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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↗
PubMed1988

Stimulation of D1 dopamine receptors reveals direct effects of the preferential dopamine autoreceptor agonist B-HT 920 on postsynaptic dopamine receptors.

Possible postsynaptic effects of the preferential dopamine autoreceptor agonist B-HT 920 were studied by means of the mouse motor activity. In reserpine-treated mice, B-HT 920 did not cause any motor activity by itself but it markedly potentiated the slight stimulating effect of the D1 dopamine agonist SKF 38 393. The effect was blocked by either the D2-receptor antagonist sulpiride or the D1-receptor antagonist SCH 23 390, indicating that motor activity is dependent on simultaneous activation of both dopamine receptor types. The hyperactivity produced by 0.1 mg kg-1 B-HT 920 in combination with SKF 38 393 in reserpine-treated mice was at least as great as that following a maximal dose of apomorphine, indicating that B-HT 920 is a full agonist at postsynaptic D2 receptors. The effect of 0.1 mg kg-1 B-HT 920 peaked earlier than those of 1 mg kg-1 and particularly, 10 mg kg-1 suggesting additional effects of the later two doses. B-HT 920 stimulates dopamine autoreceptors almost maximally following 0.1 or 1 mg kg-1 but only the latter dose (with or without SKF 38 393) caused hyperactivity of mice not treated with reserpine. This finding indicates that the postsynaptic D2 receptors are less sensitive to B-HT 920 than the D2 dopamine autoreceptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2003

Association analysis for dopamine D3 receptor, dopamine D4 receptor and dopamine transporter genetic polymorphisms and P300 event-related potentials for normal young females.

OBJECTIVE: It has been demonstrated that the P300 components, a positive event-related potential, are heritable and are influenced by dopaminergic activity. We tested the genetic effects of the dopaminergic system in P300 components by association study. METHODS: In a sample population consisting of 120 normal young Han-Chinese females, we explored the association between the P300 components, and, the genetic polymorphisms including the dopamine D3 receptor (serine-to-glycine polymorphism in exon I), the dopamine D4 receptor (variable number tandem repeat polymorphism in exon III), and the dopamine transporter (variable number tandem repeat polymorphism in promoter region). RESULTS: No associations were demonstrated between the polymorphisms of these three genes and the P300 components. CONCLUSIONS: Our negative findings suggest that these genetic polymorphisms do not play a major role in the modulation of P300 event-related potentials.

Adult↗
PubMed1990

Cardiovascular dopamine receptors: role of renal dopamine and dopamine receptors in sodium excretion.

Research efforts in the area of peripheral dopamine have now established the presence of two distinct subtypes--DA1 and DA2--of DA receptors, and have identified a potential role for dopamine produced within the kidney in the control of renal sodium excretion. Selective DA1 and DA2 receptor agonists are being developed because they exhibit therapeutic potential for treatment of cardiovascular and renal disorders. Furthermore, basic research efforts are aimed towards identifying the stimulus and/or stimuli for the production of dopamine within the kidney and characterizing the cellular signalling processes involved in mediating the renal effects of dopamine and selective DA receptor agonists.

Animals↗
PubMedDate not supplied

Comparative study on the disposition of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and dopamine hydrochloride in rats and dogs.

The pharmacokinetics of a dopamine derivative, TA-870, and dopamine (DA) after oral administration are compared in rats and dogs. The maximum concentrations of free DA in plasma after oral administration of TA-870 were 150 ng/ml in the rat (30 mg/kg) and 234 ng/ml in the dog (33.5 mg/kg). On the contrary, the maximum plasma concentrations after oral administration of DA at an equimolar dose to TA-870 were 12 ng/ml in the rat (12 mg/kg) and 36 ng/ml in the dog (13.5 mg/kg). The AUC values of free DA in plasma after oral administration of TA-870 (30 or 33.5 mg/kg) were 4-6 times higher than those after DA in both animal species. The peak tissue levels of radioactivity in rats after oral administration of [14C]TA-870 (30 mg/kg) were also 5.5 times higher in the liver and 1-2 times higher in other tissues than those after [14C]DA dose (12 mg/kg). In rats, the main excretion route of radioactivity after oral administration of [14C]TA-870 or DA was via the urine. The total recoveries of radioactivity in the urine and feces were 91-96% of the dose within 24 hr for both compounds. Biliary excretion in rats accounted for 19.8% of the dose of [14C]TA-870 and 12.6% of the dose of [14C]DA within 24 hr. These results demonstrate that TA-870 was well absorbed from the digestive tract, extensively metabolized to dopamine, and proved to be an orally usable dopamine prodrug.

