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PubMed1982

Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor.

The interactions of dopaminergic agonists and antagonists with binding sites in bovine anterior pituitary membranes have been investigated with radioligand-binding techniques and computer-modeling procedures. 3H-labeled agonist binding is stereospecific, reversible, saturable, and of high affinity. The rank order of catecholamines, phenothiazines, and related drugs in competing for 3H-agonist binding is indicative of interactions with a D-2 dopamine receptor. Both agonist/3H-agonist and antagonist/3H-agonist competition curves are monophasic and noncooperative (nH = 1) with computer analysis indicating a single class of binding sites. Specific 3H-agonist binding can be completely inhibited by guanine nucleotides. GppNHp us the most potent nucleotide followed by GTP and GDP which are equipotent. The equilibrium binding capacity for 3H-labeled antagonists is twice that for 3H-agonists. Unlabeled antagonists inhibit 3H-antagonist binding competitively and exhibit antagonist/3H-antagonist competition curves which model best to a state of homogeneous affinity. In contrast, unlabeled agonists inhibit 3H-antagonist binding in a heterogeneous fashion displaying multiphasic (nH less than 1) competition curves which can be resolved into high and low affinity binding sites. In the presence of saturating concentrations of guanine nucleotides, however, the agonist/3H-antagonist curves model best to a single affinity state which is identical with the low affinity state seen in control curves. The binding data can be explained by postulating two states of the D-2 dopamine receptor, inducible by agonists but not antagonists and modulated by guanine nucleotides.

Animals↗

PubMed1991

In vivo assessment of release and metabolism of dopamine in the ventrolateral striatum of awake rats following administration of dopamine D1 and D2 receptor agonists and antagonists.

The ability of specific dopamine (DA) receptor agonists and antagonists to modify the release and metabolism of DA in the ventrolateral striatum of awake rats was assessed using in vivo microdialysis. The specific DA D2 receptor antagonist, raclopride (0.1, 0.5 and 2.0 mg/kg, i.p.), dose-dependently increased release of DA and levels of the metabolites DOPAC and HVA, while the D2 receptor agonist, quinpirole (0.03, 0.1 and 0.3 mg/kg), decreased levels of DA, DOPAC and HVA. The DA D1 receptor antagonist, SCH23390 [(R + (+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol) (0.01, 0.05 and 0.25 mg/kg), produced an increase in DA, DOPAC and HVA but of a lesser magnitude than raclopride. The D1 agonist SKF38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (1.0, 3.0 and 10.0 mg/kg) failed to affect the release of metabolism of DA at any dose. These results support previous findings that activation of D2 receptors has greater control over in vivo DA function, than drugs specifically affecting D1 receptors.

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

PubMed1998

Effects of the D3 preferring dopamine agonist pramipexole on sleep and waking, locomotor activity and striatal dopamine release in rats.

Quantitation of 2 h sessions after administration of the D3 preferring dopamine (DA) agonist pramipexole (10-500 microg/kg) showed dose-related effects on wakefulness (W), slow wave sleep (SWS) and REM sleep in rats. The 30 microg/kg dose of the DA agonist increased SWS and REM sleep and reduced W during the first recording hour, while the 500 microg/kg dose augmented W. On the other hand, W was increased while SWS and REMS were decreased after the 500 microg/kg dose during the second recording hour. The mixed D2- and D3 receptor antagonist YM-09151-2 (30-500 microg/kg), which per se affected sleep variables prevented the increase of REMS induced by pramipexole. Furthermore, the highest doses (500-1000 microg/kg) of the DA antagonist effectively antagonized the increase of W and reduction of SWS induced by the 500 microg/kg dose of the DA agonist. Pramipexole (30-100 microg/kg) induced a decrease of locomotor activity during the 2 h recording period. In addition, the 500 microg/kg dose gave rise to an initial reduction of motor behavior which was reverted 2 h later. Pramipexole (30 and 500 microg/kg) did not significantly affect striatal DA release during the first two hours following drug administration, as measured by microdialysis. It is tentatively suggested that D3 receptor could be involved in the pramipexole-induced increase of sleep and reduction of locomotor activity. On the other hand, the increase of W and of motor behavior after relatively high doses could be related to activation of postsynaptic D2 receptor.

Animals↗

PubMed2001

Cocaine-induced increases in vesicular dopamine uptake: role of dopamine receptors.

