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At least 19 recordsLinked to original sources

PubMed1989

Dopamine uptake by platelets is selective, temperature dependent and not influenced by the dopamine-D1 or dopamine-D2 receptor.

The human platelet, which takes up and releases dopamine, has been proposed as a peripheral model for the study of dopaminergic neurons in the central nervous system (CNS). In addition, the platelet has been shown to possess membrane components with pharmacological properties similar to the dopamine-D1 (DA-D1) and D2 (DA-D2) receptor on dopaminergic neurons. We have therefore studied the specificity of the platelet uptake system for dopamine and, as dopamine uptake comprises both internalised and membrane bound dopamine, the contribution of the DA-D1 and DA-D2 receptor to the uptake of dopamine has been assessed. Significant uptake of 3H-dopamine by platelet rich plasma (PRP) occurred after 10 min incubation at 37 degrees C, uptake being maximal after 90 min. In contrast, at 4 degrees C no uptake of 3H-dopamine occurred up to 60 mins incubation but at 20 degrees C was approximately 8% of the 60 min uptake at 37 degrees C. The neurotransmitters serotonin and dopamine inhibited dopamine uptake by platelets in a dose dependent manner. Uptake of dopamine appeared to be via two systems, one of high affinity with low capacity and the other of lower affinity but high capacity. In contrast, noradrenaline, adrenaline, acetylcholine, gamma-aminobutyric acid and histamine (10 microM) had no effect on dopamine uptake by platelets. The DA-D1 receptor antagonist SCH 23390 (10 microns) and the DA-D2 receptor antagonists (10 microM) spiperone, domperidone and (+)-butaclamol did not significantly affect dopamine uptake by platelets. In addition, ouabain and desipramine (100 microM) inhibited dopamine uptake by 21% and 24% respectively whilst reserpine and imipramine (100 microM) increased uptake by 14% and 15%. We therefore conclude that platelets take up dopamine via a selective, temperature dependent mechanism. Our data also suggest that dopamine uptake by platelets does not involve the DA-D1 or DA-D2 receptor.

Biological Transport↗

PubMed1981

Effects of acute central and peripheral administration of nicotine on ascending dopamine pathways in the male rat brain. Evidence for nicotine induced increases of dopamine turnover in various telencephalic dopamine nerve terminal systems.

The actions of intraventicular injections and intravenous infusions of nicotine were studied on dopamine stores and turnover in discrete areas of the forebrain of normal male rats. This was done by measuring the decline of the dopamine stores after tyrosine hydroxylase inhibition using alpha-methyl-tyrosine methyl ester (H44/68). The dopamine concentrations in the various telencephalic dopamine nerve terminal systems were measured using the Falck-Hillarp methodology involving quantitative microfluorimetry. The catecholamine concentrations in the anteromedial frontal cortex were measured biochemically using high pressure liquid chromatography combined with electrochemical detection. Intraventricular experiments. The dopamine levels in discrete areas of nuc. caudatus and nuc. accumbens were significantly reduced even with the lowest dose of nicotine (1 microgram/rat). Intraventricular injections of nicotine in a dose of 100 microgram/rat produced significant increases of dopamine turnover in various types of dopamine nerve terminal systems in the nuc. caudatus, nuc. accumbens and tuberculum olfactorium, and following a dose of 10 microgram/rat increases of dopamine turnover were observed in the medial part of the nuc. caudatus. Furthermore, nicotine (100 microgram/rat) significantly increased noradrenaline but not dopamine turnover within the anterofrontal cortex. Intravenous experiments. The dopamine levels were selectively reduced by nicotine (1000 microgram/kg) in the cholecystokinin positive and negative dopamine nerve terminal systems of the nuc. accumbens. On the other hand, dopamine levels in the anteromedial frontal cortex were increased after this dose of nicotine. Intravenous infusions of nicotine (10-1000 microgram/kg) produced dose-related increases of dopamine turnover in the various dopamine nerve terminal systems analysed in the telencephalon. These effects became significant with a dose of 1000 microgram/kg/h. The dopamine terminals in the nuc. caudatus showed a higher sensitivity to intravenous infusions of nicotine, being affected by 10-100 microgram/kg of nicotine. These findings suggest that relatively low dose of nicotine via an activation of central nicotine-like cholinergic receptors can reduce dopamine concentration and increase dopamine turnover in discrete limbic and striatal areas. These actions may in part represent the neurochemical basis for the rewarding actions of nicotine and for nicotine dependence in man.