Animals↗
PubMedDate not supplied

The role of dopamine (D2), alpha and beta-adrenoceptor receptors in the decrease in gastrointestinal transit induced by dopamine and dopamine-related drugs in the rat.

This study analyses the effects of dopamine receptor agonists and antagonists on rat gastrointestinal transit (GIT) in an attempt to identify the mechanisms involved. Dopamine (DA), apomorphine, quinpirole, bromocriptine and fenoldopam were given by subcutaneous (s.c.), intrathecal (i.t.), intracisternal (i.c.) and/or intraperitoneal (i.p.) routes. In general, DA (200 micrograms, i.t.), apomorphine (3, 5 and 10 mg/kg, s.c.; or 10, 30 and 100 micrograms, i.t.), and bromocriptine (1, 5 and 10 mg/kg, s.c.) elicited decreases in gastrointestinal transit which were significantly antagonized by the D2 receptor antagonists domperidone or alizapride (both 5 mg/kg, s.c.), but remained unaffected by the D1 receptor antagonist SCH 23390 (5 mg/kg, s.c.). Similarly, DA (50, 100 and 200 micrograms, i.c.) and apomorphine (12 and 50 micrograms; i.c.) produced dose-dependent decreases in gastrointestinal transit amenable to blockade by the classical DA receptor antagonist haloperidol (10 micrograms, i.c.). The responses to apomorphine (3, 5 and 10 mg/kg, s.c.) were unaltered by 6-hydroxydopamine (100 mg/kg, i.p.)-induced sympathectomy but were antagonized by both propranolol (1 mg/kg, s.c.) and phentolamine (5 mg/kg, s.c.). Significantly, after bilateral (cervical) vagotomy, gastrointestinal transit was markedly reduced, but apomorphine (5 mg/kg, s.c.) apparently further reduced gastrointestinal transit. The D1 agonists fenoldopam (5, 10 and 20 mg/kg, s.c.) significantly reduced GIT. Fenoldopam-induced antitransit effects were markedly modified by the D1 receptor antagonist, SCH 23390 (5 mg/kg, s.c.); only the response induced by 5 mg/kg of fenoldopam was apparently antagonized by SCH 23390. The mixed D2 and D3 receptor agonist quinpirole (4 and 8 mg/kg, s.c.; or 8 mg/kg, i.p.; 200 micrograms, i.t.) did mimic DA eliciting significant reductions in gastrointestinal transit which, however, were not antagonized by domperidone (5 mg/kg, s.c.). Taken together, the present results support the contention that the decrease in rat gastrointestinal transit induced by DA and apomorphine may be mediated by an interaction with central and/or peripheral D2 receptors. The presence of dopamine receptors (D2) in the alimentary canal are strengthened by antitransit effect of fenoldopam and bromocriptine in the gastrointestinal tract.

Animals↗
PubMed1999

Stimulation of adenosine A1 receptors attenuates dopamine D1 receptor-mediated increase of NGFI-A, c-fos and jun-B mRNA levels in the dopamine-denervated striatum and dopamine D1 receptor-mediated turning behaviour.

