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PubMed1982

Effects of dopamine agonists and antagonists on murine melanoma: correlation with dopamine binding activity.

The biosynthetic pathway melanin is present in many melanomas. Previous investigations have suggested that pharmacologic levels of intermediates in this pathway (L-dopa, dopamine, and their analogues) may inhibit macromolecular synthesis in some tissue culture melanoma cell lines and prolong survival in tumor-bearing mice. Recently, a potent antidopamine drug (pimozide) has been developed. This study was designed to investigate the effects of these drugs on murine melanomas and to correlate effects on macromolecular synthesis with competitive dopamine binding activity (receptors) and melanin synthesis. Three murine melanomas (F1, F10, B16) were studied. The amelanotic B16 cell line showed no inhibition by dopa, dopamine, or pimozide when assayed for 14C-leu or 3H-TdR incorporation. Using a competitive binding assay, only low levels of dopamine binding were present. The very melanotic F1 cell line showed no inhibition by dopa or dopamine, but pimozide inhibited 14C-leu and 3H-TdR incorporation in a dose-response fashion; 50% inhibition was noted at 10(-9) M concentration with no loss in cell viability as tested by trypan blue exclusion or cell counting. Competitive dopamine binding was present (19 pmoles per g of wet tissue) with a Kd of 0.2 nM, figures approximating those seen in normal dog caudate nucleus controls. The F10 line, with melanin production between the B16 and F1, was intermediate in terms of inhibition of 14C-leu and 3H-TdR incorporation and dopamine binding. Purified melanin did not bind and, thus, does not appear to explain these binding results. These data suggest that pimozide, a drug which is a potent dopamine antagonist, may inhibit 14C-leu and 3H-TdR incorporation in murine melanoma cells and that competitive dopamine binding (receptor) appears to correlate with this inhibition. This drug and the dopamine binding assay may be useful in the study of human melanoma.

Animals↗
PubMed1984

Dopamine receptors in a human colonic cancer cell line (HT29). Some receptor-related biological effects of dopamine.

The presence of dopamine receptors in normal colonic cells has been postulated from physiological studies. The existence of such receptors in human colonic tumor cells and their role in tumor progression are still unknown. The aim of the present work was to characterize the dopaminergic receptors in a human colonic adenocarcinoma cell line (HT29) and to evaluate the effect of dopamine on cAMP, protein and DNA synthesis. The binding characteristics of 3H-dopamine on the tumor cells were rapid, reversible, specific, saturable and stereospecific. The first site characterized corresponds to a D3 subtype:KD 3.09 nM, insensitive to sulpiride, unrelated to adenylate cyclase. Competitive inhibitions of 3H-dopamine binding by different drugs showed the existence of a second binding site, D1, with an apparent affinity for dopamine of 6,700 nM. The rank order of potency of inhibitors of 3H-dopamine binding was: haloperidol greater than dopamine greater than cis flupenthixol greater than (+) butaclamol greater than (-) butaclamol greater than trans flupenthixol greater than isoproterenol greater than clonidine greater than prazosin. D3 binding sites are modulated with age, Bmax was 116 fmol/10(6) cells on the 5th day and decreased to 8.2 fmol/10(6) cells on the 15th day of culture. Cell culture in serum-deprived medium allowed an increase in the number of high-affinity receptor sites. D1 sites are coupled to adenylate cyclase as shown by a dose-dependent cAMP accumulation from 10(-8) M to 10(-5) M dopamine concentrations. Interacting with D1 sites, dopamine evokes an increase in protein synthesis with no modification of 3H thymidine incorporation. The present results indicate that the human colonic cancer cell line HT29 exhibits dopamine receptors and that stimulation may induce metabolic modifications in the tumor cells.

Binding, Competitive↗
PubMed1986

Neurophysiological evidence that D-1 dopamine receptor blockade attenuates postsynaptic but not autoreceptor-mediated effects of dopamine agonists.