Afferent Pathways↗

PubMed1994

Irreversible blockade of D2 dopamine receptors by fluphenazine-N-mustard increases D2 dopamine receptor mRNA and proenkephalin mRNA and decreases D1 dopamine receptor mRNA and mu and delta opioid receptors in rat striatum.

The consequences of irreversibly-inhibiting D2 dopaminergic receptors on the expression of D1 and D2 dopamine receptor mRNAs and proenkephalin mRNA and on the levels of mu- and delta-opioid receptors in rat striatum were studied following single or repeated administration of the irreversibly-acting D2 dopamine receptor antagonist, fluphenazine-N-mustard (FNM). The density of dopamine and opioid receptors was determined by receptor autoradiography and the levels of the mRNA for the D1 and D2 dopamine receptors and proenkephalin were measured by in situ hybridization histochemistry. Repeated treatment of rats with FNM for 6 days produced more than 80% inhibition of D2 dopamine receptors but less than 25% inhibition of D1 dopamine receptors. Repeated treatment with FNM also resulted in statistically significant increases in D2 dopamine receptor mRNA but decreases in D1 dopamine receptor mRNA. In contrast, acute treatment with FNM for 3 h had no significant effects on D1 or D2 dopamine receptor mRNAs in striatum. An examination of the effects of FNM on the opioid system showed that repeated treatment with FNM for 6 days produced more than a 2-fold increase in the expression of proenkephalin mRNA in striatum. This was accompanied by significant decreases in mu- and delta-opioid receptors in striatum, mainly by reducing the size of the patch compartment of striatum. Acute treatment with FNM for 3 h produced small increases in proenkephalin mRNA and mu-opioid receptors in striatum but had no significant effects on delta-opioid receptors. These results suggest that persistent inhibition of D2 dopamine receptors differentially regulates the expression of D1 and D2 dopamine receptor mRNA in striatum, and that the magnitude, duration and interval of inhibiting dopaminergic transmission may be important factors in regulating dopamine receptor mRNA expression. These results also suggest that D2 dopamine antagonists indirectly down-regulate opioid receptors by increasing the expression of proenkephalin mRNA, thereby increasing enkephalin which, in turn, decreases opioid receptors in striatum.

Animals↗

PubMed2000

Dopamine transporter antagonists block phorbol ester-induced dopamine release and dopamine transporter phosphorylation in striatal synaptosomes.

We have reported that inhibition of protein kinase C blocks the Ca(2+)-independent reverse transport of dopamine mediated by amphetamine. In this study we investigated whether activation of protein kinase C by 12-O-tetradecanoyl phorbol-13-acetate (TPA) would mediate dopamine release through the plasmalemmal dopamine transporter. TPA, at 250 nM, increased the release of dopamine from rat striatal slices and synaptosomes while the inactive phorbol ester, 4alpha-phorbol, was ineffective. The TPA-mediated dopamine release was independent of extracellular calcium and was blocked by a selective protein kinase C inhibitor, Ro31-8220. The dopamine transporter antagonists, cocaine and GBR 12935 blocked the TPA-mediated dopamine release. In addition, cocaine blocked TPA-mediated phosphorylation of the plasmalemmal dopamine transporter. These results suggest that activation of protein kinase C results in reverse transport of dopamine through the plasmalemmal dopamine transporter and the phosphorylated substrate could be the dopamine transporter.

Animals↗

PubMed1996

Inhibition of dopamine neuron firing by pramipexole, a dopamine D3 receptor-preferring agonist: comparison to other dopamine receptor agonists.

