptors labeled with [3H]spiroperidol (27%) was most evident in the lateral striatum and topographically correlated with an increase in choline uptake sites labeled with [3H]hemicholinium-3 (20%). There was a smaller but significant decrease in D1 receptors labeled with [3H]SCH 23390 (15-18%) that was not topographically related to changes in [3H]spiroperidol or [3H]hemicholinium-3 binding. All doses of icv 6-OHDA produced a significant loss of DA and of [3H]mazindol binding as compared to vehicle injections that was more pronounced in the medial than in the lateral striatum. No increase in D1 receptors was observed with any dose of 6-OHDA and greater than 90% loss of DA and [3H]mazindol resulted in an increase in D2 receptors in the lateral striatum and a reduction in D1 receptors in the dorsal striatum. These data are consistent with the evidence that there is independent regulation of the two subtypes of the DA receptor. Moreover, the distribution and regulation of the subtypes of the muscarinic receptor were independent. Muscarinic M2 receptors ([3H]N-methylscopolamine in presence of excess pirenzepine) showed a lateral to medial gradient (highest laterally) that was related to the pattern of choline uptake sites and D2 receptors. Loss of DA resulted in a reduction in M2 receptors (24-30%) that was correlated with the increase in choline uptake sites. In contrast, M1 ([3H]pirenzepine) receptors showed a reverse gradient from the M2 receptor and a smaller reduction following loss of DA.

Animals↗

PubMed1993

Methamphetamine-induced dopamine overflow and injury to striatal dopamine terminals: attenuation by dopamine D1 or D2 antagonists.

Pharmacological blockade of either D1 or D2 dopamine (DA) receptors prevents damage of striatal DA terminals by repeated doses of methamphetamine (m-AMPH). Because the substantial DA overflow produced by multiple m-AMPH treatments appears to contribute to the subsequent injury, we have investigated the effects of blockade of D1 or D2 receptors on m-AMPH-induced DA efflux using in vivo microdialysis. Four treatments with m-AMPH (4 mg/kg, s.c., 2-h intervals) produced large increases in striatal DA overflow, with particularly marked overflow (10 times the basal values) following the fourth injection. Administered by themselves, four injections of the D1 antagonist SCH 23390 or the D2 antagonist eticlopride (0.5 mg/kg, i.p., 2-h intervals) significantly increased striatal DA overflow. However, treatment with either SCH 23390 or eticlopride 15 min before each of four m-AMPH injections attenuated the marked DA peak otherwise seen after the fourth m-AMPH injection. These effects on DA overflow were related to subsequent DA depletions. Although our m-AMPH regimen produced a 54% reduction in striatal DA tissue content 1 week later, pretreatments with either the D1 or the D2 antagonist completely prevented subsequent DA content depletions. Furthermore, the DA content of striatal tissue remaining 1 week after m-AMPH treatment was significantly correlated with the magnitude of the cumulative DA overflow during the m-AMPH treatment (r = -0.69). Thus, the extensive DA overflow seen during neurotoxic regimens of m-AMPH appears critical to the subsequent neurotoxicity, and the neuroprotective action of DA receptor antagonists seems to result from their attenuation of stimulant-induced DA overflow.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Glutamatergic antagonists attenuate ability of dopamine uptake blockers to increase extracellular levels of dopamine: implications for tonic influence of glutamate on dopamine release.

Previous in vivo studies reporting a dose-dependent increase in extracellular dopamine (DA) levels by excitatory amino acid (EAA) antagonists have been interpreted to indicate a lack of tonic excitatory effect exerted by these amino acids on striatal DA release. Alternatively, a tonic excitatory influence on DA release may affect a small fraction of DA terminals, so that blockade of this effect does not make a great enough contribution to the extracellular fluid to be detected by microdialysis. To examine this possibility, the effect of EAA antagonists was assessed by microdialysis in the presence of DA uptake blockers. It was found that in the presence of nomifensine or cocaine, antagonists of either NMDA or AMPA/kainate receptors decreased extracellular DA levels in the striatum. These data suggest that EAAs may exert a tonic facilitatory influence on striatal DA release and/or that endogenous EAAs may potentiate the action of DA uptake blockers through mechanisms that are mediated by EAA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1993

The vigilance-promoting drug modafinil counteracts the reduction of tyrosine hydroxylase immunoreactivity and of dopamine stores in nigrostriatal dopamine neurons in the male rat after a partial transection of the dopamine pathway.