The putatively selective D-1 dopamine receptor antagonist SCH 23390 was used to study the role of the D-1 dopamine receptor in mediating the pre- and postsynaptic effects of dopamine agonists in the basal ganglia. SCH 23390 (1 mg/kg) had no significant effect on the tonic activity of substantia nigra dopamine neurons in 47% of the 19 cells studied, while the firing rates of 53% of the cells were increased. SCH 23390 did not shift the dose response of these cells to apomorphine, whereas the selective D-2 antagonist, YM-09151-2 completely blocked apomorphine's inhibitory effects on nigral dopamine cell activity. These results suggest that SCH 23390 does not interact with the D-2 dopamine autoreceptors, but does excite a subpopulation of dopamine neurons presumably through postsynaptic actions. In contrast to its inability to modify the effects of apomorphine on dopamine autoreceptors, SCH 23390 partially to fully reversed the effects of apomorphine on globus pallidus and substantia nigra pars reticulata cell activity and significantly attenuated the effects of apomorphine, pergolide, quinpirole (LY 171555) and d-amphetamine on firing rates of globus pallidus neurons. The D-1 antagonist alone had no significant effect on tonic globus pallidus neuronal activity. SCH 23390 was more potent than haloperidol in its ability to attenuate the effects of apomorphine on pallidal activity, but unlike haloperidol, was unable to totally inhibit these effects, suggesting that the two antagonists block the excitatory effects of apomorphine on pallidal cell firing rates by different mechanisms. The serotonin2 receptor antagonist, ketanserin, had no effect on pallidal or dopamine cell activity, indicating that the effects of SCH 23390 were not mediated through interactions with serotonin2 receptors. These results suggest that D-1 receptor blockade attenuates the postsynaptic, but not autoreceptor-mediated effects of dopamine agonists.

Animals↗
PubMed1992

The cloned dopamine D2 receptor reveals different densities for dopamine receptor antagonist ligands. Implications for human brain positron emission tomography.

Since [3H]emonapride ([3H]YM-09151-2), a benzamide neuroleptic, consistently detects more dopamine D2 receptors than [3H]spiperone in the same tissue, we tested whether this property was inherent in the cloned dopamine D2 receptor. We found that the density of dopamine D2 receptors labelled by [3H]emonapride was 1.5-fold to 2-fold (mean of 1.8-fold) higher than the density of dopamine D2 receptors labelled by [3H]spiperone in cells expressing cloned dopamine D2 receptors (either the short form (from rat) or the long form (from human)), matching similar findings in anterior pituitary tissue (rat or pig) or in post-mortem human caudate nucleus tissue. The situation was similar for another benzamide, [3H]raclopride, which revealed 1.3-fold to 1.8-fold (mean of 1.5-fold) more binding sites than that for [3H]spiperone in cell membranes containing cloned dopamine D2 receptors. The apparently different dopamine D2 receptor densities revealed by these two types of 3H-ligands (i.e. [3H]spiperone and the [3H]benzamides), therefore, arise from an inherent property of the dopamine D2 receptor protein. These findings for the cloned dopamine D2 receptor, therefore, partly explain the higher dopamine D2 receptor density measured in human brain (by positron emission tomography) when using radioactive raclopride compared to results using radioactive methylspiperone.(ABSTRACT TRUNCATED AT 250 WORDS)

Antipsychotic Agents↗
PubMed1999

Local infusion of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione does not block D1 dopamine receptor-mediated increases in immediate early gene expression in the dopamine-depleted striatum.

Administration of selective agonists of D1 dopamine receptors increases immediate early gene expression in striatal neurons, a response which is particularly robust in the dopamine-depleted striatum. Although interactions between dopamine and glutamate receptor-mediated responses in striatal neurons have been demonstrated in a number of experimental paradigms, our previous findings indicate that N-methyl-D-aspartate antagonists do not block D1 receptor-mediated induction of immediate early genes in the dopamine-depleted striatum. In the present study, we therefore examined interactions between D1 dopamine receptors and the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate subtypes of glutamate receptor by determining whether striatal infusion of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione would block D1 receptor-mediated induction of the immediate early genes c-fos and zif268 in the dopamine-depleted striatum. Striatal infusion of 6-cyano-7-nitroquinoxaline-2,3-dione (1 mM) completely blocked (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate-induced c-fos and zif268 expression. However, 6-cyano-7-nitroquinoxaline-2,3-dione (1 microM-1 mM) did not significantly affect induction of c-fos and zif268 by D1 receptor stimulation (SKF 38393, 2 mg/kg, i.p.) in the dopamine-depleted striatum. To more generally block excitatory input, tetrodotoxin (10 microM) was infused into the striatum of rats receiving a D1 agonist. Local infusion of tetrodotoxin had minimal effect on induction of c-fos and zif268 in the dopamine-depleted striatum. In contrast, tetrodotoxin abolished induction of c-fos and zif268 messenger RNAs by the D2 antagonist eticlopride (0.5 mg/kg, i.p.) in both intact rats and dopamine-depleted rats receiving continuous D2 agonist treatment (quinpirole, 0.5 mg/kg/day). The results indicate that D1 receptor-mediated induction of immediate early genes in the dopamine-depleted striatum occurs by mechanisms that are independent of excitatory input through (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2001

Glutathione S-transferase Pi is a dopamine-inducible suppressor of dopamine-induced apoptosis in PC12 cells.

