Heterogeneous distributions of histamine H3, dopamine D1 and D2 receptors in rat brain

The changes of the histamine H3 and dopamine D1 or D2 receptor binding sites induced by quinolinic acid treatment were studied in order to discriminate the comparative distribution. This treatment resulted in similar decreases in histamine H3 and dopamine D1 receptor binding sites in the striatum and ipsilateral substantia nigra. Dopamine D2 receptor binding sites were relatively well conserved, whereas H3 receptors decreased considerably. These results suggest that histamine H3 and dopamine D1 receptor binding sites are localized on the striatonigral projection neurones which are together sensitive to quinolinic acid, and that the distributional compartment of dopamine D2 receptor binding sites is quite different from those of histamine H3 and dopamine D1 receptors.     

Comparison of D2 and D3 dopamine receptor affinity of dopaminergic compounds in rat brain

This study used quantitative autoradiography to simultaneously evaluate the relative affinities of dopaminergic compounds for dopamine D2 and D3 receptors in rat brain. PD 152255, PD 128907, and l-nafadotride exhibited significantly higher affinity for cerebellar dopamine D3 sites than [3H]quinpirole-labeled sites in caudate/putamen (6.3-, 6.0-, and 2.3-fold, respectively). In contrast, chlorpromazine, risperidone, and domperidone were more potent at striatal dopamine D2 receptors (3.8-, 31-, and 40-fold, respectively). Dopamine, quinelorane, (+)-UH 232, and RS-trans-7-OH-PIPAT exhibited relatively little D2/D3 selectivity.     

Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids

The intravenous administration of the psychoactive constituent of marijuana, delta9-tetrahydrocannabinol (delta9-THC) (62.5-1000 microg/kg), and the synthetic cannabinoid agonist WIN 55212,2 (WIN) (62.5-500 microg/kg), produced a dose-related increase in the firing rate and burst firing in the majority of antidromically identified meso-prefrontal dopaminergic neurons. In a restricted number of neurons (n=4), WIN administration did not increase firing rate but produced an increment of bursting activity. These effects of the cannabinoids were reversed by the intravenous administration of SR 141716 A, a selective cannabinoid antagonist (1 mg/kg), per se ineffective to modify the electrical activity of dopaminergic neurons. The results indicate that stimulation of cannabinoid CB1 receptors produces an activation of meso-prefrontal dopaminergic transmission. Considering that supranormal stimulation of D1 dopamine receptors in the prefrontal cortex has been shown to impair working memory, the present results suggest that the negative effects of cannabinoids on cognitive processes might be related to the activation of dopaminergic transmission in the prefrontal cortex.     

Dopamine receptors and dopaminergic nerves in the vas deferens of the rat

Phentolamine antagonized competitively the effects of noradrenaline (pA2 = 7.1), dopamine (pA2 = 8.0) and tyramine (pA2 = 8.2). Haloperidol had a pA2 value of 7.3 against dopamine and 6.5 against noradrenaline. Apomorphine antagonized competitively dopamine (pA 2 = 4.8) and tyramine (pA2 = 5.1) and noncompetitively antagonized noradrenaline (pD'2 = 3.6). From these data it is concluded that these antagonists interact with dopamine receptors and alpha-adrenergic receptors. Apomorphine (10-4 M) attenuated the maximal response to dopamine and field stimulation, whereas the same concentration of apomorphine potentiated the maximal response to noradrenaline. Assuming that tyramine and field stimulation release the naturally occurring neurohumoral transmitter from adrenergic nerve endings, it is concluded that dopamine is the physiologically functional neurohumoral transmitter in the rat vas deferens which, when released, stimulates specific dopamine receptors.     