The vesicular monoamine transporter-2 is the sole transporter responsible for sequestration of monoamines, including dopamine (DA), into synaptic vesicles. Previous studies demonstrate that agents that inhibit DA transporter function, such as cocaine, increase vesicular [(3)H]DA uptake and binding of the ligand [(3)H]dihydrotetrabenazine ([(3)H]DHTBZ), as assessed in vesicles prepared from treated rats. The present studies examine the role of DA receptors in these cocaine-induced effects. Results demonstrate that administration of the D(2) DA receptor antagonist, eticlopride, but not the D(1) DA receptor antagonist, SCH23390, inhibited these cocaine-induced increases. Similar to the effects of cocaine, treatment with the D(2) agonist, quinpirole, increased both vesicular [(3)H]DA uptake and [(3)H]DHTBZ binding. In contrast, administration of the D(1) agonist, SKF81297, was without effect on vesicular [(3)H]DA uptake or [(3)H]DHTBZ binding. Finally, coadministration of quinpirole and cocaine did not further increase vesicular [(3)H]DA uptake or [(3)H]DHTBZ binding when compared with treatment with either agent alone. These data suggest that cocaine-induced increases in vesicular DA uptake and DHTBZ binding are mediated by a D(2) receptor-mediated pathway. Furthermore, results indicate that D(2) receptor activation, per se, is sufficient to increase vesicular DA uptake.

Animals↗

PubMed1986

Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo.

The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2). Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg). Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1990

Modulation of dopamine metabolism in the retina via dopamine D2 receptors.

When rats are placed in a lighted environment from the dark retinal DOPAC increases. There is no significant change of retinal dopamine (DA) under either lighting condition. Blockade of aromatic L-amino acid decarboxylase results in a more rapid accumulation of DOPA in the retina of animals in the light than in the dark implying that DA synthesis and metabolism are more rapid in the light than in the dark. Retinal DOPAC increases in the dark and in the light when rats are treated with the DA D2 antagonists sulpiride and spiperone. Treatment with the D2 agonist, quinpirole, lowers the content of DA in the retina of rats kept in the dark or exposed to light. D1 receptor drugs induce only limited changes in DA metabolism. We conclude that D2 receptors play a principal role for modulating DA synthesis and metabolism in the rat retina.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Selective unilateral inactivation of striatal D1 and D2 dopamine receptor subtypes by EEDQ: turning behavior elicited by D2 dopamine receptor agonists.

The unilateral intrastriatal injection of the irreversible dopamine (DA) receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induces a marked decrease in the density of D1 (-48%) and D2 (-51%) DA receptors available for binding to [3H]SCH 23390 and [3H]raclopride, respectively. A challenge dose of the D2 agonist LY 171555 (1 mg/kg, i.p., 24 h after EEDQ) causes intensive ipsiversive circling behavior, whereas the selective D1 agonist SKF 38393 (20 mg/kg, i.p., 24 h after EEDQ) is unable to induce rotations. The density of D1 and D2 DA receptors returns to basal levels by 7 days after the intrastriatal infusion of EEDQ. This biochemical recovery is associated with a progressive decrease in the number of rotations elicited by a challenge dose of LY 171555, suggesting that EEDQ does not cause any relevant neuronal damage. A selective inactivation of striatal D1 or D2 DA receptors can be obtained by injecting EEDQ 30 min after the administration of the D2 antagonist raclopride (20 mg/kg, i.p.) or of the D1 antagonist SCH 23390 (2 mg/kg, s.c.), respectively. The intensity of the circling behavior induced by LY 171555 24 h after EEDQ in animals with a selective inactivation of D2 DA receptors is similar to that found in rats in which both D1 and D2 DA receptors have been inactivated. In contrast, LY 171555 does not cause rotations when the density of D1 DA receptors is selectively decreased by EEDQ in rats pretreated with raclopride.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1991

Effects of D1 and D2 antagonists on the transient increase of dopamine release by dopamine agonists by means of brain dialysis.

The effects of selective D1 and D2 antagonists, R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol(SCH-23390) and sulpiride, on the transient increase of dopamine (DA) release induced by DA agonists, apomorphine (APO) and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF-38393) were examined in the caudate-putamen of freely moving rat by means of microdialysis during local coinfusion of a DA antagonist and agonist. Infusion of 10(-5) M and/or 10(-6) M concentrations of SCH-23390 suppressed a brief increase in DA release induced by both 10(-4) M of APO and 10(-5) M of SKF-38393. On the other hand, 10(-5) M and/or 10(-6) M of sulpiride exerted little or no effect. A possible explanation for this phenomenon was discussed.

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

PubMed1992

Depletion of dopamine binding sites and changes in dopamine and dihydroxyphenylacetic acid levels in 17- and 90-day-old rat striatum after irreversible receptor antagonism.