We studied the ability of the vigilance-promoting drug modafinil to modulate the anterograde and retrograde changes in tyrosine hydroxylase (TH) immunoreactivity and in dopamine (DA) stores in the nigro-neostriatal DA neurons, following a partial hemitransection of this ascending DA system, using a combined morphometrical, biochemical and behavioural analysis. Modafinil was given daily i.p. in doses of 10-100 mg/kg, starting 15 min after the lesion, and the partially hemitransected rats were killed 2 weeks later. Changes in TH-immunoreactive nerve cell bodies and nerve terminals induced by the partial hemitransection were studied in the substantia nigra and neostriatum in combination with image analysis. The substantia nigra and neostriatum were also subjected to biochemical analysis of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels. Modafinil treatment dose-dependently (10-100 mg/kg) counteracted the hemitransection-induced disappearance of nigral TH-immunoreactive nerve cell body profiles and neostriatal TH-immunoreactive nerve terminal profiles. A 2-week treatment with 100 mg/kg of modafinil also counteracted the hemitransection-induced depletion of DA stores in the neostriatum and the ventral midbrain. Moreover, the repeated daily treatment with modafinil (100 mg/kg) protected against the hemitransection-induced disappearance of striatal 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and noradrenaline levels. Striatal DA function was analysed by studying apomorphine-induced (1 mg/kg, s.c.) ipsilateral rotational behaviour 4 and 11 days after the operation. A marked dose-dependent reduction of ipsilateral rotational behaviour was demonstrated after the daily modafinil treatment in the partially hemitransected rats. In another model involving unilateral nigral microinjections of 6-hydroxydopamine, acute (one single dose) modafinil (100 mg/kg) did not affect the contralateral rotational behaviour induced by apomorphine (0.05 mg/kg s.c.), when given 30 min before the apomorphine. Taken together, morphological, neurochemical and behavioural evidence has been obtained that anterograde and retrograde changes induced in the DA stores and TH immunoreactivity of the nigro-neostriatal DA neurons by a partial hemistransection are counteracted by modafinil in a dose dependent way with 100 mg/kg producing a significant protective action against impairment of DA transmission. The results of this study open up the possibility that modafinil may protect against the anterograde and retrograde degeneration of nigrostriatal DA neurons seen after mechanically induced injury.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1988

The dopamine autoreceptor agonist, B-HT 920, preferentially reduces brain dopamine release in vivo: biochemical indices of brain dopamine, noradrenaline and serotonin in ventriculocisternal perfusates in the cat.

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine), a candidate for selective dopamine (DA) autoreceptor agonist activity, was tested for its interactions with biochemical parameters of brain dopaminergic, noradrenergic and serotoninergic systems as measured in ventriculocisternal perfusates of chloralose-anaesthetized cats. DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA) and 5-hydroxyindolic acid (5-HIAA) were measured in samples of 30 min collection periods by high-pressure liquid chromatography with electrochemical detection. B-HT 920, in the dose range of 0.03-1 mg/kg i.v., promptly inhibited the efflux of DA and DOPAC in a dose-dependent manner. The 1 mg/kg dose of B-HT 920 reduced the DA levels below 25% of control levels for the whole length of the experiments. The HVA levels were reduced less and in a protracted manner. Only the highest dose of B-HT 920 tested (1 mg/kg) had a significant effect on the level of NA (marked, prompt reduction) and 5-HIAA (delayed, moderate reduction), reflecting its well known alpha 2-adrenoceptor agonist property. The effects of B-HT 920 on the dopaminergic indices were DA receptor-mediated as they were reversed by a low dose (0.05 mg/kg i.v.) of haloperidol. In contrast, the alpha 2-adrenoceptor blocking drug, idazoxan, 4 mg/kg i.v., while it reversed the NA and 5-HIAA reductions did not modify the effect of B-HT 920 on DA, DOPAC and HVA. Thus B-HT 920, in the dose range between 0.03-0.1 mg/kg, selectively affected brain dopaminergic parameters. Our experiments demonstrated that B-HT 920 causes an effective, long lasting and selective suppression of extracellular brain DA levels in vivo. B-HT 920 represents a promising compound for clinical use in pathological conditions known to be ameliorated by a reduction of brain DA activity, such as Huntington's disease, mania and schizophrenia.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Chronic nicotine treatment increases dopamine levels and reduces dopamine utilization in substantia nigra and in surviving forebrain dopamine nerve terminal systems after a partial di-mesencephalic hemitransection.