The finding that the neurotransmitter dopamine induces apoptosis in neurons implies the existence of a cellular mechanism by which dopaminergic neurons protect themselves from dopamine-induced apoptosis. By profiling the expression of a number of genes in differentiating PC12 cells which exhibit elevated levels of dopamine biosynthesis, we found that expression of glutathione S-transferase class Pi (GSTp) mRNA was selectively up-regulated. Interestingly, dopamine added to the culture medium of PC12 cells also augmented their expression of GSTp mRNA. Suppression of GSTp expression by transfection of its antisense expression vector augmented dopamine-induced apoptosis of PC12 cells. Conversely, overexpression of GSTp made the resultant PC12 transfectants highly resistant to dopamine-induced apoptosis. Transfection of the antisense or sense GSTp expression vectors also resulted in corresponding augmentation or suppression of dopamine-induced activation of cell-associated Jun-N-terminal kinase (JNK), which has been suggested to mediate dopamine-induced apoptosis in neuronal cells. These results indicate that GSTp is a dopamine-inducible suppressor of dopamine-induced apoptosis in PC12 cells, and suggest that this activity is exerted through inhibition of JNK activity.

Animals↗
PubMed2002

Studies, using in vivo microdialysis, on the effect of the dopamine uptake inhibitor GBR 12909 on 3,4-methylenedioxymethamphetamine ('ecstasy')-induced dopamine release and free radical formation in the mouse striatum.

The present study examined the mechanisms by which 3,4-methylenedioxymethamphetamine (MDMA) produces long-term neurotoxicity of striatal dopamine neurones in mice and the protective action of the dopamine uptake inhibitor GBR 12909. MDMA (30 mg/kg, i.p.), given three times at 3-h intervals, produced a rapid increase in striatal dopamine release measured by in vivo microdialysis (maximum increase to 380 +/- 64% of baseline). This increase was enhanced to 576 +/- 109% of baseline by GBR 12909 (10 mg/kg, i.p.) administered 30 min before each dose of MDMA, supporting the contention that MDMA enters the terminal by diffusion and not via the dopamine uptake site. This, in addition to the fact that perfusion of the probe with a low Ca(2+) medium inhibited the MDMA-induced increase in extracellular dopamine, indicates that the neurotransmitter may be released by a Ca(2+) -dependent mechanism not related to the dopamine transporter. MDMA (30 mg/kg x 3) increased the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) from salicylic acid perfused through a probe implanted in the striatum, indicating that MDMA increased free radical formation. GBR 12909 pre-treatment attenuated the MDMA-induced increase in 2,3-DHBA formation by approximately 50%, but had no significant intrinsic radical trapping activity. MDMA administration increased lipid peroxidation in striatal synaptosomes, an effect reduced by approximately 60% by GBR 12909 pre-treatment. GBR 12909 did not modify the MDMA-induced changes in body temperature. These data suggest that MDMA-induced toxicity of dopamine neurones in mice results from free radical formation which in turn induces an oxidative stress process. The data also indicate that the free radical formation is probably not associated with the MDMA-induced dopamine release and that MDMA does not induce dopamine release via an action at the dopamine transporter.

Animals↗
PubMed2004

D1 dopamine receptor mediates dopamine-induced cytotoxicity via the ERK signal cascade.

