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At least 703 records · Page 39Linked to original sources

PubMed1986

The selective dopamine D2 receptor antagonist raclopride discriminates between dopamine-mediated motor functions.

The actions on central dopamine (DA) mechanisms of raclopride, a new substituted benzamide, were studied by means of behavioural and biochemical methods in the rat. Raclopride blocked the in vitro binding of the dopamine D2 antagonist 3H-spiperone (IC50 = 32 nM), but not of the unselective D1 antagonist 3H-flupenthixol (IC50 greater than 100,000 nM) in rat striatum, and failed to inhibit striatal DA-sensitive adenylate cyclase in vitro (IC50 greater than 100,000 nM). Raclopride caused a dose-dependent increase in the DA metabolites HVA and DOPAC in the striatum and olfactory tubercle. Behavioural studies showed that raclopride discriminates between the motor behaviours induced by the DA agonist apomorphine. Thus, unlike haloperidol, raclopride blocked apomorphine-induced hyperactivity at considerably lower doses than those inhibiting oral stereotypies. Moreover, raclopride showed a high separation between the doses for blockade of apomorphine-induced hyperactivity and those inducing catalepsy in rats. Raclopride caused a dose-dependent blockade of the specific binding of 3H-spiperone and 3H-N-n-propylnorapomorphine (3H-NPA) in vivo at doses similar to those blocking the behavioural effects of apomorphine. The maximal blockade of 3H-spiperone binding in vivo was lower for raclopride than for haloperidol. Raclopride caused a greater inhibition of 3H-NPA than of 3H-spiperone in vivo binding in the striatum. It is suggested that the ability of raclopride to discriminate between different DA-mediated functions may be attributed to a preferential blockade of a subclass of functionally coupled dopamine D2 receptors in striatal as well as in extrastriatal brain regions in the rat.

Adenylyl Cyclases↗

PubMed1990

Dopamine enhances a voltage-dependent transient K+ current in the MMQ cell, a clonal pituitary line expressing functional D2 dopamine receptors.

The influence of dopamine on voltage-dependent K+ current (IK) was studied in cultured MMQ cells using the whole-cell patch-clamp technique. IK in nearly all MMQ cells revealed a transient outward current component and inactivated during maintained depolarization lasting 60 ms. The transient component was inhibited by prepulse potentials more positive than -40 mV or by addition of 4 mM 4-aminopyridine to the bathing solution and was insensitive to the external Ca2+ concentration. Thus, this transient K+ current resembled the A-current (IA) found in other cells. Dopamine at 1 microM increased by 50% (P less than 0.001) the peak of IK evoked by a test potential to +80 mV and the response was prevented by pretreatment with 100 nM haloperidol, a D2 receptor antagonist. These data suggest that MMQ clonal pituitary cells possess a voltage-gated K+ A-current and that this current can be modulated by dopamine via D2 receptors.

4-Aminopyridine↗

PubMed1992

Striatal dopamine D1-like receptors have higher affinity for dopamine in ethanol-treated rats.

Experiments were carried out with brain tissues of ethanol-experienced (long-term ethanol intake but withdrawn) vs. ethanol-naive animals. The in vitro 3H antagonist binding of [3H]SCH 23390 and of [3H]spiperone to striatal dopamine D1- and D2-like receptors revealed no significant changes in KD and Bmax values. Displacement of the 3H antagonist binding by dopamine indicated high- and low-affinity states, which also showed no significant alteration at the D2-like receptor but a 5-fold increase of dopamine affinity at the high-affinity state of the D1-like receptor of the ethanol-experienced rats.

Animals↗

PubMed1992

Lesions of the mesotelencephalic dopamine system enhance the effects of selective dopamine D1 and D2 receptor agonists on striatal acetylcholine release.