In order to further study the previously demonstrated protective action of chronic nicotine treatment on lesioned meso-striatal dopamine (DA) pathways, the following study was carried out on DA utilization in these lesioned neurons. Male Sprague-Dawley rats were partially hemitransected at the meso-diencephalic junction and treated with nicotine (0.125 mg.kg-1.h-1) by means of Alzet minipumps implanted subcutaneously for 2 weeks. The overall serum nicotine level obtained was 64.6 +/- 2.7 ng.ml-1. The results demonstrated that partial di-mesencephalic hemitransections produced a marked reduction of DA fluorescence (quantitative histofluorimetry) on the lesioned side in the nucleus caudatus putamen, anterior nucleus accumbens and posterior lateral tuberculum olfactorium. No significant effects were observed on the intact side. Furthermore, studies on changes in DA utilization as evaluated 2 h after tyrosine hydroxylase inhibition showed an augmentation in the alpha-methyl-(+/-)-p-tyrosine methyl ester (alpha-MT)-induced depletion of the DA stores on the hemitransected side in comparison with the operated side of the sham-operated animals. On the hemitransected side chronic nicotine treatment increased DA stores in the DA nerve terminals of the nucleus caudatus putamen and the posterior lateral tuberculum olfactorium. No significant effects were observed on the intact side. Following chronic nicotine treatment a marked and preferential attenuation of the alpha-MT-induced depletion of DA stores was seen in the various DA nerve terminal systems of the forebrain on the hemitransected side. In the substantia nigra reduced DA levels (HPLC) were demonstrated on the hemitransected side, while no effects on the non-operated side were observed. Also an increase of the alpha-MT-induced depletion of the DA stores was seen on the hemitransected side in comparison with the operated side of the sham-operated animals. In contrast, on the non-operated side an attenuation of the alpha-MT-induced depletion of the DA stores was found. Following chronic nicotine treatment the lesion induced reduction of the nigral DA stores on the hemitransected side was counteracted, as was the lesion induced increase in the alpha-MT-induced depletion of DA stores, which was replaced by a reduction of the alpha-MT-induced depletion of the nigral DA stores. However, on the non-operated side an increased DA depletion was observed after alpha-MT treatment in rats treated chronically with nicotine. Chronic nicotine treatment under the present conditions did not significantly alter serum levels of corticosterone and reduced prolactin serum levels in sham-operated rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1982

Dopamine turnover estimated by simultaneous LCEC assay of dopamine and dopamine metabolites.

The estimation of changes in tissue levels of dopamine (DA) and its metabolites has been employed to approximate the turnover rate or release of DA. We have developed an assay using high pressure liquid chromatography with electrochemical detection to quantify DA, dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) simultaneously in brain homogenates. The assay is simple, inexpensive, rapid and accurate; the sensitivity of the assay for DA and DOPAC was 10 pg, for HVA 50 pg, and 200 pg for 3-MT. Apomorphine treatment resulted in a reduction in tissue levels of DOPAC and HVA, while haloperidol administration increased tissue levels of DOPAC and HVA. Neither drug treatment caused changes in DA levels. Administration of d-amphetamine 2.5 mg/kg S.C. resulted 1 hour later in increases in the striatal concentration of DA (57%) and 3-MT (44%) and decreases in DOPAC (40%) and HVA (39%). These data are consistent with the agonistic effect of apomorphine and antagonistic effect of haloperidol on DA autoreceptors and post-synaptic receptors. In the case of amphetamine, the increases in the levels of DA and 3-MT probably reflect the ability of d-amphetamine to induce DA release and block re-uptake. The reduction of DOPAC and HVA levels are consistent with the ability of d-amphetamine to competitively inhibit monoamine oxidase activity as well as the neuronal reuptake of DA. The simultaneous estimation of DA, DOPAC, 3-MT, and HVA should facilitate the understanding of dopaminergic drugs with complicated mechanisms of action.

Animals↗

PubMed1979

A method to determine dopamine levels and turnover rate in discrete dopamine nerve terminal systems by quantitative use of dopamine fluorescence obtained by Falck--Hillarp methodology.