Adenosine A1 receptors antagonistically and specifically modulate the binding and functional characteristics of dopamine D1 receptors. In the striatum this interaction seems to take place in the GABAergic strionigro-strioentopeduncular neurons, where both receptors are colocalized. D1 receptors in the strionigro-strioentopeduncular neurons are involved in the increased striatal expression of immediate-early genes induced by the systemic administration of psychostimulants and D1 receptor agonists. Previous results suggest that a basal expression of the immediate-early gene c-fos tonically facilitates the functioning of strionigro-strioentopeduncular neurons and facilitates D1 receptor-mediated motor activation. The role of A1 receptors in the modulation of the expression of striatal D1 receptor-regulated immediate-early genes and the D1 receptor-mediated motor activation was investigated in rats with a unilateral lesion of the ascending dopaminergic pathways. The systemic administration of the A1 agonist N6-cyclopentyladenosine (CPA, 0.1 mg/kg) significantly decreased the number of contralateral turns induced by the D1 agonist SKF 38393 (3 mg/kg). Higher doses of CPA (0.5 mg/kg) were necessary to inhibit the turning behaviour induced by the D2 agonist quinpirole (0.1 mg/kg). By using in situ hybridization it was found that CPA (0.1 mg/kg) significantly inhibited the SKF 38393-induced increase in the expression of NGFI-A and c-fos mRNA levels in the dopamine-denervated striatum. The increase in jun-B mRNA expression could only be inhibited with the high dose of CPA (0.5 mg/kg). A stronger effect of the A1 agonist was found in the ventral striatum (nucleus accumbens) compared with the dorsal striatum (dorsolateral caudate-putamen). The results indicate the existence of antagonistic A1-D1 receptor-receptor interactions in the dopamine-denervated striatum controlling D1 receptor transduction at supersensitive D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Dynamic dopamine-antagonist interactions at recombinant human dopamine D(2short) receptor: dopamine-bound versus antagonist-bound receptor states.

Antipsychotic drugs comprise a wide range of structurally diverse compounds and are considered to be antagonists at dopamine D2 receptors. High-resolution kinetic analyses of their antagonist properties was performed by monitoring dynamic dopamine (DA)-antagonist interactions at the recombinant human dopamine D(2short) receptor. Time-dependent Ca2+ responses were measured following activation of a chimeric G(alphaq/o) protein in Chinese hamster ovary-K1 cells. DA (10 microM) induced a rapid, high-magnitude Ca2+ response (T(max) = 13.2 +/- 0.7 s) followed by a low-magnitude phase, which continued throughout the recorded time period (15 min). Of a large series of putative DA antagonists, (+)-UH 232 and bromerguride demonstrated positive, DA-like intrinsic activity at the presumably unoccupied, DA-free receptor; the other antagonists being silent. Antagonists differed in terms of their abilities to prevent the high-magnitude Ca2+ phase in the antagonist-bound receptor state, and to reverse the low-magnitude Ca2+ phase in the DA-bound state. The benzamide derivatives tropapride and nemonapride fully antagonized both the high- and low-magnitude Ca2+ response. Haloperidol, risperidone, and S 14066 also antagonized both responses but with a maximal effect of only 62 to 79%. Although preventing the high-magnitude response (85-95%), the further putative antagonists (+)-butaclamol (6%), bromerguride (27%), and domperidone (41%) reversed the low-magnitude response only weakly and partially. These Ca2+ data indicate that putative DA antagonists act differently, in particular, at the DA-bound D(2short) receptor.

Animals↗
PubMed1998

Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice.

Dopamine (DA) autoreceptors expressed along the somatodendritic extent of midbrain DA neurons modulate impulse activity, whereas those expressed at DA nerve terminals regulate both DA synthesis and release. Considerable evidence has indicated that these DA autoreceptors are of the D2 subtype of DA receptors. However, many pharmacological studies have suggested an autoreceptor role for the DA D3 receptor. This possibility was tested with mice lacking the D3 receptor as a result of gene targeting. The basal firing rates of DA neurons within both the substantia nigra and ventral tegmental area were not different in D3 receptor mutant and wild-type mice. The putative D3 receptor-selective agonist R(+)-trans-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin+ ++-9-ol (PD 128907) was equipotent at inhibiting the activity of both populations of midbrain DA neurons in the two groups of mice. In the gamma-butyrolactone (GBL) model of DA autoreceptor function, mutant and wild-type mice were identical with respect to striatal DA synthesis and its suppression by PD 128907. In vivo microdialysis studies of DA release in ventral striatum revealed higher basal levels of extracellular DA in mutant mice but similar inhibitory effects of PD 128907 in mutant and wild-type mice. These results suggest that the effects of PD 128907 on dopamine cell function reflect stimulation of D2 as opposed to D3 receptors. Although D3 receptors do not seem to be significantly involved in DA autoreceptor function, they may participate in postsynaptically activated short-loop feedback modulation of DA release.

Animals↗
PubMed1990

Metabolism of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and dopamine after oral administration to rats and dogs.