In vivo microdialysis was used to determine the effects of 6-hydroxydopamine (6-OHDA) lesions of the mesotelencephalic dopamine system on dopamine receptor agonist induced changes in extracellular acetylcholine (ACh) concentrations in the striatum. Such lesions increased the inhibitory effect of a low dose of the D2 receptor agonist quinpirole (0.05 mg/kg s.c.) on striatal ACh release. In addition, 6-OHDA lesions enhanced the facilitatory effect of the selective D1 receptor agonist CY 208-243 on striatal ACh release, enabling a subthreshold (0.2 mg/kg s.c.) dose to increase striatal dialysate concentrations of ACh by over 60%. These results indicate that denervation supersensitivity potentiates both the facilitatory effects of D1 receptor agonists and the inhibitory effects of D2 receptor agonists on striatal cholinergic activity. It was also found that the 6-OHDA lesions reduced basal interstitial ACh concentrations by 75% in the ipsilateral striatum. The later results are consistent with the hypothesis that the prepotent action of dopamine in the forebrain is to enhance striatal ACh release via a D1 receptor mechanism.

Acetylcholine↗

PubMed1993

Grooming and vacuous chewing induced by SK&F 83959, an agonist of dopamine 'D1-like' receptors that inhibits dopamine-sensitive adenylyl cyclase.

The benzazepine SK&F 83959 demonstrates high affinity for dopamine D1 receptors and potently inhibits the stimulation of adenylyl cyclase by dopamine. This compound induced the same intense grooming behaviour identified previously as a characteristic response to typical dopamine D1 receptor agonists such as SK&F 77434 that stimulate adenylyl cyclase; it also induced vacuous chewing. These findings constitute direct evidence for a behaviourally relevant subtype of 'D1-like' receptor that is not linked to adenylyl cyclase.

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

PubMed1987

Dopamine turnover and glutamate decarboxylase activity in the rat brain after acute and chronic treatment with raclopride, a dopamine D2-selective antagonist.

The effect of acute and chronic (94, 141 and/or 199 days) oral treatment of rats with the dopamine D2-selective antagonist raclopride (0, 5, 15, 45 and 135 mumol/kg) upon the turnover of dopamine in the striatum and limbic system and upon the activity of glutamate decarboxylase (GAD) in the s. nigra, striatum and frontal cortex has been investigated. A dose-dependent tolerance to the effect of raclopride on the turnover of dopamine was observed after chronic treatment, although the degree of tolerance was marginal at the 5 and 15 mumol/kg doses. Acute treatment with raclopride was without effect on the activity of GAD in the s. nigra, striatum or frontal cortex, whereas chronic (199 days) treatment with 45 mumol/kg of raclopride produced an increase in the activity of GAD in the s. nigra and striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Different effects of dopamine and piribedil (a dopamine D2 agonist) on frog monocular optokinetic nystagmus asymmetry.

Frog monocular optokinetic nystagmus (OKN) displays a directional asymmetry, reacting only to stimulations in the temporal-nasal (T-N) direction. The nasal-temporal (N-T) component is almost absent. The systemic or intrapretectal injection of Piribedil, a D2 dopamine agonist, provokes the appearance of a N-T component suppressing the monocular OKN asymmetry. Conversely, dopamine or haloperidol (a dopamine antagonist, acting mainly on D2 receptors) have no effect upon the monocular OKN unidirectionality. The monocular OKN N-T component still appears after administration of Piribedil even if this injection is preceded by administration of haloperidol which blocks the dopaminergic D2 receptors. Moreover administration of atropine (a cholinergic muscarinic antagonist) following that of Piribedil suppresses the N-T component; when injected before Piribedil, atropine prevents the appearance of the N-T component. These results suggest that in our experiments, Piribedil binds with muscarinic receptors.

Animals↗

PubMed1986

Thalamic control of dopaminergic functions in the caudate-putamen of the rat--III. The effects of lesions in the parafascicular-intralaminar nuclei on D2 dopamine receptors and high affinity dopamine uptake.