Pramipexole, an amino-benzathiazole [(S)-4,5,6,7-tetrahydro-N-6-propyl-2, 6-benzothiazolediamine dihydrochloride monohydrate] direct-acting dopamine receptor agonist effective in treating Parkinson's disease, bound selectively and with high affinity to dopamine D2-like receptors, with highest affinity at dopamine D3 receptors. Ergot dopamine receptor agonists (bromocriptine, lisuride, pergolide) bound to both dopamine and non-dopamine receptors. Although all agonists depressed dopamine neuron firing, only pramipexole and quinpirole completely silenced firing when administered in slowly-accumulating doses. High-dose pergolide, but not other ergots, completely suppressed firing when given by a prompt bolus i.v. injection, suggesting efficacy limitations may have involved receptor desensitization for pergolide, but not for bromocriptine and lisuride. We conclude that pramipexole differs from ergot dopamine receptor agonists currently used in the treatment of Parkinson's disease by virtue of its selectivity for dopamine receptors, its preferential affinity for the dopamine D3 receptor subtype, and its greater efficacy for stimulating dopamine receptors, as indicated in these electrophysiology assays.

Animals↗

PubMed1998

D2 dopamine antisense RNA expression vector, unlike haloperidol, produces long-term inhibition of D2 dopamine-mediated behaviors without causing Up-regulation of D2 dopamine receptors.

Long-term inhibition of D2 dopamine receptors using classic D2 dopamine receptor antagonists such as haloperidol often causes a compensatory up-regulation of the D2 dopamine receptors. We investigated whether the long-term inhibition of D2 dopamine receptors using an eukaryotic expression vector housing a cDNA sequence encoding an antisense RNA directed to the D2 dopamine receptor transcript (D2 antisense vector) would also produce up-regulation of the D2 receptors. Single, bilateral injections of the D2 antisense vector into the corpora striata of mice inhibited the stereotypy induced by acute challenge injections with the D2/D3 dopamine receptor agonist quinpirole but did not inhibit the grooming induced by acute challenge injections with the D1 agonist SKF 38393. Similar treatment with the D2 antisense vector produced a long-term (>1 month) cataleptic response without producing tolerance to challenge injections with haloperidol. By contrast, catalepsy induced by a single injection of haloperidol lasted only approximately 2 days, and tolerance developed to its effects after long-term treatment. Repeated treatment of mice with haloperidol resulted in an inhibition of apomorphine-induced climbing behavior throughout the time of treatment with haloperidol, but the climbing behavior markedly increased to levels significantly higher than that of the control mice immediately after withdrawal from haloperidol treatment. This increased climbing was accompanied by increased levels of D2 dopamine receptors in the striatum. By contrast, single, bilateral intrastriatal injections of the D2 antisense vector significantly inhibited apomorphine-induced climbing for approximately 30 days but failed to increase the climbing behavior or the levels of D2 dopamine receptors in striatum over those of the control values. These results suggest that a single injection of a D2 antisense RNA expression vector into mouse striatum produces specific, long-term inhibition of D2 dopamine receptor behaviors without causing a compensatory increase in the levels or function of D2 dopamine receptors.

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

PubMed1987

D-2 dopamine-receptors regulate the release of [3H]dopamine in rat cortical regions showing dopamine immunoreactive fibers.

Using an antibody raised against dopamine the occurrence of dopamine-containing fibers was demonstrated in the prefrontal cortex, anterior cingulate cortex, parietal neocortex, piriform cortex and entorhinal cortex. In extracts of these cortical regions significant amounts of dopamine, although approximately a 100-fold less than in the neostriatum or nucleus accumbens, were detected with high performance liquid chromatography. The release of [3H]dopamine from slices of all these cortical regions was studied in vitro in a superfusion system and desipramine was used to prevent the uptake of [3H]dopamine in noradrenergic nerve terminals. It appeared that the electrically evoked release of radioactivity was inhibited by drugs stimulating D-2 dopamine-receptors in all the regions studied. Cation-exchange column chromatography revealed that the radioactivity released consisted predominantly of [3H]dopamine, indicating that D-2 receptors mediate the inhibition of the release of [3H]dopamine from dopaminergic nerve terminals. Likewise, in the neostriatum as well as in the nucleus accumbens D-2 receptor stimulation inhibits the release of [3H]dopamine. Therefore it is our conclusion that D-2 receptors regulate the release of dopamine from dopaminergic neurons originating in the ventral tegmental area as well as in the substantia nigra.