The metabolism of an orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and of dopamine (DA), were studied by use of thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) for identification and analysis of urinary and biliary metabolites after p.o. and/or i.v. administration to rats and dogs. The conjugated/free ratios of the metabolites were also determined. The urinary metabolites and order of the excretion in rats after p.o. dosing of TA-870 (30 mg/kg) were DA greater than homovanillic acid (HVA) greater than 3,4-dihydroxyphenylacetic acid (DOPAC) greater than 3-hydroxyphenylacetic acid (3-HPAC). Those in dogs (33.5 mg/kg p.o.) were DA greater than HVA greater than de-ethoxycarbonylated TA-870 (DEC-TA-870) not equal to DOPAC. The urinary metabolites and order of the excretion in rats after p.o. dosing of DA (12 mg/kg, equimolar dose to TA-870) were DA greater than DOPAC greater than HVA greater than 3-HPAC, while those in dogs (13.5 mg/kg) were DOPAC greater than DA greater than HVA. The composition of the main urinary metabolites of TA-870 are similar in rats and dogs but after p.o. dosing of DA, excretion of DOPAC in dogs is much (ca. 3 times) higher than that in rats. After administration of DA and TA-870, 3-HPAC was found as a novel metabolite of DA, which was thought to be formed by dehydroxylation of DOPAC or DA with intestinal flora.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Neonatal dopamine lesion in the rat results in enhanced adenylate cyclase activity without altering dopamine receptor binding or dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32) immunoreactivity.

Newborn male Sprague-Dawley rats were treated neonatally with an intracisternal injection of 75 micrograms 6-hydroxydopamine (6-OHDA) following desipramine pretreatment in order to induce a permanent selective dopamine (DA) lesion. At 60-70 days of age a massive loss of tyrosine hydroxylase (TH) immunoreactive (IR) cells was seen in substantia nigra. The TH-IR terminal density was reduced by 92% in striatum, 77% in nucleus accumbens and by 72% in tuberculum olfactorium. Quantitative autoradiography using 3H-SCH-23390 and 3H-spiperone did not reveal any alteration of DA D1 and D2 receptor binding in the denervated regions studied. Furthermore, no change in the Bmax or Kd of 3H-SCH-23390 or 3H-spiperone in vitro binding was observed in membrane preparations of striatum following the neonatal DA lesion. Basal and DA-stimulated accumulation of cAMP was increased in striatal membrane preparations of the neonatally DA-lesioned rats. No alteration of the immunoreactivity of the D1 receptor associated phosphoprotein dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32), was observed as visualized using quantitative immunohistochemistry. Thus, neonatal DA lesions seem to induce a selective functional supersensitivity reflected by an enhanced activity of D1 receptor-coupled adenylate cyclase, without any alteration in the number of affinity of D1 and D2 receptor sites. Furthermore, the appearance of DARPP-32 seems to be independent of intact DA input during development.

Adenylyl Cyclases↗
PubMed1992

An antibody to dopamine D2 receptor inhibits dopamine antagonist and agonist binding to dopamine D2 receptor cDNA transfected mouse fibroblast cells.

A polyclonal antibody to dopamine D2 receptor (D2-receptor) has been used to examine the immuno-inhibition in the binding of a D2 antagonist, [3H]YM09151-2 and an agonist, PPHT-fluorescein to dopamine receptor DNA transfected mouse fibroblast cells. The specific activity of the [3H]YM09151-2 binding to transfected (Ltk-RGB) cells is 4-5 fold higher than untransfected (Ltk-) cells. The antibody is able to inhibit the [3H]YM09151-2 binding to the cell membranes from Ltk-RGB cells (Bmax 110.56 +/- 5.26 and 76.20 +/- 5.18 fmoles/mg protein in the presence of preimmune and immune sera, respectively, with no change in the Kd). The flow cytometric analysis of the PPHT-fluorescein labeled Ltk- and Ltk-RGB cells indicated that ligand specific fluorescence is associated only with small Ltk-RGB cells (second peak) and autofluorescence with large cells (first peak). Preincubation of the Ltk-RGB cells with antibody, reduced the fluorescence intensity of the PPHT-fluorescein by 20-25% without changing the auto-fluorescence. These results suggest that peptide antibody recognize D2-receptor in both membranes and in intact cells and interact at or near the ligand binding site of the receptor.

Animals↗
PubMed1996

Uptake and release of dopamine through the rat dopamine transporter expressed in Xenopus laevis oocyte: evaluation by voltammetric measurement of intracellular dopamine concentration.