Dopamine receptor binding in the caudate-putamen was studied following bilateral lesions of the thalamostriatal pathway. Receptor binding was assayed using [3H]spiperone and defined with both (+)-butaclamol and S(-)-sulpiride. Radiofrequency lesions resulted in an increase in the Bmax of [3H]spiperone binding defined with both (+)-butaclamol and S(-)-sulpiride between 7 and 14 days following surgery. At longer survival times a fluctuating response was seen in which a decrease in receptor binding was observed at 28 days following lesion and a further rise again at 70 days. At no time point was significant change in Kd recorded. Further experiments were carried out to control for the possible effects of damage to fibres of passage and for inadvertent damage to habenula, as well as to define the receptor subtype involved. Ibotenic acid lesions resulted in similar effects to those reported with the radiofrequency method. Thus, 7 days following lesion, Bmax for (+)-butaclamol-defined [3H]spiperone binding increased by approximately 14-20% over that recorded in sham-lesioned animals. Using S(-)-sulpiride to define binding, Bmax was found to increase 13-17% in the same membrane preparations. Similar results were obtained in experiments at 14 days following ibotenic acid induced lesions. Again, no change in Kd was recorded. When radiofrequency lesions were made, which were largely restricted to habenula and associated fibres of passage, only small [(+)-butaclamol defined] or insignificant [S(-)-sulpiride defined] changes in Bmax were recorded. Combined radiofrequency lesions of habenula and ibotenic acid lesions of the thalamus resulted in a larger increase in Bmax for (+)-butaclamol defined binding than with S(-)-sulpiride defined binding. Our interpretation of these findings, in the light of the histology of the lesions, is that the predominant effect of removing thalamic input to the caudate-putamen is an increase in the number of D2 receptors, but without any change of affinity. A small component of the change in Bmax defined with (+)-butaclamol found with radiofrequency lesions may be due to a response at non-dopamine sites (possibly a 5-hydroxytryptamine receptor subtype) following damage to other caudate-putamen afferents which pass near the habenula or fasciculus retroflexus. Following unilateral ibotenic acid lesions of the thalamus, the number of high affinity uptake sites for dopamine was increased at long survival times.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Fluctuation of the dopamine uptake inhibition potency of cocaine, but not amphetamine, at mammalian cells expressing the dopamine transporter.

Cocaine, amphetamines and other psychostimulants inhibit synaptic dopamine uptake by interfering with dopamine transporter (DAT) function. The resultant potentiation of dopaminergic neurotransmission is associated with psychostimulant addiction. Fluctuations in dopamine uptake inhibition potency (DUIP) were observed for classical DAT blockers including cocaine, mazindol, methylphenidate (Ritalintrade mark) and benztropine in CHO cells expressing wild type DAT; cocaine potency also decreased in DAT-expressing non-neuronal COS-7 cells and neuronal N2A neuroblastoma cells. In contrast, the DAT substrate (+)-amphetamine did not display this DUIP fluctuation. In parallel experiments, no fluctuation was observed for the apparent binding affinities of these 5 drugs. The DUIP decrease appeared to correlate with an increase in cell surface DAT expression level, as measured by B(max) values and confocal microscopy. The fact that the DUIP profile of amphetamine diverged from that of the classical DAT blockers is consistent with the idea of fundamental differences between the mechanisms of abused psychostimulant DAT substrates and inhibitors. Identification of the cellular factors that underlie the DAT inhibitor DUIP fluctuation phenomenon may be relevant to anti-psychostimulant drug discovery efforts.

Amphetamine↗

PubMed2000

Dopamine tone regulates D1 receptor trafficking and delivery in striatal neurons in dopamine transporter-deficient mice.

In vivo, G protein-coupled receptors (GPCR) for neurotransmitters undergo complex intracellular trafficking that contribute to regulate their abundance at the cell surface. Here, we report a previously undescribed alteration in the subcellular localization of D1 dopamine receptor (D1R) that occurs in vivo in striatal dopaminoceptive neurons in response to chronic and constitutive hyperdopaminergia. Indeed, in mice lacking the dopamine transporter, D1R is in abnormally low abundance at the plasma membrane of cell bodies and dendrites and is largely accumulated in rough endoplasmic reticulum and Golgi apparatus. Decrease of striatal extracellular dopamine concentration with 6-hydroxydopamine (6- OHDA) in heterozygous mice restores delivery of the receptor from the cytoplasm to the plasma membrane in cell bodies. These results demonstrate that, in vivo, in the central nervous system, the storage in cytoplasmic compartments involved in synthesis and the membrane delivery contribute to regulate GPCR availability and abundance at the surface of the neurons under control of the neurotransmitter tone. Such regulation may contribute to modulate receptivity of neurons to their endogenous ligands and related exogenous drugs.