Irreversible antagonism of dopamine (DA) receptors by the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) results in a depression of DA agonist mediated behaviors in adult, but not preweanling rats. DA D1 and D2 receptors, dihydroxyphenylacetic acid (DOPAC) and DA levels were assessed in 17- and 90-day-old rats in order to identify a neurochemical mechanism for this difference. EEDQ caused a depletion in D1 and D2 receptors in both young and adult rats, with the depletion in adults being relatively greater. In both age groups, EEDQ caused an unexpected decrease in DA levels which returned to normal levels by 30 days post-injection. In addition, DOPAC levels of adult rats, but not rat pups, were elevated after EEDQ treatment. The depletion of endogenous DA levels must be considered when interpreting the effects of EEDQ. Age-dependent differences in DA metabolism may be important for understanding the ontogenetic differences in EEDQ's behavioral effects.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Intrastriatal dopamine-rich implants reverse the changes in dopamine D2 receptor densities caused by 6-hydroxydopamine lesion of the nigrostriatal pathway in rats: an autoradiographic study.

The aim of the present study was to test whether intrastriatal implants of embryonic dopaminergic neurons are able to normalize the lesion-induced hypersensitivity of striatal dopaminergic receptors. The ascending dopaminergic pathway of adult rats was unilaterally lesioned using 6-hydroxydopamine. Three weeks later a cell suspension obtained from the mesencephali of ED 14 rat embryos was implanted into the denervated striatum. Rotational responses to dopaminergic agonists were tested five months after implantation. One month later animals were killed and striatal dopaminergic receptor densities were quantified using autoradiography, the dopaminergic reinnervation of the host striatum being visualized with [3H]GBR 12935, a ligand labelling dopamine uptake sites. The lesion induced a behavioural hypersensitivity to dopaminergic agonists and lesioned animals displayed a strong rotation contralateral to the lesion in response to a test dose of the D1 agonist compound SKF 38393 (2.5 mg/kg) or of the D2 agonist LY 171555 (0.15 mg/kg). These responses were completely abolished by the graft. The normal distribution of D1 and D2 dopaminergic receptors in the rat striatum was similar to that described previously. Seven months after the lesion of the nigrostriatal dopaminergic pathway, the density of D1 receptors was not significantly affected while the density of D2 receptors was increased by about 25-50%. The implantation of embryonic dopaminergic neurons into the denervated striatum led to a slight decrease of D1 receptor densities and to a reversal of the lesion-induced increase of striatal dopaminergic D2 receptors six months later. Moreover, this reversal concerned not only the reinnervated striatal region but also extended into non-reinnervated areas of the striatum. It is concluded that grafts of embryonic dopaminergic neurons can normalize the density of dopaminergic D2 receptors.

Animals↗

PubMed2004

Bimodal induction of dopamine-mediated striatal neurotoxicity is mediated through both activation of D1 dopamine receptors and autoxidation.

Striatal neurodegeneration occurs through unknown mechanisms in certain neurodegenerative disorders characterized by increased and sustained synaptic levels of dopamine (DA). Treatment of rat primary striatal neurons with DA causes profound neurotoxicity, with increased production of free radicals and accelerated neuronal death. DA effects were partly reduced by the antioxidant sodium metabisulfite (SMBS), and the D1 DA receptor antagonist, SCH 23390, and were completely blocked upon co-treatment with SMBS and SCH 23390. Part of DA effects were mimicked by either H(2)O(2), or by the D1 agonist, SKF R-38393, indicating the existence of two distinct signaling pathways through which the neurotoxicity of DA is manifest. DA effects did not proceed through D2-like DA or beta-adrenergic receptor signaling pathways. The D1 receptor-mediated and the autoxidative pathways of DA neurotoxicity converge to cause activation and/or increased synthesis of neuronal and inducible, but not endothelial, nitric oxide synthase (NOS). The reduction of DA striatal neurotoxicity through blockade of D1 DA receptors, suggests novel therapeutic approaches in the management of striatal neurodegeneration.

Animals↗

PubMed2005

Dopamine D1 and D2 receptor contributions to L-DOPA-induced dyskinesia in the dopamine-depleted rat.