Animals↗

PubMed1993

Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum.

Dopamine-mediated behaviors and certain biochemical and molecular events associated with these behaviors were examined following continuous infusion of the D1 dopamine agonist SKF38393 or the D2 dopamine agonist quinpirole into mice for six days. SKF38393 produced a transient grooming behavior while quinpirole initially induced stereotypy, which was followed by an increased locomotor behavior. Continuous infusion of quinpirole caused a significant down-regulation of striatal D2 dopamine receptors without significantly changing the density of D1 receptors. This was accompanied by a decrease in the level of D2 receptor messenger RNA in striatum as measured by Northern analysis. The down-regulation of dopamine receptors was selective for D2 dopamine receptors, since treatment with SKF38393 had no significant effects on either D1 or D2 dopamine receptors, nor did it alter the messenger RNAs for the D1 and D2 receptors. Continuous treatment with quinpirole resulted in a significant increase in striatal mu opioid receptor levels without significant changing delta opioid receptors. This treatment also induced a significant decrease in proenkephalin messenger RNA in striatum. Taken together, these results suggest that the down-regulation of D2 dopamine receptor and D2 receptor messenger RNA is the result of the persistent stimulation of D2 receptors and that the up-regulation of mu opioid receptors may be a compensatory response to a decreased biosynthesis of enkephalin. They suggest further that the biochemical and molecular changes that take place in dopaminergic and enkephalinergic systems following continuous treatment with dopamine agonists may underlie the mechanisms by which certain dopamine-mediated behaviors occur.

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

PubMed1986

Effects of chronic SCH23390 treatment on the biochemical and behavioral properties of D1 and D2 dopamine receptors: potentiated behavioral responses to a D2 dopamine agonist after selective D1 dopamine receptor upregulation.

Chronic treatment of rats with SCH23390 (0.5 mg/kg/day s.c.), a D1 dopamine receptor antagonist, for 21 days resulted in an increase in D1 dopamine receptors but produced no change in D2 dopamine receptors. During habituation to locomotor activity cages the rats treated chronically with SCH23390 showed significantly higher locomotor activity than controls treated chronically with saline. When injected with the selective D1 dopamine receptor agonist SKF38393 (3 mg/kg), rats treated chronically with SCH23390 showed significantly greater stereotypy and locomotor activity responses. Surprisingly, rats treated chronically with SCH23390 also showed significantly higher locomotor activity and stereotypy responses when treated with the selective D2 dopamine receptor agonist, quinpirole (LY171555) (0.3 mg/kg). These results indicate that a selective increase in D1 receptors may not be necessary, but is sufficient, to lead to an enhanced behavioral response to either selective D1 or D2 dopamine receptor agonists. If, indeed, an enhanced stereotypy and locomotor activity response to dopaminergic agonists in rats after a brief chronic treatment with a neuroleptic drug is predictive of tardive dyskinesia potential in the clinical setting, these results can suggest that SCH23390 may also induce tardive dyskinesia in humans. Adenylate cyclase activity stimulated by guanine nucleotides, forskolin or dopamine was enhanced after chronic treatment with SCH23390. However, dopamine-stimulated adenylate cyclase activity was not potentiated detectably by the increase in receptor number over the more general increase in guanine nucleotide-stimulated cyclic AMP production. Additionally, no change was observed in dopamine competition for [3H]SCH23390 binding, with dopamine's RH/RL ratio remaining unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1999

Both dopamine and the putative dopamine D3 receptor antagonist PNU-99194A induce a biphasic inhibition of phorbol ester-stimulated arachidonic acid release from CHO cells transfected with the dopamine D3 receptor.