Colocalization of dopamine D1 and D2 receptor mRNAs in rat placenta

Dopamine is present in the human placenta. The major function of dopamine is the inhibition of human placental lactogen (hPL) release from human trophoblastic cells. This effect is mediated by cAMP through dopamine D2 receptors. However, studies on the effects of cAMP in the control of hPL release have yielded conflicting results. The purpose of this study is to explore the distribution of dopamine receptors in the rat placenta. Dopamine D1 and D2 receptor mRNAs were colocalized in the rat placenta by in situ hybridization histochemistry using radiolabeled cRNA probes. Dopamine D1 and D2 receptor mRNAs were detected in large cells of the endometrium of the uterus on day 10 of gestation. On days 12-16 of gestation, hybridization signals were localized mainly in the spongiotrophoblast and giant cells of the junctional zone of the placenta. With the development of the placenta, signals were moving from the junctional zone to the labyrinth zone. Pit-1 mRNA was detected in the placental lactotrophs and was also colocalized in neighboring placental sections. Our results clearly showed that dopamine D1 and D2 receptor mRNAs were coexpressed in the placental lactotrophs that express Pit-1 mRNA.     

Visualization of D1 dopamine receptors on living nucleus accumbens neurons and their colocalization with D2 receptors

To examine the substrate for dopamine (DA) synaptic action in the nucleus accumbens (nAcc), we visualized the cellular and subcellular distribution of DA receptors on postnatal nAcc neurons in culture using fluoroprobe derivatives of DA receptor ligands. Previously, we have shown that rhodamine-N-(p-aminophenethyl)-spiperone (NAPS) (10 nM), a derivative of the D2 antagonist spiperone, labels D2-like receptors on living nAcc neurons. We now show that rhodamine-Sch-23390 (30 nM), a derivative of the D1 antagonist, labels D1-like receptors. Putative specific membrane labeling reached a plateau after about 20 min. Labeling was stereospecific, as it was unaffected by competition with (-)-butaclamol, but blocked with (+)-butaclamol. We found that 52 +/- 7% of nAcc medium-sized neurons showed D1 labeling, which extended onto the dendrites. Labeling was also seen on presynaptic terminals, often abutting D1-positive and D1-negative cell bodies, consistent with a presynaptic modulatory role for D1 receptors. Larger neurons, which may be GABAergic or cholinergic interneurons, were also labeled. By sequential labeling first with rhodamine-Sch-23390 and then rhodamine-NAPS, we found that 38 +/- 6% of medium-sized neurons express both D1- and D2-like receptors, indicating that D1-D2 interactions may occur at the level of single postsynaptic neurons.     

Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward

The objectives of this study were to examine the involvement of D1 and D2 receptors within the nucleus accumbens (ACB) in mediating reinforcement. The intracranial self-administration (ICSA) of D1 and D2 agonists was used to determine whether activating D1 and/or D2 receptors within the ACB of Wistar rats is reinforcing. At concentrations of 0.25, 0.50, and 1.0 mM (25, 50, and 100 pmol/100 nl of infusion), neither the D1 agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393 (SKF)] hydrochloride nor the D2 agonist (-)-quinpirole (Quin) hydrochloride was self-administered into the shell region of the ACB. On the other hand, equimolar mixtures of SKF and Quin (SKF+Quin), at concentrations of 0.25, 0.50, and 1.0 mM each, were significantly self-infused into the ACB shell. The core region of the ACB did not support the ICSA of SKF+Quin at any of these concentrations. Rats increased lever pressing when the response requirement was increased from a fixed ratio 1 (FR1) to FR3, and they responded significantly more on the infusion lever than they did on the control lever. Coadministration of either 0.50 mM R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390) hydrochloride, a D1 antagonist, or 0.50 mM S(-)-sulpiride, a D2 antagonist, completely abolished the ICSA of the mixture of SKF+Quin (each at 0.50 mM) into the ACB shell. The present results suggest that concurrent activation of D1- and D2-type receptors in the shell of the ACB had a cooperative effect on DA-mediated reward processes.     