Postsynaptic striatal neurodegeneration occurs through unknown mechanisms, but it is linked to high extracellular levels of synaptic dopamine. Dopamine-mediated cytotoxicity of striatal neurons occurs through two distinct pathways: autoxidation and the D1 dopamine receptor-linked signaling pathway. Here we investigated the mitogen-activated protein kinase (MAPK) signaling pathways activated upon the acute stimulation of D1 dopamine receptors. In SK-N-MC neuroblastoma cells, endogenously expressing D1 dopamine receptors, dopamine caused activation of phosphorylated (p-)ERK1/2 and of the stress-signaling kinases, p-JNK and p-p38 MAPK, in a time- and dose-dependent manner. Selective stimulation of D1 receptors with the agonist SKF R-38393 caused p-ERK1/2, but not p-JNK or p-p38 MAPK activation, in a manner sensitive to the receptor-selective antagonist SCH 23390, protein kinase A inhibition (KT5720), and MEK1/2 inhibition (U0126 or PD98059). Activation of ERK by D1 dopamine receptors resulted in oxidative stress and cytotoxicity. In cells transfected with a catalytically defective mutant of MEK1, the upstream ERK-specific kinase, both dopamine- and SKF R-38393-mediated cytotoxicity was markedly attenuated, confirming the participation of the ERK signaling pathway. Cell fractionation studies showed that only a small amount of p-ERK1/2 was translocated to the nucleus, with the majority retained in the cytoplasm. From coimmunoprecipitation studies, p-ERK was found to form stable heterotrimeric complexes with the D1 dopamine receptor and beta-arrestin2. In cells transfected with the dominant negative mutant of beta-arrestin2, the formation of such complexes was substantially inhibited. These data provide novel mechanistic insights into the role of ERK in the cytotoxicity mediated upon activation of the D1 dopamine receptor.

Cell Line, Tumor↗
PubMedDate not supplied

Effects of dopamine receptor agonists and antagonists at peripheral neuronal and vascular dopamine receptors in the anaesthetised cat.

The potencies of several putative dopamine receptor agonists and antagonists have been determined and compared at neuronal and vascular dopamine receptors in anaesthetised cats. N,N-diethyldopamine and the N,N-di-n-propyl derivatives of 5,6-ADTN (6-amino-5,6,7,8-tetrahydro-1,2-napthalenediol) and 6,7-ADTN (6-amino-5,6,7,8-tetrahydro-2,3-napthalenediol) were, relatively, much more potent agonists than dopamine at neuronal dopamine receptors on the terminals of sympathetic nerves supplying the heart and nictitating membrane than at the vascular dopamine receptors in the mesenteric vascular bed. SK&F 82526 [6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-di ol] showed the reverse profile. Haloperidol, (+/-) sulpiride, cis alpha-flupenthixol, and fluphenazine were much more potent antagonists at neuronal dopamine receptors than at vascular dopamine receptors. The profiles of activity of the agonists and antagonists show that neuronal and vascular dopamine receptors in the cat are different; in addition, the neuronal dopamine receptors in the cat heart and nictitating membrane closely resemble those in the dog femoral vasculature, whereas the vascular dopamine receptors in the cat mesenteric vascular bed are very similar to those in the dog mesenteric circulation.

Anesthesia↗
PubMed1995

Pharmacokinetic and pharmacodynamic studies of chlorpromazine in rats: effect of chlorpromazine on dopamine and dopamine metabolite concentration in rat striatum.

The concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum were increased after the i.v. administration of chlorpromazine (CPZ). Assuming that the enhancement of dopamine concentration in the striatum after CPZ administration is caused by the release of dopamine from the dopamine neuronal terminals, the relationship between the enhancement of dopamine concentration in the striatum and CPZ concentration in the cerebrospinal fluid (CSF) and the striatum were analyzed using the sigmoid Emax model. The enhancement of dopamine concentration in the striatum could be described quantitatively by this model. The time courses of DOPAC and HVA concentration in the striatum after CPZ administration were analyzed using the dopamine metabolism model, which has an apparent first-order clearance from dopamine to DOPAC and HVA, and also using the Michaelis-Menten type elimination kinetics of DOPAC and HVA. The values of the metabolism parameters for DOPAC and HVA were fixed to the estimated values of the L-dopa study. The calculated values of DOPAC and HVA concentrations in the striatum were greater than those of the observed data. The elimination parameters for DOPAC and HVA were reestimated by the nonlinear least squares method. The time courses of DOPAC and HVA concentration in the striatum could be described using these reestimated elimination parameters. These results indicated that the turnover rate of dopamine and dopamine metabolites, DOPAC and HVA in the striatum after CPZ administration is different from that after L-dopa administration.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Effect of dopamine and dopamine-antagonist infusion on blood platelet count, size and release reaction in hypertensive and normotensive subjects.