In Chinese hamster ovary (CHO) cells transfected with the cDNA for the dopamine D3 receptor, low concentrations of dopamine (IC50: 0.5 nM) counteracted the release of arachidonic acid (AA) induced by the protein kinase C activator TPA (maximal inhibition: 15% at 10 - 30 nM). The effect of dopamine -- which was antagonized by pretreatment with pertussis toxin (PTX) or by the dopamine receptor antagonist haloperidol -- was biphasic; thus, at increasing concentrations of dopamine (100 nM - 1 microM), AA levels approached baseline. The preferential dopamine D3 receptor ligand PNU-99194A displayed an effect similar to that of dopamine; thus, whereas low concentrations of PNU-99194A (IC50: 1.9 nM) reduced TPA-induced AA release (maximal inhibition: 15% at 30 - 100 nM), higher concentrations (> or =1 microM) were ineffective. When dopamine and PNU-99194A were administered together at concentrations yielding maximal inhibition of AA release, no additive effect was observed; moreover, a high concentration of dopamine counteracted the AA-reducing effect of a low concentration of PNU-99194A and vice versa. It is suggested that D3 receptors in transfected CHO cells may exert mainly an inhibitory, but also a stimulatory influence on TPA-induced AA release, and that PNU-99194A acts as an agonist in this system.

Animals↗

PubMed1996

Intrastriatal administration of an oligodeoxynucleotide antisense to the D2 dopamine receptor mRNA inhibits D2 dopamine receptor-mediated behavior and D2 dopamine receptors in normal mice and in mice lesioned with 6-hydroxydopamine.

Previous studies have shown that the intracerebroventricular injection of antisense oligodeoxynucleotides targeted to the mRNAs encoding the different subtypes of dopamine receptors inhibited behaviors mediated by these receptors. The present studies were designed to determine whether such antisense oligodeoxynucleotides could produce similar effects when injected into a discrete brain area. A D2 dopamine receptor antisense oligodeoxynucleotide (D2 antisense) was repeatedly injected into one corpus striatum of either normal mice or mice with unilateral lesions of the striatum induced by 6-hydroxydopamine. In the latter, intrastriatal injection of D2 antisense blocked the contralateral rotational behavior induced by the parenteral administration of the D2 dopamine receptor agonist quinpirole. The inhibitory effect of D2 antisense was dose- and time-related and was reversed upon cessation of D2 antisense treatment. This inhibitory effect was also selective in that D2 antisense treatment inhibited the rotational behavior induced by quinpirole but not that induced by the D1 dopamine receptor agonist SKF 38393 or by the muscarinic cholinergic agonist oxotremorine. Following repeated intrastriatal injections of D2 antisense into normal mice, parenteral administration of quinpirole caused rotational behavior ipsilateral to the side in which the D2 antisense was injected. No such rotational behavior was seen when similarly treated mice were challenged with SKF 38393 or oxotremorine. The quinpirole-induced rotational behavior in mice given intrastriatal injections of D2 antisense disappeared upon cessation of D2 antisense treatment. Repeated intrastriatal administration of D2 antisense also caused a significant reduction in the levels of D2, but not D1, dopamine receptors in striatum, as determined by receptor autoradiography. The levels of D2 dopamine receptors returned to normal upon cessation of D2 antisense treatment. Intrastriatal administration of an oligodeoxynucleotide with randomly placed nucleotides failed to alter the rotational response to quinpirole in either 6-hydroxydopamine-lesioned or normal mice and failed to alter the levels of D2 dopamine receptors in striatum. These results show that selective inhibition of behavioral responses mediated by D2 dopamine receptors can be achieved by the direct injection of a D2 antisense oligodeoxynucleotide into a discrete brain area.

Animals↗

PubMed1994

In vivo administration of an oligodeoxynucleotide antisense to the D2 dopamine receptor messenger RNA inhibits D2 dopamine receptor-mediated behavior and the expression of D2 dopamine receptors in mouse striatum.