Dopamine D2-like receptors in the rat kidney: effect of denervation

A new method for estimation of agonist-affinity (KA) and relative efficacy was introduced. This method afforded a procedure by which relative efficacy may be estimated while the actual KA values of agonist-receptor complexes are unknown. The relative efficacy may be estimated by employing a newly defined drug parameter, namely the eES value. The eES value is related to drug efficacy and is defined in such a manner that an isolated eES is a meaningful quantity which may indicate whether or not spare receptors are present in an agonist-effector system. The estimation of eES was based on the fact that fixed agonist-competitive antagonist combinations mimic partial agonists and mediate submaximal concentration-effect curves. However, for the practical estimation of eES one may employ data acquired from agonistic concentration-effect curves determined in the absence and presence of increasing concentrations of a competitive antagonist. This procedure was illustrated by utilizing theoretical concentration-effect curves and applied practically by estimating eES and KA values acquired from sets of carbachol and salbutamol curves. The sets of carbachol and salbutamol concentration-effect curves were determined in the absence and presence of their respective competitive antagonists, namely tripitramine and pindolol.     

Central dopaminergic D1 agonists and treatment of Parkinson disease

A glucose analogue labelled with iodine-123 in position 6 has been synthesized: [123I]-6-deoxy-6-iodo-D-glucose (6DIG). The aim of this study was to examine its biological behaviour in order to assess whether it could be used to evaluate glucose transport with SPECT. To establish whether 6DIG enters the cells using the glucose transporter, four biological models have been used: human erythrocytes in suspension, neonatal rat cardiomyocytes in culture, isolated perfused rat hearts, and biodistribution in mice. 6DIG competed with D-glucose to enter the cells and its entry was increased by insulin and inhibited in the presence of cytochalasin B. The biological behaviour of 6DIG was similar to that of 3-O-methyl-D-glucose. 6DIG is a tracer of glucose transport which is very promising for clinical studies.     

Striatal and extrastriatal imaging of dopamine D2 receptors in the living human brain with [123I]epidepride single-photon emission tomography

The complete sequence of a 36775 bp DNA segment located on the right arm of chromosome XV of Saccharomyces cerevisiae has been determined and analysed. The sequence encodes 26 open reading frames of at least 100 amino acids. Eight of these correspond to known genes, whereas 18 correspond to new genes.     

The roles of accumbal dopamine D1 and D2 receptors in maternal memory in rats.

Female rats show enhanced maternal responsiveness toward their young if they have had maternal experiences before. This kind of maternal experience-based memory is critically dependent on the mesolimbic dopamine (DA) system, especially the nucleus accumbens (NA) shell. However, the relative contributions of the two main DA receptor systems (D? and D?) within the shell have not been delineated. This study investigates the roles of dopamine D? and D? receptors in maternal memory by infusing a selective D? antagonist, SCH-23390; a selective D? antagonist, sulpiride; or a combination D?/D? antagonist, cis-Z-flupenthixol, into the NA shell of postpartum female rats. Sulpiride-infused rats showed a significantly longer latency to exhibit full maternal behavior following a 10-day pup isolation period in comparison to the controls that received a vehicle. Cis-Z-flupenthixol disrupted maternal memory to a greater extent, as rats receiving this showed the longest latencies to express maternal behavior. SCH-23390 infusions had only marginal effects. These findings suggest that both the D? and the D? receptor subtypes play a role in the consolidation of maternal memory and they might do so by mediating the motivational salience of pup stimulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral effects of selective and nonselective dopamine agonists on young rats after irreversible antagonism of D1 and/or D2 receptors

In general, preweanling and adult rats respond similarly when challenged with competitive dopamine (DA) agonists or antagonists. In contrast, results using a noncompetitive antagonist suggest that the D1 and D2 receptor systems of preweanling and adult rats differ in some critical way. To further assess this phenomenon, the behavioral effects of irreversible receptor blockade were assessed across 8 days in NPA (a nonselective DA agonist), quinpirole (a D2 agonist), or SKF 38393 (a D1 agonist) treated 17-day-old rat pups. The irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) did not block the locomotor activity and rearing of NPA- or quinpirole-treated rat pups, nor did EEDQ reduce SKF 38393-induced grooming. Moreover, pretreatment with EEDQ appeared to potentiate the normal increases in locomotor activity and rearing produced by NPA, but only when D2 receptors were not protected by a previous injection of sulpiride (a D2 antagonist). Taken together, these results are consistent with the presence of large reserves of D1 and D2 receptors in the preweanling rat pup.     