Animals↗

PubMed2005

Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons.

Anti-parkinsonian agents, pramipexole (PPX) and ropinirole (ROP), have been reported to possess neuroprotective properties, both in vitro and in vivo. The mechanisms underlying neuroprotection afforded by the D3-preferring receptor agonists remain poorly understood. The present study demonstrates that incubation of primary mesencephalic cultures with PPX and ROP or the conditioned medium from PPX- or ROP-treated primary cultures induced a marked increase in the number of dopamine (DA) neurons in the cultures. Similar effects can be observed after incubating with the conditioned medium derived from PPX- and ROP-treated substantia nigra astroglia. Meanwhile, PPX and ROP can protect the primary cells from insult of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Furthermore, the neurotrophic effects of PPX and ROP on mesencephalic dopamine neurons could be significantly blocked by D3 receptor antagonist, but not by D2 receptor antagonist. Moreover, we found that the levels of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the conditioned medium of mesencephalic cultures treated with PPX and ROP were significantly increased. Blocking GDNF and BDNF with the neutralizing antibodies, the neurotrophic effects of PPX and ROP were greatly diminished. These results suggest that D3 dopamine receptor-preferring agonists, PPX and ROP, exert neurotrophic effects on cultured DA neurons by modulating the production of endogenous GDNF and BDNF, which may participate in their neuroprotection.

Animals↗

PubMed1987

Characterization of D2 dopamine receptors in dopamine-resistant prolactin-secreting rat pituitary tumors 7315a and MtTW15.

We have investigated the structure of D2 receptors present in two prolactin-secreting, dopamine-resistant, transplantable rat pituitary tumors, 7315a and MtTW15. These receptors specifically bind with high affinity the dopamine antagonist [3H]spiroperidol when membrane bound or solubilized by [3-(3-cholamidopropyl)-dimethyl-ammonio]-1-propane sulfonate 10 mM and are pharmacologically characterized as D2 type. Target-size analysis by radiation inactivation indicated a molecular mass of approximately 100,000 and 200,000 daltons for receptors present respectively in 7315a and MtTW15 tumors either membrane bound or solubilized. The minimal size of the D2 binding site was evaluated at 94,000 daltons by photoaffinity labeling with [125I]azido-N-(p-aminophenethyl)-spiperone followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A guanine nucleotide had no effect on the displacing potency of the agonist N-propylnorapomorphine evaluated with membrane-bound or solubilized receptors obtained from either tumor. These results suggest the absence or inactivation of a guanine nucleotide binding protein in the receptorial complex of these tumors. Thus, our data indicate that a structural anomaly is present in the D2 receptorial complex of these prolactin-secreting rat pituitary tumors, which may be responsible for their resistance to the inhibitory effects of dopamine.

Affinity Labels↗

PubMed2000

The D2s dopamine receptor stimulates phospholipase D activity: a novel signaling pathway for dopamine.