An attempt was made to evaluate the uptake and release of dopamine (DA) through the rat dopamine transporter (DAT) expressed in Xenopus laevis oocytes. A carbon electrode was placed intracellularly into the oocyte to measure directly the intracellular concentration of DA ([DA]i) by voltammetric analyzer. Oocytes injected with the rat DAT cRNA showed a rapid rise and fall of [DA]i in response to the perfusion solution in the presence and absence of DA. In the control experiment, oocytes injected with water showed no response to external DA. An increase in [DA]i which was induced in control oocytes injected with DA into cytosol was not affected by DA-free perfusion solution, suggesting that in the absence of the transporter the accumulated DA never leaked out from the cell. Thus, the bi-directional DA fluxes through the transporter were demonstrated electrochemically in real time on-line mode.

Animals↗
PubMed1999

In vivo dopamine clearance rate in rat striatum: regulation by extracellular dopamine concentration and dopamine transporter inhibitors.

Dopamine transporter (DAT) inhibitors are expected to decrease dopamine (DA) clearance from the extracellular space of the brain. However, mazindol and cocaine have been reported to "anomalously" increase DA clearance rate. To better understand in vivo DAT activity both in the absence and presence of DAT inhibitors, clearance of exogenously applied DA was measured in dorsal striata of urethane-anesthetized rats using high-speed chronoamperometry. As higher amounts of DA were ejected, DA signal amplitudes, but not time courses, increased. Clearance rates increased until near maximal rates of 0.3 to 0.5 microM/s were attained. Provided baseline clearance rates were relatively low (< 0.1 microM/s), local application of either nomifensine or cocaine markedly increased exogenous DA signal amplitudes and time courses. Relative to the low baseline group, locally applied nomifensine decreased clearance rate when baseline clearance was high ( approximately 0.4 microM/s). However, even when baseline clearance rates were high, systemic injection of nomifensine, mazindol, GBR 12909, or benztropine increased DA signal amplitudes to a greater extent than time courses, consistent with the observed increases in clearance rates. In contrast, despite low baseline clearance rates, systemic injection of cocaine, WIN 35,428, or d-amphetamine preferentially increased DA signal time course, consistent with the observed decreases in clearance rates. Our results emphasize that as extracellular DA concentrations increase, DAT velocity increases to a maximum, partially explaining the ability of DAT inhibitors to increase DA clearance rates. However, by itself, kinetic activation is not sufficient to explain the ability of certain systemically administered DAT inhibitors to anomalously increase DA clearance.

Animals↗
PubMed1999

Chronic dopamine D1, dopamine D2 and combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys: antiamphetamine effects and extrapyramidal side effects.

To determine: (1) whether the apparent lack of efficacy of dopamine D1 (D1) antagonists in the clinic might be attributable to development of tolerance to antipsychotic effects; and (2) whether combined D1 and D2 antagonism might contribute to clozapine's clinical profile, eight Cebus apella monkeys were chronically treated with a D1 antagonist (NNC 756) ((+)-8-chloro-7-hydroxy-3-methyl-5-(7-(2,3- dihydrobenzofuranyl)-2,3,4,5-tetrahydro-1H-3-benzazepine), a D2 antagonist (raclopride) or a combination of the two antagonists. Prior neuroleptic exposure had resulted in oral dyskinesia in seven monkeys and sensitization to dystonia in all, yielding a model for acute and chronic extrapyramidal side effects (EPS). Dextroamphetamine-induced motoric unrest and stereotypies were used as a psychosis model. We found tolerance toward dystonic symptoms during D1 and D1 + D2 treatments but not during D2 treatment. D2 but not D1 or D1 + D2 antagonism caused exacerbation of dyskinesia. Both D1 and D1 + D2 antagonism were superior to D2 antagonism alone in counteracting the amphetamine-induced behaviors, with no tolerance to antiamphetamine effects. These findings suggest: (1) reasons other than tolerance (e.g., differences among antagonists) may explain the lack of efficacy in clinical trials with D1 antagonists; and (2) that D1 antagonism alone or combined and modest D1 and D2 antagonism offers the potential of antipsychotic efficacy with a lower risk of EPS than traditional D2 antagonism. Further clinical trials with D1 or combined D1 and D2 antagonists are, therefore, recommended.

Amphetamine↗
PubMed1997

Effects of the dopamine D3 antagonist PD 58491 and its interaction with the dopamine D3 agonist PD 128907 on brain dopamine synthesis in rat.