To examine the effect of dopamine on in vivo platelet function and a possible platelet contribution to the clearance of dopamine we measured platelet count, platelet size and plasma concentration of the platelet specific protein beta-thromboglobulin (BTG) in groups of 40 year old untreated hypertensive and normotensive men. One hypertensive (n = 10) and one normotensive (n = 10) group received dopamine infusion at doses from 0.5 to 2.0 micrograms/kg/min which increased plasma dopamine 100-fold from baseline. Two other groups of hypertensive (n = 10) and normotensive (n = 11) subjects received 10 mg of the dopamine antagonist metoclopramide intravenously, upon which serum prolactin concentration increased 10-fold. No significant effect on platelet function in any group was observed during these interventions. Platelet phenol-sulphotransferase may contribute to dopamine conjugation. However, the selected platelet parameters correlated only weakly with dopamine kinetics during the infusion. Neither dopamine nor a dopamine antagonist altered the selected platelet parameters, nor did these parameters influence the clearance of dopamine during a short-lasting pharmacological infusion.

Blood Platelets↗
PubMed1985

Interactions of dopaminergic agonists and antagonists with dopaminergic D3 binding sites in rat striatum. Evidence that [3H]dopamine can label a high affinity agonist-binding state of the D1 dopamine receptor.

The interactions of dopaminergic agonists and antagonists with 3H-agonist labeled D3 dopaminergic binding sites of rat striatum have been characterized by radioligand-binding techniques. When the binding of [3H]dopamine and [3H]apomorphine to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone, these ligands appear to label selectively the previously termed "D3" binding site. Antagonist/[3H]dopamine competition curves are of uniformly steep slope (nH = 1.0), suggesting the presence of a single D3 binding site. The relative potencies of antagonists to inhibit D3 specific [3H]dopamine binding are significantly correlated with their potencies to block D1 dopamine receptors as measured by the inhibition of both dopamine-stimulated adenylate cyclase and [3H]flupentixol-binding activities. The affinities of agonists to inhibit D3 specific [3H]dopamine binding are also correlated with estimates of these agonists' affinities for the high affinity binding component of agonist/[3H]flupentixol competition curves. Both D3 specific [3H] dopamine binding and the high affinity agonist-binding component of dopamine/[3H]flupentixol competition curves show a similar sensitivity to guanine nucleotides. Taken together, these data strongly suggest that the D3 binding site is related to a high affinity agonist-binding state of the D1 dopamine receptor.

Animals↗
PubMed2005

Interactions of dopamine D1 and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions.

The effects of the dopamine D1 receptor antagonist R(+)-SCH-23390 and D2 receptor antagonist S(-)-eticlopride on d-methamphetamine-induced striatal monoamine reductions 72 h after treatment were investigated in relation to changes in body temperature. Rats were administered four 10-mg/kg doses of d-methamphetamine or saline with a 2-h interval between treatments; 0.5 mg/kg eticlopride or SCH-23390 was administered 15 min before each methamphetamine or saline injection. Two ambient temperature conditions were investigated: 24 and 33 degrees C. Methamphetamine administered at 24 degrees C induced hyperthermia and reduced striatal dopamine content by 73%; 0.5 mg/kg eticlopride or SCH-23390 administered in combination with methamphetamine at 24 degrees C attenuated methamphetamine-induced hyperthermia and prevented significant reductions in dopamine content. At 33 degrees C, eticlopride and SCH-23390 were ineffective in blocking methamphetamine-induced hyperthermia and dopamine content was reduced by 65% in the SCH-23390-methamphetamine group. By contrast, dopamine content was reduced by only 31% in the 33 degrees C eticlopride-methamphetamine group. Thus, although the eticlopride-methamphetamine treatment combination at 33 degrees C exhibited a hyperthermic response comparable to that seen with methamphetamine alone at 24 degrees C, reductions in dopamine content were attenuated in the combination group compared with methamphetamine alone at 24 degrees C. Serotonin changes showed similar attenuated reductions after SCH-23390 or eticlopride pretreatment at 24 degrees C in combination with methamphetamine, but this attenuation was absent at 33 degrees C. The dissociation of methamphetamine-induced striatal dopamine reduction and hyperthermia seen after eticlopride pretreatment suggests a dopamine D2 receptor mechanism in mediating methamphetamine-induced dopamine depletion. However this D2 mechanism does not apply to methamphetamine-induced striatal serotonin reductions.

Animals↗
PubMed1991

Effect of the dopamine D2 receptor agonist quinpirole on the in vivo release of dopamine in the caudate nucleus of hypertensive rats.