The D2 dopamine receptor isoforms signal to a variety of cellular effectors in both the central nervous system and periphery. Two alternative splice forms of the D2 dopamine receptor exist, the D2s (short) and D2l (long), which has an insertion of 29 amino acids in the third intracellular loop (). In cells of the anterior lobe of the pituitary, D2 dopamine receptors (both forms) are present on lactotroph cells coupled to the inhibition of adenylyl cyclase, activation of voltage-gated calcium channels, and inhibition of potassium channels. We describe here a novel signaling pathway for the D2s, which is the activation of phospholipase D (PLD). GH4C1 cells, a clonal line derived from a rat pituitary tumor, were stably transfected with the gene encoding the D2s, generating GH4-121 cells. Treatment of GH4-121 cells with a dopaminergic agonist resulted in activation of PLD in both a dose-dependent and time-dependent manner. This signaling pathway was not inhibited by prior treatment of cells with pertussis toxin at concentrations that ablate other D2s receptor signaling in this cell line. The stimulation of PLD activity by D2s appeared to correlate with the presence of a specific protein kinase C isoform, PKCepsilon. The D2s stimulation of PLD activity was blocked by preincubation of cells with C3 exoenzyme, indicating that the stimulation of PLD may involve Rho family members. The stimulation of PLD by dopaminergic agonists took place in the absence of any detectable stimulation of phosphoinositide metabolism.

ADP Ribose Transferases↗

PubMed1984

The dissociation rate of unlabelled dopamine antagonists and agonists from the dopamine-D2 receptor, application of an original filter method.

A filtration technique was developed to measure the dissociation rate of unlabelled drugs from membrane receptors. Receptor preparations saturated with unlabelled drug were adsorbed to glass fibre filters positioned on a filtration apparatus. Dissociation of the drug from the receptor sites was achieved by repeatedly applying small buffer samples on the filter, this was followed by short incubation on the filter with a [3H]ligand. Rat striatal membrane preparations adsorbed on filters retained the same dopamine-D2 receptor binding properties as the tissue in aqueous suspension. Stereospecific [3H]haloperidol binding was maximal with 20 mg tissue per filter and 5 min incubation, KD = 2.8 nM and Bmax = 24 fmoles/mg tissue was found. The dissociation from the dopamine-D2 receptor for 18 dopamine antagonists and 3 agonists followed first order reaction kinetics. Half-lifes of dissociation ranged from 3.5 min for azaperone to 233 min for metitepine. There was no strict relationship between dissociation half-life and apparent equilibrium binding affinity or lipophilicity of the drugs. Half-life of receptor dissociation appeared neither to be a primary determining factor in the duration of pharmacological action of the drugs. The importance of the drug receptor dissociation rate for binding experiments in vitro as well as for chronic drug treatment is discussed.

Animals↗

PubMed2001

Blockade of D1 dopamine receptors in the ventral tegmental area decreases cocaine reward: possible role for dendritically released dopamine.

This study was designed to assess the involvement of D1 dopamine actions in the ventral tegmental area (VTA) on intravenous cocaine self-administration. Rats were trained to self-administer intravenous injections of cocaine (1.0 mg/kg per injection) on a fixed-ratio 1 (FR-1) schedule or a progressive ratio (PR) schedule of reinforcement and then were tested under the influence of bilateral VTA injections of the D1 dopamine receptor antagonist SCH 23390 or the 5-HT2 receptor antagonist ketanserin. SCH 23390 increased cocaine self-administration on the FR-1 schedule but decreased it on the PR schedule. Injections of ketanserin were ineffective, as were injections of SCH 23390 in a site 1 mm dorsal or 1 mm rostral to the effective VTA site. These data suggest a role for dendritically released dopamine, presumably acting through D1 receptors located on the axons of GABAergic or glutamatergic inputs to the VTA, in the effectiveness of cocaine reward.

Animals↗

PubMed1993

D2 dopamine receptor stimulation of mitogenesis in transfected Chinese hamster ovary cells: relationship to dopamine stimulation of tyrosine phosphorylations.