A 20-mer phosphorothioate oligodeoxynucleotide (D2 antisense) to the D2 antisense dopamine receptor messenger RNA (mRNA) was administered i.c.v. to mice with unilateral 6-hydroxydopamine lesions of the corpus striatum. The mice were then challenged with acute injections of various agents that cause contralateral rotational behavior, and the levels of D1 and D2 dopamine receptors and their respective mRNAs were determined in the corpus striatum. Administering the D2 antisense inhibited rotations induced by the D2 dopamine receptor agonists quinpirole and N-propyl-N-2-thienylethylamine-5-hydroxytetralin but did not block rotations induced by the D1 dopamine receptor agonist 1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine-7,8-diol HCl or by the muscarinic cholinergic receptor agonist oxotremorine. The reduction in quinpirole-induced rotational behavior was related to the amount and length of time the D2 antisense was given. Significant reductions in behavior were seen within 1 day of repeated injections of D2 antisense, and almost complete inhibition was seen after 6 days of treatment. Recovery from inhibition occurred by 2 days after cessation of antisense treatment. Repeated treatment with D2 antisense significantly reduced the levels of D2 dopamine receptors and D2 dopamine receptor mRNA, but not the levels of D1 receptors or D1 mRNA, in the dorsolateral area of the lesioned striatum. Treatment with an oligodeoxynucleotide with randomly placed nucleotides did not inhibit quinpirole-induced rotations or alter D2 dopamine receptors or D2 dopamine receptor mRNA in either area of striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed2001

The dopamine D3 receptor partial agonist, BP 897, is an antagonist at human dopamine D3 receptors and at rat somatodendritic dopamine D3 receptors.

Recent studies have fueled the interest in dopamine D3 receptor antagonists and partial agonist for the treatment of psychosis and drug abuse, respectively. N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide (BP 897) is a dopamine D3 receptor selective ligand recently described as partial agonist with potential effects on drug-dependence. The aim of the present study was to determine both the functional activity of BP 897 at human dopamine D3 receptors expressed in Chinese hamster ovary (CHO) cells and in an electrophysiological in vivo model of dopaminergic activity. BP 897 failed to stimulate the human dopamine D3 receptor and showed antagonistic effects (cpIC(50)=9.51) in a [(35)S]GTPgammaS binding assay in cells expressing the human dopamine D3 receptor. In vivo, BP 897 up to 8.2 mg/kg, i.v., had no agonistic effects on firing rate of substantia nigra dopaminergic neurons and antagonized the quinpirole-induced inhibition of firing (DID(50)=1.1 mg/kg). Our data demonstrate that BP 897 acts, in vivo and in vitro, as a dopamine D3 receptor antagonist.

Animals↗

PubMed1994

Invariance of the density of dopamine uptake sites and dopamine metabolism in the rat brain after a chronic treatment with the dopamine uptake inhibitor GBR 12783.

A chronic treatment (10 mg/kg, twice daily during 9 days) with the dopamine uptake inhibitor GBR 12783 was performed in rats at a dose increasing their locomotor activity. Forty-eight hours after the last administration, animals were sacrificed and 3H mazindol binding was performed on brain slices. Autoradiographic analysis revealed no change in this binding relatively to control animals in regions with high dopamine contents: striatum, nucleus accumbens, olfactory tubercle, substantia nigra and ventral tegmentum area. The treatment did not either modify the levels of dopamine (DA) and metabolites (HVA, DOPAC) both in the striatum and the nucleus accumbens. Thus, early after the end of the treatment, the chronic blockade of the dopamine uptake complex regulates neither the dopamine uptake complex nor the dopamine metabolism.

Afferent Pathways↗

PubMed2002

Dopamine efflux via wild-type and mutant dopamine transporters: alanine substitution for proline-572 enhances efflux and reduces dependence on extracellular dopamine, sodium and chloride concentrations.

The dopamine transporter (DAT) can mediate not only inward uptake of dopamine, but also its outward efflux by mechanisms that have been only partially elucidated. DAT-dependent dopamine efflux can be studied kinetically and apparent substrate affinity and V(max) values determined. We now report that wild-type DAT displays apparent affinities for efflux more than 300-fold lower than those for uptake. Efflux rates are enhanced by increased extracellular concentrations of dopamine or amphetamine and by lowered extracellular concentrations of Na(+) or Cl(-). Alanine substitutions for six proline residues located in or near DAT transmembrane domains increase apparent affinity and decrease V(max) values for dopamine efflux mediated by these mutant transporters. Mutant 12P572A displays increased DAT efflux with reduced dependence on ion or dopamine concentrations. These data add to evidence for the specificity of transporter-mediated efflux processes and begin to elucidate DAT candidate domains that may be preferentially involved with efflux activities.

Alanine↗

PubMed2000

Regulation of the phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors.