In tissue sections of regions with evenly distributed dopamine (DA) nerve terminals such as the nucleus caudatus, it is possible to obtain absolute amounts (nmol/g) of DA by means of quantitative microfluorimetrical measurements of catecholamine (CA) fluorescence intensity in the tissue and in DA-containing albumin-agar standards. The values agree well with mass-fragmentographical determinations of DA. The steady-state DA levels of heterogenously innervated areas such as the tuberculum olfactorium determined by quantitative microfluorimetry can be made comparable to the steady-state levels of DA obtained by biochemistry in the entire tuberculum olfactorium by means of a conversion factor which considers the dilution of the DA-containing structures by non-DA-containing nerve cells in the biochemical analysis. This factor is obtained by making biochemical determinations in such regions of untreated animals (e.g. the tuberculum olfactorium). The results of this paper have demonstrated that the histochemical approach not only has a high power of resolution and makes it possible to perform studies on an intact morphological substrate but also allows the determination of DA steady-state (nmol/g) and DA turnover rate (nmol/g x min-1) in discrete DA nerve terminal systems of the brain in absolute amounts.

Analysis of Variance↗

PubMed2000

Role of oxidative changes in the degeneration of dopamine terminals after injection of neurotoxic levels of dopamine.

Dopamine may contribute to the loss of dopamine neurons in Parkinson's disease by generating reactive oxygen species and quinones. A previous report from this laboratory showed that intrastriatal injection of dopamine resulted in the selective reduction of tyrosine hydroxylase immunoreactivity, accompanied by an increase in indices of dopamine oxidation. However, conclusive proof that decreased tyrosine hydroxylase immunoreactivity represented a loss of dopamine terminals was lacking. In this paper, we demonstrate that injection of dopamine results in a selective loss of dopamine terminals by (i) showing that immunoreactivity for another selective marker for dopamine terminals, the dopamine transporter, is also reduced; and (ii) that amino-cupric-silver stain reveals terminal degeneration within the area of selective loss of dopamine terminals. To determine the dopamine concentration that is selectively toxic to dopamine terminals, we examined changes in extracellular dopamine and 3,4-dihydroxyphenylacetic acid in the area of selective terminal loss following intrastriatal dopamine. Dopamine and 3,4-dihydroxyphenylacetic acid in this region reached peak levels 1-2h after the injection, and then returned towards baseline. The peak level of dopamine in the area of selective dopamine terminal damage was 10(2)-10(3)-fold lower than the injected concentration. Changes in striatal tissue levels of cysteinyl-catechols and glutathione were examined at 2, 4, 8, and 24h after intrastriatal dopamine. Levels of protein cysteinyl-dopamine and cysteinyl-3,4-dihydroxyphenylacetic acid were increased at all time-points following the dopamine injection. High levels of free cysteinyl-catechols and glutathione-dopamine were detected within 2h after the dopamine injection. Glutathione levels were decreased significantly at 4 and 8h after the injection of dopamine, and returned to control levels by 24h. These data indicate that dopamine terminals actively degenerate following a single intrastriatal injection of dopamine, and furthermore that oxidative stress plays a key role in this process. As oxidative stress is thought to play an active role in the pathobiology of Parkinson's disease, these data may be relevant to our understanding of the disorder.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Production of cysteinyl-dopamine during intravenous dopamine therapy.

BACKGROUND: Oxidized dopamine rapidly forms thiol-conjugates with --SH groups on cysteine, glutathione, and proteins. We used cysteinyl-dopamine production as an index of thioester production during intravenous dopamine treatment of critically ill patients. METHODS: Cysteinyl-dopamine and catecholamines were measured by high-performance liquid chromatography with electrochemical detection. The production of cysteinyl-dopamine by purified human neutrophils was measured using dopamine (1 micromol/L) and cysteine (1 mmol/L) concentrations similar to those found during dopamine treatment. To examine the impact of endotoxic shock on cysteinyl-dopamine production, anesthetized rats were given dopamine (12 to 15 microg/kg/min intravenously) with or without endotoxin (50 mg/kg intravenously). RESULTS: In vitro, neutrophils converted 26% of dopamine to cysteinyl-dopamine (30 min at 37 degrees C). Activating neutrophils with zymogen increased dopamine consumption from 26 to 68%, but only 36% appeared as cysteinyl-dopamine. The remainder may have been oxidized to other cysteinyl derivatives. Endotoxin increased cysteinyl-dopamine in rat plasma from 2.5 nmol/L (range <0.2 to 11) to 9.7 nmol/L (range <0.3 to 31, P = 0.1). After four hours, with or without endotoxin, cysteinyl-dopamine was <0.3 nmol/L in cerebrospinal fluid. In the plasma of eight patients receiving dopamine (6 to 20 microg/kg/min for 1 to 3 days), dopamine was 0.5 to 9.9 micromol/L, and cysteinyl-dopamine was 48 to 1660 nmol/L. Cysteinyl-dopamine was 4.3 to 22.6% of dopamine and correlated with leukocyte count (r(2) = 0.388, P = 0.099). CONCLUSIONS: A significant fraction of exogenously administered dopamine reacts with -SH groups of cysteine and probably also with -SH groups on peptides and proteins. During brief dopamine treatment of endotoxic shock in rats, neither dopamine nor cysteinyl-dopamine crossed the blood-brain barrier.