Melatonin administration increases the affinity of D2 dopamine receptors in the rat striatum

Rats receive melatonin (MEL) (476 +/- 6.5 microg/kg/day) via their drinking water for 2 weeks. At the end of this period, the density of D2 dopamine (DA) receptors and their affinity for [3H]-YM-09151-2 are measured in the striatum. MEL treatment increases the apparent affinity (decreases the Kd) of D2 DA receptors for [3H]YM-09151-2 by 48%, while it does not significantly alter the density (Bmax). These findings indicate that the affinity of D2 DA receptors in the striatum is influenced by exposure to MEL. The possible implications of these results are discussed.     

The effect of chronic L-dopa administration on supersensitive pre- and postsynaptic dopaminergic receptors in rat brain

Chronic administration of haloperidol induced supersensitivity of the pre- and postsynaptic dopaminergic receptors in rat brain. The response of the presynaptic receptors was determined by an enhanced inhibitory effect of apomorphine on dopamine synthesis after gamma-butyrolactone injection. This change in the receptor function was detected both in the nigrostriatal and mesolimbic pathways. Haloperidol also increased the 3H-spiperone binding sites in striatal membranes, indicating supersensitivity of the postsynaptic receptors. Subsequent prolonged treatment with high doses of L-DOPA/carbidopa resulted in a decrease in 3H-spiperone binding sites, but had no effect on the supersensitive presynaptic receptors. It is suggested that tardive dyskinesia may be a state of both pre- and postsynaptic dopamine receptor supersensitivity and that chronic L-DOPA treatment may have a differential effect on these sites.     

Photoaffinity labeling of D1 and D5 dopamine receptors

Although human D1 and D5 dopamine receptors are encoded by distinct genes and share only 50% sequence homology at the amino acid level, their pharmacological properties are identical. Using a selective D1 receptor photoaffinity radioligand, (+/-)-7-[125I]iodo-8-hydroxy-3-methyl-1-(4-azidophenyl)-2,3,4,5-tetrahyd ro-1H-3-benzazepine ([125I]MAB), we have further probed the molecular properties of these receptors in transfected GH4C1 rat pituitary cells. Under reversible, non-covalent binding conditions, [125I]MAB bound to both the D1 and the D5 receptors with identical affinities, dopaminergic selectivity and stereospecificity. Upon photoactivation of the bound [125I]MAB, the label was incorporated into a approximately 64,000 mol. wt protein corresponding to the D1 dopamine receptor. However, there was no specific photoincorporation of the ligand observed in D5 receptors. The lack of [125I]MAB photolabeling of D5 receptors was independent of the cell line chosen, since similar results were obtained using other transfected cells. The data suggest that although both D1 and D5 receptors share structurally similar binding sites, the protein domains around the sites are different. Thus, although there are currently no specific compounds which bind preferentially to D1 or D5 receptors, these receptors can be distinguished from one another by the inability of [125I]MAB to photolabel D5, but not D1, receptors. Such selective targeting of a specific receptor may be useful in understanding the functional importance and/or interaction between closely related members of the same receptor family when co-expressed in the same cell.     

Impact of metyrapone on MK-801-induced alterations in the rat dopamine D1 receptors

The control of cytomegalovirus infection and disease continues to be a major problem in transplantation and different strategies have been developed to reduce its incidence. Early diagnosis of infection soon after transplantation, using molecular tools such as the polymerase chain reaction, have resulted in successful clinical trials using the strategy of pre-emptive therapy. Adoptive transfer of immune cells, which are predominantly the cytomegalovirus-specific cytotoxic T lymphocytes, into transplant recipients has been shown to restore effective immunity. A vaccine preparation has been in development aimed at preventing primary infections in allograft recipients though effective protection has yet to be shown. The mechanisms of viral pathogenesis in chronic graft rejection remain unclear; however, recent contributions from the field of cell biology have increased our understanding of possible processes which have the potential for application in the field of gene therapy for the treatment of disease.     