Using an in vivo microdialysis method, we found that the extracellular concentrations of dopamine and its main metabolite dihydroxyphenylacetic acid (DOPAC) were lower in the caudate nucleus of 8-week-old spontaneously hypertensive rats (SHR) than in the same area of age-matched normotensive Wistar-Kyoto rats (WKY). No differences in the extracellular concentrations of dopamine and DOPAC were found between renal and deoxycorticosterone acetate (DOCA)-salt hypertensive rats when compared to their respective controls. After subcutaneous administration of the dopamine D2 receptor agonist quinpirole (10, 33 and 100 micrograms/kg), the amount of dopamine and DOPAC in the dialysates was diminished dose dependently. The quinpirole-mediated inhibition of dopamine release was more pronounced in SHR than in WKY, whereas inhibition of the extracellular DOPAC concentration was not different. Compared to WKY, the dose-response curve for the inhibition of dopamine release by quinpirole was shifted to the left in SHR and the maximal inhibition in response to the highest dose was significantly greater. Renal and DOCA-salt hypertensive rats showed no differences in the quinpirole-induced inhibition of the extracellular concentrations of striatal dopamine and DOPAC compared to their controls. The present findings on changes in dopaminergic neurotransmission and D2 autoreceptor-mediated modulation of dopamine release in genetically hypertensive rats but not in rats with experimentally induced hypertension provide further evidence for the hypothesis that alterations in the nigrostriatal dopamine system may be involved in the initiation of the development of spontaneous hypertension.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Dopamine receptor agonist potencies for inhibition of cell firing correlate with dopamine D3 receptor binding affinities.

The potencies for in vivo inhibition of substantia nigra pars compacta dopamine single cell firing were determined for apomorphine, BHT 920, N-0923, (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), pramipexole, quinelorane, quinpirole, RU 24926, U-86170, and U-91356. Significant correlation was obtained between the potencies of these 11 highly efficacious dopamine receptor agonists and the in vitro binding affinities at dopamine D3 receptors, but not at dopamine D2L receptors. These results support a functional role for the dopamine D3 receptor subtype in the autoreceptor-mediated regulation of dopamine cell activity, while a role for dopamine D2 receptors awaits further analysis. In addition, the results demonstrate the limitations of using currently available dopamine receptor agonists to delineate relative in vivo roles for the dopamine D2 and D3 receptor subtypes.

Aminoquinolines↗
PubMed1998

Modification of cataleptic responses to dopamine receptor antagonists after withdrawal from chronic cocaine or cocaine plus dopamine antagonist administration.

1. In mice pretreated chronically with cocaine (indirect dopamine agonist: 10 mg/kg, s.c. on alternating days for 15 days), haloperidol (dopamine D2 antagonist: 0.3 mg/kg i.p.) exerted an enhanced cataleptic response, but SCH23390 (dopamine D1 antagonist: 0.3 mg/kg i.p.) produced an attenuated response at 24 h, which converted to a supernormal response, when it was administered 15-60 days after withdrawal from cocaine. 2. A challenge dose of SCH23390 exhibited enhanced catalepsy when given 15 days, but not at 24 h, after the last pretreatment dose of SCH23390 (0.1-1.0 mg/kg s.c.). In contrast, haloperidol catalepsy was not affected by the SCH23390 pretreatment. 3. However, in animals chronically pretreated with haloperidol (0.1-1.0 mg/kg s.c.), a challenge dose of SCH23390 as well as haloperidol exhibited attenuated cataleptic effects at 24 h and normal cataleptic responses at 15 days after the last dose of the pretreatment regimen. 4. Challenge doses of haloperidol or SCH23390 given to mice 24 h after chronic cocaine pretreatment produced enhanced and attenuated cataleptic responses, respectively; however, these responses were no longer produced when haloperidol or SCH23390 was given to mice pretreated chronically with a combination of cocaine and either haloperidol or SCH23390. 5. The enhanced catalepsy produced by a challenge dose of SCH23390 (15-60 days after chronic cocaine) was further potentiated when it was administered to animals that had been pretreated chronically with a combination of SCH23390 and cocaine, but was antagonized in animals pretreated chronically with haloperidol and cocaine. In contrast, the degree of enhanced cataleptic responses produced by a challenge dose of haloperidol 30-60 days after pretreatment chronically with a combination of cocaine + SCH23390 was similar to that seen after chronic cocaine alone. However, this enhanced response was antagonized in animals that had been pretreated chronically with the combination of cocaine + haloperidol. 6. The results suggest that the coadministration of SCH23390 with cocaine was able to block indirectly dopamine D2 receptor inhibition (subsensitivity) induced during the early withdrawal period from chronic cocaine, despite the fact that by itself SCH23390 did not have an effect on haloperidol catalepsy. Accordingly, the stimulatory effects of dopamine D2 receptors by a single administration of cocaine may be mediated mainly by an indirect stimulation of dopamine D2 receptor function via its D1 receptor stimulating action. 7. The coadministration of SCH23390 with cocaine rather aggravate the subsensitive effect of dopamine D1 receptors (increased SCH23390 catalepsy) produced during long-term withdrawal period from chronic cocaine, but did not affect that of the dopamine D2 receptor. On the other hand, the coadministration of haloperidol with cocaine normalized both D1 and D2 receptor subsensitive effect. 8. These result suggest that a single administration of SCH23390 or haloperidol after long-term withdrawal periods from chronic cocaine may not be effective as antipsychotic drugs because of further aggravation of suppressive behaviors. These results also provide evidence that D2 receptor antagonists may be more effective as antipsychotic drugs than dopamine D1 receptor antagonist, since the coadministration of haloperidol with cocaine normalized the abnormal behaviors seen during early and long-term withdrawal periods from chronic cocaine.