Animals↗

PubMed1992

Autoradiographic identification of D1 dopamine receptors labelled with [3H]dopamine: distribution, regulation and relationship to coupling.

On the basis of experiments made on striatal membranes, Leff and Creese [Molec. Pharmac. (1985) 27, 184-192] have proposed that tritiated dopamine binds to a high-affinity agonist state of D1 dopamine receptors (D1h) which adopt this conformation when they are associated with the GTP-binding protein involved in the transduction process. Quantitative autoradiography was thus used to look for the distribution of these D1h sites in the rat brain and to compare it with that of D1 receptors labelled with [3H]7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz aze pine [( 3H]SCH23390), a D1 antagonist. The effects of unilateral 6-hydroxydopamine lesion of the ascending dopamine pathways on the density of [3H]dopamine D1h and [3H]SCH23390 binding sites in the striatum and the nucleus accumbens were also analysed. In the striatum, when D2 receptors were blocked by spiroperidol (20 nM), [3H]dopamine was found to bind specifically to dopamine receptors of the D1 type. Complementary experiments made with dopamine uptake blockers indicated that high-affinity dopamine uptake sites were not labelled by [3H]dopamine under our experimental conditions. The anatomical distribution of [3H]dopamine D1h binding sites was found to be markedly different from that of [3H]SCH23390 binding sites. This was particularly the case in the substantia nigra, some amygdaloid nuclei and the prefrontal cortex--structures in which the ratios between [3H]SCH23390 and [3H]dopamine binding sites were more than seven-fold higher than that observed in the striatum. [3H]SCH23390 binding was not significantly affected in either the striatum or the nucleus accumbens six weeks after a complete unilateral destruction of ascending dopamine pathways. In contrast, a marked decrease in [3H]dopamine D1h binding sites was found in both structures, but this effect was lower in the medioventral (-60%) than in the laterodorsal (-81%) part of the striatum, even though dopamine denervation was uniform throughout the structure. Preincubation of the sections with dopamine (0.5 microM) led to a partial recovery (+126%) in the lesioned striatum and an increase of [3H]dopamine labelling in the control striatum (+68%). This suggest that the presence of dopamine stabilizes the D1h state of D1 receptors. The absence or low amount of dopamine, either due to dopamine denervation or naturally occurring (prefrontal cortex), would then impair the [3H]dopamine D1h binding. In addition, a lower coupling of D1 receptors with adenylate cyclase was observed in the substantia nigra when compared to that in the striatum: this may explain the relatively weak [3H]dopamine binding in the substantia nigra.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗

PubMed1994

D2 dopamine receptor messenger RNA is altered to a greater extent by blockade of glutamate receptors than by blockade of dopamine receptors.