The effects of anandamide on memory consolidation in mice involve both D1 and D2 dopamine receptors

Post-training administration of anandamide (1.5, 3, 6 mg/kg) dose-dependently impairs the retention of an inhibitory avoidance response in mice. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation, as they were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. Pretreatment with either selective D1 or D2 dopamine (DA) receptor agonists, SKF 38393 and quinpirole, at doses that were ineffective when given alone (5 and 0.25 mg/kg, respectively), antagonized the effects of anandamide on memory consolidation, suggesting that D1 and D2 receptors are similarly involved in the effects of anandamide on memory consolidation. These results are discussed in terms of a possible inverse relationship between the modulation of memory processes by endogenous cannabinoid and DA systems.     

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

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

Differential influence of D1 and D2 dopamine receptors on acute opiate withdrawal in guinea-pig isolated ileum

1. The effects exerted by D1 and D2 dopamine agonists and antagonists on the acute opiate withdrawal induced by mu- and kappa-receptor agonists were investigated in vitro. 2. Following a 4 min in vitro exposure to morphine (moderately selective mu-agonist), [D-Ala2, Me-Phe4, Gly-ol5]enkephalin (DAMGO, highly selective mu-agonist) or U-50488H (highly selective kappa-agonist) the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. 3. The non-selective dopamine receptor antagonist haloperidol when added before or after the opioid agonists, was able dose-dependently to prevent or to reverse the naloxone-induced contracture after exposure to mu- (morphine and DAMGO) and kappa- (U-50488H) opioid agonists. The non-selective dopamine receptor agonist, apomorphine, was able to exert the same effects only at the highest concentration used. 4. The selective D2 dopamine receptor antagonist, sulpiride, was also able to reduce dose-dependently both mu- and kappa-opioid withdrawal, whereas the D1-receptor selective antagonist SCH 23390 did not affect either mu- or kappa-opioid withdrawal. 5. Bromocriptine, a D2 selective dopamine receptor agonist was able to increase significantly, and in a concentration-dependent manner, the naloxone-induced contracture by mu- and kappa-opioid agonists, whereas SKF 38393, a D1 selective dopamine receptor agonist, increased only the withdrawal after morphine or U50-488H. 6. Our data indicate that both D1 and D2 dopamine agonists and antagonists are able to influence opiate withdrawal in vitro, suggesting an important functional interaction between the dopaminergic system and opioid withdrawal at both the mu- and kappa-receptor level. 7. Furthermore, the ability of sulpiride to block strongly opiate withdrawal when compared to SCH 23390, as well as the effect of bromocriptine to increase opiate withdrawal suggest that D2 dopamine receptors may be primarily involved in the control of opiate withdrawal.     

Localization of dopamine receptor subtypes in corpus striatum and nucleus accumbens septi of rat brain: comparison of D1-, D2-, and D4-like receptors

The purpose of this study was to determine whether bradykinin mediates ovalbumin-induced increase in macromolecular efflux from the nasal mucosa of ovalbumin-sensitized hamsters in vivo and, if so, whether the L-arginine/nitric oxide biosynthetic pathway transduces, in part, this response. We found that suffusion of ovalbumin onto the in situ nasal mucosa of ovalbumin-sensitized hamsters, but not of controls, elicited a significant time- and concentration-dependent increase in clearance of fluorescein isothiocyanate-labeled dextran (mol mass, 70 kDa; P < 0.05). HOE-140, but not des-Arg9,[Leu8]-bradykinin, and NG-L-arginine methyl ester (L-NAME), but not NG-D-arginine methyl ester, significantly attenuated ovalbumin-induced responses. L-Arginine, but not D-arginine, abolished the effects of L-NAME. L-NAME also significantly attenuated bradykinin-, but not adenosine-induced increase in macromolecular efflux from the in situ nasal mucosa. Overall, these data suggest that ovalbumin increases macromolecular efflux from the in situ nasal mucosa of ovalbumin-sensitized hamsters, in part, by producing bradykinin with subsequent activation of the L-arginine/ nitric oxide biosynthetic pathway.