Animals↗
PubMed1999

Adaptive changes in postsynaptic dopamine receptors despite unaltered dopamine dynamics in mice lacking monoamine oxidase B.

Monoamine oxidase (MAO) B is considered a key enzyme in dopamine metabolism. The present studies, conducted in MAO B knockout mice, show that lack of MAO B does not alter extracellular levels of dopamine in striatum. Similarly, the synthesis, storage, uptake, and release of dopamine are also unaltered. However, autoradiography revealed a significant up-regulation of the D2-like dopamine receptors in the striatum of MAO B knockout mice. Mutant mice also exhibit a functional supersensitivity of D1-dopamine receptors in the nucleus accumbens. Thus, the agonist SKF 38,393-induced c-Fos immunoreactivity was significantly increased in knockout mice as compared with wild-type controls. In view of the apparently normal basal dopamine dynamics observed in MAO B knockout mice, we hypothesize that a dopamine-independent mechanism underlies adaptations in dopamine receptor function that occur as a consequence of MAO B depletion. Finally, these findings suggest that chronic administration of MAO inhibitors, as occurs in the treatment of Parkinson's disease and depression, may be associated with an increased responsiveness of CNS neurons to dopamine receptor ligands.

Animals↗
PubMed1991

Do renal tubular dopamine receptors mediate dopamine-induced diuresis in the anesthetized cat?

The aim of this study was to investigate whether the pentobarbitone anesthetized cat is a suitable preparation in which to characterize renal tubular dopamine receptors. Intravenous infusion of dopamine (10-100 micrograms/kg/min) resulted in a dose-related increase in mean blood pressure (MBP), urine output, sodium excretion (UNaV), and fractional sodium excretion (FENa). This diuretic effect occurred despite little change in glomerular filtration rate, suggesting that it is a consequence of decreased tubular reabsorption. Dopamine (10-100 micrograms/kg/min, i.v.) also induced marked dose-related falls in renal vascular conductance; however, renal blood flow was not significantly reduced. The increases in MBP, urine output, UNaV, and FENa induced by dopamine (10-100 micrograms/kg/min, i.v.), were unaffected by pretreatment of cats with either the selective dopamine DA1 or DA2 receptor antagonists, SCH 23390 (30 micrograms/kg, i.v.), or domperidone (100 micrograms/kg, i.v.) respectively. In contrast, pretreatment of cats with the nonselective alpha-adrenoceptor antagonist, phentolamine (1 mg/kg, i.v.) prevented dopamine-induced increases in urine output and MBP. Infusion of the selective dopamine DA1 receptor agonist fenoldopam (0.01-10 micrograms/kg/min) into the left renal artery failed to increase left renal vascular conductance, or left kidney urine output, UNaV, or FENa. In conclusion, this study provides no evidence for the involvement of renal tubular dopamine receptors in dopamine-induced diuresis in anesthetized cats. Rather, the diuretic effect appears to be linked to stimulation of alpha-adrenoceptors.

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