Using a rat model of L-DOPA-induced dyskinesia (LID), the contributions of dopamine D1 and D2 receptors to axial, limb, and orolingual (ALO) abnormal involuntary movements (AIMs) elicited by L-DOPA were examined. Chronic L-DOPA-treated rats received the D1 receptor antagonist SCH23390 (0.01, 0.1, and 1.0 mg/kg; i.p.), the D2 receptor antagonist Eticlopride (0.01, 0.1, and 1.0 mg/kg; i.p.), a mixture of both antagonists (0.01, 0.1, 1.0 mg/kg each; i.p.), or vehicle 30 min prior to L-DOPA (6 mg/kg; i.p.)+Benserazide (15 mg/kg; i.p.). SCH23390 (0.1 and 1.0 mg/kg) significantly reduced axial and limb AIMs, while the same doses of Eticlopride significantly decreased axial, limb, and orolingual AIMs. Co-administration of SCH23390+Eticlopride significantly reduced axial (0.01, 0.1 and 1.0 mg/kg), limb (0.1 and 1.0 mg/kg), and orolingual (0.1 and 1.0 mg/kg) AIMs. These results indicate the importance of D1 and D2 receptors to LID and further validate the rat AIMs model.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2005

Hippocampal dopamine receptors modulate the motor activation and the increase in dopamine levels in the rat nucleus accumbens evoked by chemical stimulation of the ventral hippocampus.

A number of studies have shown that chemical stimulation (using N-methyl-D-aspartate (NMDA) infusions) or electrical stimulation of the ventral hippocampus (VH) elicits locomotor activation and sustained increases in nucleus accumbens (NAc) dopamine (DA) levels in rodents. How DA neurotransmission in NAc is involved in these effects has also been well established. However, the modulatory role of the DA receptors located in VH is not yet fully understood. The purpose of this study was to characterize the role played by VH D1 and D2 subtype receptors in both the locomotor activation and NAc DA increases induced by NMDA stimulation of the VH. This was assessed by studying how retrodialysis application of NMDA (50 mM, 10 min) affects motor activity and NAc DA levels during simultaneous retrodialysis administration of the D1/D5 receptor antagonist SCH 23390 (100 and 250 microM, 60 min) or the D2 receptor antagonist raclopride (100 and 250 microM, 60 min). SCH 23390 attenuated or completely abolished NMDA-evoked locomotor activation and the concurrent increase in NAc DA levels. On the other hand, raclopride was initially able to attenuate the effects of VH NMDA stimulation. However, in the last phase of the experiments, animals showed an important increase in clonic seizure activity with a simultaneous and dramatic increase in NAc DA levels. Our results show that the NMDA receptor-mediated effects in the VH require both D1 and, probably, D2 receptors and suggest that DA in VH strongly modulates the excitatory outputs from this brain area.

Animals↗

PubMed1996

Dopamine D3 (auto) receptors inhibit dopamine release in the frontal cortex of freely moving rats in vivo.

In freely moving rats, the novel, selective dopamine (DA) D3 receptor agonist PD 128,907 dose-dependently [effective dose (ED25) = 0.07 mg/kg, s.c.] reduced dialysate levels of DA in the frontal cortex, a structure innervated by the ventral tegmental area (VTA). This action of PD 128,907 (0.16 mg/kg, s.c.) was abolished by a selective DA D3 receptor antagonist S 14297 (1.25 mg/kg, s.c.), which alone did not modify levels of DA. In contrast to S 14297, its inactive distomer, S 17777, did not modify the actions of PD 128,907. In addition, PD 128,907 dose-dependently and potently inhibited the firing rate of VTA-localized neurons in anesthetized rats (ED50 = 0.001 mg/kg, i.v.). S 14297, but not S 17777, completely reversed the actions of PD 128,907 (0.005 mg/kg, i.v.) with a 50% inhibitory dose of 0.03 mg/kg, i.v. and did not itself significantly modify the firing rate. In conclusion, these data provide the first direct evidence that DA D3 (auto) receptors modulate (inhibit) the release of DA in the frontal cortex.

2-Naphthylamine↗

PubMed1990

Alpha 1 (but not alpha 2)-adrenoceptor agonists in combination with the dopamine D2 agonist quinpirole produce locomotor stimulation in dopamine-depleted mice.