Several neurotransmitters that act through G protein-linked receptors have been shown to affect the growth rate of dividing cells. An analysis of the early signaling events that mediate this response revealed some novel activities for G protein-linked receptors. Activation of D2 receptors heterologously expressed in CHO cells also stimulates the synthesis of DNA, which results in increased proliferation. Pertussis toxin pretreatment abolishes D2 agonist-stimulated mitogenesis, which indicates the need for a G protein. D2 receptor-stimulated mitogenesis occurs in the presence of a membrane-soluble cyclic AMP analog and, in Chinese hamster ovary cells with a mutated protein kinase A, which is resistant to the growth effects of cyclic AMP. Therefore, the proliferative response is independent of changes in cyclic AMP. It was determined that a number of other signaling pathways commonly used by Gi-linked receptors are not involved in the D2-mediated mitogenic response. These include arachidonic acid release, stimulation of protein kinase C, stimulation of inositol phosphates, opening of K+ channels and activation of amiloride sensitive Na+/H+ exchange. D2 receptor-stimulated mitogenesis is blocked by genistein, a tyrosine kinase inhibitor, at the same concentrations that block thrombin-stimulated mitogenesis. In fact, dopamine and thrombin stimulate a rapid increase in tyrosine phosphorylation of a number of substrates in the transfected Chinese hamster ovary cells. These results reveal a novel signaling event for D2 dopamine receptors, activation of tyrosine phosphorylations. They suggest the importance of these events for D2 dopamine receptor-stimulated mitogenesis.

Animals↗

PubMed1995

D1 and D2 dopamine receptor function in the striatum: coactivation of D1- and D2-dopamine receptors on separate populations of neurons results in potentiated immediate early gene response in D1-containing neurons.

D1- and D2-dopamine receptor-mediated regulation of immediate early gene levels in identified populations of neurons in the striatum was examined with quantitative in situ hybridization histochemical techniques. Levels of messenger RNA (mRNA) encoding the immediate early genes zif268 and c-fos were examined in two experiments in rats with unilateral lesions of the nigrostriatal dopamine pathway. In a dose-response study, animals were treated with doses of 0.5, 1.0, and 1.5 mg/kg of the D1 agonist SKF-38393 either alone or in combination with the D2 agonist quinpirole (1 mg/kg). Levels of immediate early gene mRNAs 60 min following drug treatments showed a dose-related increase to the D1 agonist alone and a potentiation to combined D1 and D2 against treatment. In a second experiment, in animals receiving 1 mg/kg SKF-38393 either alone or in combination with 1 mg/kg quinpirole, the level of zif268 mRNA was measured with a double-labeling method in striatal neurons containing enkephalin mRNA, a marker of D2-containing neurons, and in neurons not containing enkephalin, putative D1-containing neurons. In the dopamine-depleted striatum, D1 agonist treatment alone did not affect enkephalin-positive neurons but significantly elevated zif268 mRNA levels in nearly all enkephalin-negative neurons. Combined D1 and D2 agonist treatment further increased zif268 mRNA levels in this population of enkephalin-negative neurons and decreased zif-268 mRNA levels in enkephalin-positive neurons. These data indicate that the synergistic response to combined D1- and D2-receptor stimulation is mediated by interneuronal interactions involving the activation of D1 and D2 receptors on separate populations of striatal neurons.

Animals↗

PubMed1997

Direct approach for attenuating cocaine's effects on extracellular dopamine: targeting the dopamine transporter.

Using in vivo microdialysis techniques, the effects of RTI-55 and/or cocaine on extracellular dopamine (DA) concentrations were measured in the nucleus accumbens (NACC) of freely moving rats. In control animals, cocaine (20 mg/kg) increased NACC DA approximately 458% 60 minutes following administration, returning to baseline values within 200 minutes. Similarly, RTI-55 administration (0.25 mg/kg) increased NACC DA levels approximately 347%. When combined, however, cocaine further increased NACC DA to 705% of baseline values when given 4 hours following RTI-55. This increase was significantly larger than cocaine alone (P < 0.05). In addition, chronic RTI-55 administration (5 days) further potentiated cocaine's ability to increase NACC DA (783%) but this did not reach statistical significance (P > 0.1) compared to acute RTI55/cocaine animals. These findings indicate that RTI-55, a drug that binds directly to the dopamine transporter (DAT) with higher affinity than cocaine, does not appear to be effective in attenuating cocaine's effects on NACC dopamine levels. In fact, acute RTI-55 potentiates cocaine's effects on NACC DA.

Animals↗