Dopamine D(1), dopamine D(2), and adenosine A(2A) receptors are highly expressed in striatal medium-sized spiny neurons. We have examined, in vivo, the influence of these receptors on the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). DARPP-32 is a potent endogenous inhibitor of protein phosphatase-1, which plays an obligatory role in dopaminergic transmission. A dose-dependent increase in the state of phosphorylation of DARPP-32 occurred in mouse striatum after systemic administration of the D(2) receptor antagonist eticlopride (0.1-2.0 mg/kg). This effect was abolished in mice in which the gene coding for the adenosine A(2A) receptor was disrupted by homologous recombination. A reduction was also observed in mice that had been pretreated with the selective A(2A) receptor antagonist SCH 58261 (10 mg/kg). The eticlopride-induced increase in DARPP-32 phosphorylation was also decreased by pretreatment with the D(1) receptor antagonist SCH 23390 (0.125 and 0.25 mg/kg) and completely reversed by combined pretreatment with SCH 23390 (0.25 mg/kg) plus SCH 58261 (10 mg/kg). SCH 23390, but not SCH 58261, abolished the increase in DARPP-32 caused by cocaine (15 mg/kg). The results indicate that, in vivo, the state of phosphorylation of DARPP-32 and, by implication, the activity of protein phosphatase-1 are regulated by tonic activation of D(1), D(2), and A(2A) receptors. The results also underscore the fact that the adenosine system plays a role in the generation of responses to dopamine D(2) antagonists in vivo.

Animals↗

PubMed2003

A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes.

We assessed the role of some dopamine metabolism genes in the genetic susceptibility to migraine. We performed an association study using three functional polymorphisms: a 48-base-pair (bp) tandem repeat in the D4 dopamine receptor gene ( DRD4), a 40-bp tandem repeat in the dopamine transporter gene ( DAT) and a dinucleotide repeat in the dopamine beta-hydroxylase ( DBH) gene. Allelic and genotypic frequencies for each polymorphism were assayed in two migraine populations (93 individuals with migraine with aura (MA) and 101 with migraine without aura (MO)) and were compared with those in a control group (117 individuals). No significant differences were found between control and migraine groups for DAT and DBH polymorphisms. Instead, the distribution of alleles for the DRD4 gene in the MO group was significantly different from those in both MA and control groups, with the shortest and longest alleles being less frequent in MO. Our data indicate that MO, but not MA, shows significant genetic association with DRD4.

Adolescent↗

PubMed1993

D1 dopamine receptor binding and mRNA levels are not altered after neonatal 6-hydroxydopamine treatment: evidence against dopamine-mediated induction of D1 dopamine receptors during postnatal development.

The role of dopaminergic innervation on the postnatal developmental expression of D1 dopamine receptors was investigated. Bilateral destruction of dopamine-containing neurons was achieved by treating rats intracisternally with 6-hydroxydopamine (6-OHDA) on postnatal day 3, and rats were killed on day 21. To ensure effective reduction of D1 receptor activation by residual dopamine, a group of 6-OHDA-lesioned rats was given twice daily injections of the D1 receptor antagonist SCH-23390, from day 4 to 20. D1 dopamine receptor binding was assessed in the caudate-putamen, nucleus accumbens, and olfactory tubercle by quantitative autoradiographic analysis of [3H]SCH-23390 binding. In addition, the relative amount of D1A receptor mRNA was assessed by in situ hybridization of a 35S-labeled riboprobe. In the developing rats, neither the amount of [3H]SCH-23390 binding nor the amount of D1A receptor mRNA was altered by 6-OHDA lesioning followed by chronic treatment with SCH-23390. Thus, bilateral destruction of dopamine-containing neurons and treatment with SCH-23390 in neonatal rats did not interfere with the developmental expression of D1 receptors or alter the levels of mRNA that code for this receptor protein. Treatment of intact rats with SCH-23390 from postnatal day 4 to 20 also did not alter [3H]SCH-23390 binding or levels of D1 receptor mRNA. However, adult rats treated chronically with SCH-23390 exhibited increased [3H]SCH-23390 binding but did not show a significant change in D1 receptor mRNA levels.

Animals↗