To study further the molecular mechanisms by which glutamate and dopamine interact to regulate the functions of the basal ganglia, the effects of persistently inhibiting dopamine receptors and glutamate N-methyl-D-aspartate receptors on the density of D1 and D2 dopamine receptors and on the level of their transcripts were examined in mouse brain. To block dopamine receptors, mice were treated with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline once daily for two and six days, or were treated with fluphenazine-N-mustard once daily for five days. To block N-methyl-D-aspartate receptors, mice were treated with dizocilpine by continuous infusion with osmotic mini-pumps for two and six days. The density of D1 and D2 dopamine receptors was measured by receptor autoradiography, and the level of D1 and D2 dopamine receptor messenger RNA was measured by in situ hybridization histochemistry. The results showed that N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline blocked about 90% of both D1 and D2 dopamine receptors, but had no significant effect on the level of either D1 or D2 dopamine receptor messenger RNA. Fluphenazine-N-mustard, which was as effective as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in blocking D2 dopamine receptors but had little effect on D1 dopamine receptors, also had no significant effect on the level of D1 and D2 dopamine receptor messenger RNAs. By contrast, continuously infusing dizocilpine significantly decreased the levels of D2 dopamine receptor messenger RNA in striatum, nucleus accumbens and olfactory tubercle. Dizocilpine also caused small decreases in the density of D2 dopamine receptors, but only in posterior striatum was this decrease statistically significant. Dizocilpine slightly and transiently decreased the levels of D1 dopamine receptor messenger RNA in striatum but had no significant effect on the density of D1 dopamine receptors in any region examined. This study demonstrates that persistent blockade of D1 and D2 dopamine receptors has relatively little effect on the levels of D1 and D2 dopamine receptor messenger RNA, but that blockade of N-methyl-D-aspartate receptors produces a rapid and profound decrease in the levels of D2 dopamine receptor messenger RNA and a smaller decrease in the density of D2 dopamine receptors. These results suggest that N-methyl-D-aspartate receptors play an important role in the expression of D2 dopamine receptors in basal ganglia.

Animals↗

PubMedDate not supplied

Dopamine-induced relaxation of the guinea-pig isolated jejunum is not mediated through dopamine receptors.

The possible involvement of specific dopamine receptors in the relaxing effect of dopamine in the guinea-pig isolated jejunum has been investigated. The relaxing effect of dopamine does not show the tachyphylaxis phenomenon and it is present in preparations from guinea-pigs pretreated with reserpine. These results indicate that dopamine has a direct action. Comparison of the effect of dopamine with those of other dopamine receptor agonists, i.e. apomorphine, bromocriptine and the DA1 selective fenoldopam, were made to calculate potency ratios. Since apomorphine, bromocriptine and fenoldopam were shown to relax the guinea-pig jejunum, partly behaving as indirectly acting agents, comparisons were made on reserpine-pretreated guinea-pigs. It has been found that apomorphine is 2.5 times, fenoldopam 3 times and bromocriptine 20 times more active than dopamine in relaxing the guinea-pig jejunum. The order of potency is different from that found in other dopamine receptors containing tissues. The effects of the dopamine receptor blockers, haloperidol and cis-alpha-flupenthixol and the DA1 selective blocker SCH 23390 on the relaxing effect of dopamine were also studied. The relaxing effect of dopamine was not reduced by haloperidol, cis-alpha-flupenthixol and SCH 23390. It is concluded that specific postjunctional dopamine receptors are not involved in the relaxing action of dopamine. Since dopamine is known to interact with alpha- and beta-adrenoceptors in a variety of tissues, the effects of the alpha-adrenoceptor blocker phentolamine and the beta-adrenoceptor blocker propranolol on the relaxing effect of dopamine were also studied. Noradrenaline has been used to check the responsiveness of the tissue. Phentolamine did not block the responses to dopamine and propranolol was able only to partially reduce responses to dopamine, at concentrations higher than those at which it antagonized noradrenaline. Mechanisms other than dopamine, alpha- or beta-receptor activation should be involved in the relaxing effect of dopamine in the guinea-pig jejunum.

Adrenergic alpha-Antagonists↗

PubMed2002

Tyrosine-induced release of dopamine is under inhibitory control of presynaptic dopamine D2 and, probably, D3 receptors in the dorsal striatum, but not in the nucleus accumbens.