The dopamine (DA) D3 receptor antagonist PD 58491 [3-[4-[1-[4-[2-[4-(3-diethylaminopropoxy)phenyl]benzoimidazol++ +-1-yl-butyl]-1H-benzoimidazol-2-yl]phenoxy]propyl]diethylamine] bound with high affinity and selectivity to recombinant human DA D3 versus D2L and D4.2 receptors transfected into Chinese hamster ovary cells: Ki values of 19.5 nM versus 2,362 and >3,000 nM, respectively. In contrast, the putative DA D3 receptor antagonist (+)-AJ76 displayed low affinity and selectivity for D3 versus D2L and D4.2 receptors (91 nM vs. 253 and 193 nM, respectively). In vitro, PD 58491 (1 nM-1 microM) exhibited D3 receptor antagonist activity, reversing the quinpirole (10 nM)-induced stimulation of [3H]thymidine uptake in D3 CHOpro-5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the gamma-butyrolactone-induced increase in DA synthesis (L-3,4-dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D2/D3 receptor agonist action at DA autoreceptors. PD 58491 (3-30 mg/kg, i.p.) generally did not alter DA or serotonin synthesis in either the striatum or mesolimbic region of rat brain. The D3-preferring agonist PD 128907 decreased DA synthesis in striatum and mesolimbic regions, and this effect was attenuated by pretreatment with PD 58491. These findings support the hypothesis that DA D3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions.

5-Hydroxytryptophan↗
PubMed1999

Dopamine D2 receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum.

Presynaptic D2 dopamine (DA) autoreceptors, which are well known to modulate DA release, have recently been shown to regulate DA transporter (DAT) activity. To examine the effects of D2 DA receptor deficiency on DA release and DAT activity in dorsal striatum, we used mice genetically engineered to have two (D2+/+), one (D2+/-), or no (D2-/-) functional copies of the gene coding for the D2 DA receptor. In vivo microdialysis studies demonstrated that basal and K+-evoked extracellular DA concentrations were similar in all three genotypes. However, using in vivo electrochemistry, the D2-/- mice were found to have decreased DAT function, i.e., clearance of locally applied DA was decreased by 50% relative to that in D2+/+ mice. In D2+/+ mice, but not D2-/- mice, local application of the D2-like receptor antagonist raclopride increased DA signal amplitude, indicating decreased DA clearance. Binding assays with the cocaine analogue [3H]WIN 35,428 showed no genotypic differences in either density or affinity of DAT binding sites in striatum or substantia nigra, indicating that the differences seen in DAT activity were not a result of decreased DAT expression. These results further strengthen the idea that the D2 DA receptor subtype modulates activity of the striatal DAT.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Effect of intravenous dopamine infusion on plasma concentrations of dopamine and dopamine sulfate in men, during and up to 18 h after infusion.

OBJECTIVE: We investigated whether sulfoconjugation contributes to the inactivation of intravenously infused dopamine (DA) in low concentrations with a predominant action on the kidney. METHODS: Plasma DA and dopamine sulfate (DA-S) concentrations were determined during 4 h of intravenous infusion of DA (2 microg/kg/min) and up to 18 h after cessation of infusion. Twenty-seven healthy young subjects participated in the placebo controlled, randomised and double-blind study. RESULTS: Intravenously administered DA was sulfoconjugated rapidly and to a great extent. After starting the infusion, DA levels rose within minutes and reached a steady state after 30-60 min. The steady-state levels averaged 151.3 +/- 8.2 nmol/l. DA-S levels also increased markedly with infusion from 16.7 +/- 9.9 nmol/l at the start of infusion up to 261.2 +/- 24.2 nmol/l at 30 min after cessation of infusion. Plasma DA concentrations after cessation of the infusion decreased rapidly with an initial half-life of elimination of 4.8 min. Concentrations of plasma DA-S declined with a half-life of 4.5 h. Persistent elevations of free and conjugated DA compared with pre-treatment levels were observed even 18 h after cessation. Heart rate and blood pressure remained unchanged both during DA and saline infusion. CONCLUSION: Findings indicate that the sulfoconjugation pathway contributes markedly to the inactivation of intravenously infused DA and seems not to be saturable by DA infusion in low doses.

Adult↗