Mice were premedicated with reserpine and alpha-methyl-p-tyrosine to deplete stores of dopamine (DA) (and other neurotransmitters) and to stop DA (and noradrenaline (NA] synthesis. In DA-depleted mice, the mixed alpha 1/alpha 2 agonist clonidine potentiated locomotor stimulation induced by a low dose of apomorphine as measured in automated activity cages. Clonidine and the slightly alpha 1-selective agonist ST587, but not ST91, an alpha-agonist which does not readily cross the blood brain barrier, produced marked stimulation when combined with the selective D2 agonist quinpirole. The D1 -selective agonist SKF38393 also produced marked excitation when combined with quinpirole. All the selective agonists, bar quinpirole which in some cases produced a significant locomotor stimulation, were relatively inactive when given alone. A "blind" observational analysis of the animals challenged with clonidine plus quinpirole indicated an increase in sniffing, rearing and shaking behaviour. In contrast, observation of the animals challenged with SKF38393 plus quinpirole indicated increased sniffing, rearing and biting and, in one case, increased grooming behaviour. Clonidine did not produce excitation (in automated cages) when combined with the selective D1 agonist SKF38393. The excitation produced by clonidine plus quinpirole was blocked by the selective D2 antagonist raclopride but not by the selective D1 antagonist SCH23390. The stimulation was also blocked by the alpha 1 antagonist prazosin but not by the alpha 2 antagonists idazoxan or yohimbine. Biochemical analysis in the striata of mice challenged with clonidine plus quinpirole did not provide any obvious biochemical basis for the behavioural interaction. It is concluded that alpha 1 receptor agonists in combination with D2 DA agonists can produce marked stimulation in DA depleted mice.

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

PubMed2004

Ethologically based resolution of D2-like dopamine receptor agonist-versus antagonist-induced behavioral topography in dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of 32 kDa "knockout" mutants congenic on the C57BL/6 genetic background.

Given the critical role of dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32) in the regulation of dopaminergic function, DARPP-32-null mutant mice congenic on the inbred C57BL/6 strain for 10 generations were examined phenotypically for their ethogram of responsivity to the selective D2-like receptor agonist RU 24213 (N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylamine) and the selective D2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide), using procedures that resolve all topographies of behavior in the natural repertoire. After vehicle challenge, levels of sniffing and rearing seated were reduced in DARPP-32 mutants; the injection procedure seems to constitute a "stressor" that reveals phenotypic effects of DARPP-32 deletion not apparent under natural conditions. Topographical effects of 0.3 to 10.0 mg/kg RU 24213, primarily induction of sniffing and ponderous locomotion with accompanying reductions in rearing, grooming, sifting and chewing, were not altered to any material extent in DARPP-32-null mice. However, topographical effects of 0.005 to 0.625 mg/kg YM 09151-2, namely, reduction in sniffing, locomotion, rearing, grooming, and chewing but not sifting, were essentially absent in DARPP-32 mutants. Thus, the D2-like receptor agonist-mediated ethogram was essentially conserved, whereas major elements of the corresponding D2-like receptor antagonist-mediated ethogram were essentially absent in DARPP-32-null mice. This suggests some relationship between 1) extent of tonic dopaminergic activation of DARPP-32 mechanisms and 2) compensatory mechanisms consequent to the developmental absence of DARPP-32, which may emerge to act differentially on individual elements of the DARPP-32 system. Critically, the present data indicate that phenotypic effects of a given gene deletion using an agonist acting on the system disrupted cannot be generalized to a corresponding antagonist, and vice versa.

Animals↗

PubMed1995

D-1 dopamine receptors mediate dopamine-induced pancreatic exocrine secretion in anesthetized dogs.

Characterization of dopamine (DA) receptor subtypes was examined on the canine exocrine pancreas using selective DA receptor agonists and antagonists in anesthetized dogs. Each drug was injected i.a. in a single bolus fashion. Graded doses of DA (0.01-3 mumol) produced dose-dependent increases in the secretory rate of pancreatic juice, with a maximum effect at approximately 1 mumol. SCH23390 (3-30 nmol), a selective D-1 DA receptor antagonist, caused a progressive parallel shift to the right in the dose-response curve for DA-induced pancreatic secretion without changes in the maximal response. However, domperidone (3 mumol), a selective D-2 DA receptor antagonist, did not antagonize the DA-induced pancreatic exocrine secretion. A Schild analysis of the data indicates that the inhibitory constant value for SCH23390 to inhibit DA-stimulated secretion was 6.9 nmol. In addition, the stimulatory effects of SKF38393 (0.1-10 mumol) and YM435 (0.3-30 nmol), selective D-1 DA receptor agonists, and LY171555 (1-10 mumol), a selective D-2 DA receptor agonist, on pancreatic secretion were demonstrated. The rank order of agonist potency was YM435 > DA > SKF38393 >> LY171555. These results suggest that DA-induced pancreatic exocrine secretion is mediated by activation of D-1 DA receptors.

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

PubMed2005

D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways.

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of G GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D2-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D2-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D2DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D2DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D2DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D2DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease.

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