Stimulation of dopamine D2-like receptors decreases extracellular dopamine in the dorsal striatum and the nucleus accumbens. It is unknown whether the role of these receptors differs from that of dopamine D3 receptors. It is also unknown to what extent the role of these two types of receptors varies across both structures. Using microdialysis, we therefore investigated whether intracerebrally administered quinpirole, a dopamine D2-like receptor agonist, and PD 128907, (S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano[4,3-b]-1,4-oxazin-9-ol, a dopamine D3 receptor preferring agonist, differentially alter the tyrosine-induced increase of extracellular dopamine in the dorsal striatum and the nucleus accumbens, respectively. Perfusion of tyrosine (100 microM) into the dorsal striatum and the nucleus accumbens enhanced extracellular dopamine in a physiological manner in both areas. Infusion of the Na(+) channel blocker tetrodotoxin (2 microM) suppressed the enhanced level of dopamine derived from exogenous tyrosine in both brain areas. Infusion of the dopamine D2-like receptor agonist quinpirole at a concentration (1 nM), which alone did not affect basal extracellular dopamine, reduced tyrosine-enhanced extracellular dopamine when infused into the dorsal striatum, but not into the nucleus accumbens; the preferential dopamine D3 receptor agonist, PD 128907, had similar effects. Haloperidol, a dopamine D2-like receptor antagonist, given systemically at a dose, which alone did not significantly affect basal dopamine levels (10 nmol/kg i.p.), enhanced extracellular dopamine derived from exogenous tyrosine. This haloperidol treatment antagonized only the quinpirole-induced, but not the PD 128907-induced reduction in dopamine levels seen in tyrosine-treated rats. The results show that extracellular dopamine derived from exogenous tyrosine is under inhibitory control of presynaptic dopamine D2-like receptors in the dorsal striatum, but not in the nucleus accumbens; to what extent the same holds for dopamine D3 receptors remains to be proven. Future studies are required to elucidate whether the noted difference is absolute or not.

Animals↗

PubMed1998

Opposing roles for dopamine D1 and D2 receptors in the regulation of hypothalamic tuberoinfundibular dopamine neurons.

The purpose of the present study was to characterize pharmacologically dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons in males rats, and to determine if inhibitory dopamine D1 receptors oppose stimulatory dopamine D2 receptors and account for the inability of mixed dopamine receptor agonists to alter the activity of these neurons. Tuberoinfundibular dopamine neuronal activity was estimated by measuring the concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence, the region of the hypothalamus containing terminals of these neurons. Administration of the dopamine D1 receptor agonist (+/-)-1 phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF38393) decreased median eminence DOPAC and increased plasma prolactin concentrations, whereas administration of the dopamine D1 receptor antagonist ((-)-trans,6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo[d]naphtho-[2,1 b]azepine (SCH39166) increased median eminence DOPAC concentrations but had not effect on plasma prolactin. The inhibitory effect of SKF38393 on median eminence DOPAC concentrations was blocked by SCH39166. These results demonstrate that acute activation of dopamine D1 receptors inhibits the activity of tuberoinfundibular dopamine neurons and thereby increases prolactin secretion, and that under basal conditions dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons is tonically active. Administration of the dopamine D2 receptor agonist (5aR-trans)-5,5a,6,7,8,9,9a,10-octahydro-6-propyl-pyridol[2, 3-g]quinazolin-2-amine (quinelorane) increased median eminence DOPAC concentrations, and SKF38393 caused a dose-dependent reversal of this effect. Administration of the mixed dopamine D1/D2 receptor agonist R(-)-10,11-dihydroxy-apomorphine (apomorphine) had no effect per se, but blocked quinelorane-induced increases in DOPAC concentrations in the median eminence. These results reveal that concurrent activation of dopamine D1 and D2 receptors nullifies the actions of each of these receptors on tuberoinfundibular dopamine neurons, which likely accounts for the lack of an acute effect of mixed dopamine D1/D2 receptor agonists on these hypothalamic dopamine neurons.

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

PubMed2000

Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice.

We have previously found that mice homozygous for the deletion of the dopamine D(2) receptor gene (D(2)(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test". In the present study, we sought to analyse the reactivity of D(2) receptor mutant mice to the cataleptogenic effects of dopamine D(2)-like or D(1)-like receptor antagonists. In parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D(3) receptor mutant mice. D(2)(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D(2)-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D(2)(+/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D(2) receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [3H]spiperone for D(2)(+/+), D(2)(+/-) and D(2)(-/-) mice, respectively). However, D(2)(-/-) and D(2)(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D(1)-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390: 0.03-0.6 mg/kg s.c.). Striatal dopamine D(1) receptor expression (as measured using [3H]SCH 23390 binding) was not significantly affected by the genotype. The ability of SCH 23390 to induce catalepsy in D(2)(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D(2) receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D(2) and dopamine D(1) receptor expression was essentially identical in D(3)(+/+), D(3)(+/-) and D(3)(-/-) mice, dopamine D(3) receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D(3) receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D(3) receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D(2) and dopamine D(1) receptors in this model. These results suggest that the dopamine D(2) receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D(3) receptor subtype appears to exert no observable control over the catalepsy produced by dopamine D(2)-like, D(1)-like and the combination of D(1)-like and D(2)-like receptor antagonists.

Animals↗