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At least 433 records · Page 24Linked to original sources
PubMed1980

Effects of chronic treatment with l-sulpiride and haloperidol on central monoaminergic mechanisms.

Chronic treatment with l-sulpiride (20 mg/kg, twice daily) and haloperidol (0.2 mg/kg, twice daily) for 2 weeks produced behavioral signs of DA receptor supersensitivity in both the striatum and the nucleus accumbens-tuberculum olfactorium region. Thus, 48 hr after treatment apomorphine-induced locomotion, total activity, and rearing activity was significantly enhanced. These behavioral results were correlated with 10% increases in the number of binding sites for the DA agonist 3H-ADTN and the DA antagonist 3H-spiperone in striatum, but the latter sites appeared to be markedly increased in number in the subcortical limbic region. A marked loss of stereoselectivity was demonstrated in the 3H-ADTN binding site, a change that could also in part be involved in producing the signs of enhancement of DA effector mechanisms observed. A corresponding loss of stereoselectivity was not observed in the 3H-spiperone binding site to which, instead, the (+)-butaclamol had an increased affinity. Haloperidol, but not l-sulpiride, in the doses used produced a further enhancement of degeneration-induced supersensitivity at DA receptor sites.

5-Hydroxytryptophan↗
PubMed1982

The effect of the alkaloid (-)cathinone on the motor activity in mice.

Khat leaves, widely used as a stimulant in East Africa and the Arab Peninsula, contain the alkaloid, (-)cathinone. This substance was found to cause in mice an increase of locomotor activity characterized by a dose-effect relationship typical for amphetamine. Furthermore, the effect of (-)cathinone was inhibited by pretreatment of the animals with the neuroleptics haloperidol, spiroperidol, pimozide, flupentixol and butaclamol. Pretreatment with reserpine reduced the effect of (-)cathinone moderately; in reserpinized mice the effect of (-)cathinone was antagonized by the uptake inhibitors mazindol and nomifensine. Together, these observations indicate that the pharmacology of (-)cathinone hypermotility closely parallels that of amphetamine hypermotility. The results suggest that the stimulating properties of khat leaves are due to the presence of an alkaloid with amphetamine-like effects.

Alkaloids↗
PubMed1981

Evidence for a D1 dopamine receptor in the salivary glands of Amblyomma americanum (L.).

Adenylate cyclase from the salivary gland of the lone star tick, Amblyomma americanum, is stimulated by several derivatives of phenylethylamine; dopamine, noradrenaline, adrenaline and isoproterenol. Octopamine and iota-DOPA had no effect on basal adenylate cyclase activity. Dopamine had the highest potency and the lowest Ka, 0.4 micron; followed by adrenaline and noradrenaline, 23 micron; and isoproterenol, 0.15mM. When either noradrenaline or adrenaline was added to dopamine, each at its maximally effective concentration, no additional stimulation of gland cyclase activity was noted. Furthermore, adrenaline and noradrenaline together did not equal the potency of dopamine alone. The most potent inhibitors of gland cyclase activity were the dopamine receptor antagonists. The phenothiazine drugs (thioridazine, chlorpromazine, and fluphenazine) were more effective inhibitors of cyclase activity than the butyrophenone drug (haloperidol). The inhibition constants (Ki) for the phenothiazine drugs were: 60nM for thioridazine, 1.9 micron for chlorpromazine and 2.3 micron for fluphenazine. The inhibition of adenylate cyclase activity was found to be specific for the (+) enantiomer of butaclamol, a stereospecific dopamine receptor antagonist. Our findings suggest that the lone star tick salivary gland adenylate cyclase has a D1 type dopamine receptor.

Adenylyl Cyclases↗
PubMed1981

Activation of adenylate cyclase by ethanol in mouse striatal tissue.

The effects of ethanol on adenylate cyclase activity were investigated in homogenates of mouse striatum. Ethanol (34--340 mM) elicited a linear increase in basal and dopamine-stimulated adenylate cyclase activities. The increase in dopamine-stimulated activity was statistically significant at ethanol concentrations of 68 mM and above. The increase in maximal adenylate cyclase activity observed in the presence of ethanol was not entirely due to the increase in basal activity. In the presence of 100 and 300 mM ethanol maximal adenylate cyclase activities were increased by 26 and 71% even after correcting for the increase in basal activity. The concentration of dopamine required for half-maximal activation was not changed by the presence of ethanol. Activation of adenylate cyclase by ethanol was found to be reversible and was not blocked by the dopaminergic antagonist butaclamol, the alpha adrenergic antagonist phentolamine or the beta adrenergic antagonist propranolol. Concentrations of ethanol of up to 500 mM did not change either the affinity of the receptor for [3H]-spiroperidol or the density of binding sites. A decrease in the affinity of the receptor for the radioligand was observed at higher concentrations of ethanol. The affinity of the receptor for dopamine was decreased by 2-fold in the presence of 300 mM ethanol. Addition of 300 microM GTP elicited a 5-fold decrease in the affinity o the receptor for dopamine in both the presence and absence of ethanol. The activation of adenylate cyclase by ethanol was not unique to striatal tissue. In studies carried out with homogenates of cerebral cortex and cerebellum, addition of ethanol increased basal, isoproterenol-stimulated and sodium fluoride-stimulated activities. The results show that pharmacologically relevant concentrations of ethanol can alter adenylate cyclase activity.

Adenylyl Cyclases↗
PubMed1995

[3H]-quinelorane binds to D2 and D3 dopamine receptors in the rat brain.

Quinelorane is a BCD partial ergoline with potent dopaminergic effects in vitro and in vivo. Partial ergoline compounds of this series consist of the B-, C- and D-rings of the four ring ergoline skeleton. Many of the pharmacological effects of quinelorane are believed to be due to stimulation of the D2 subtype of the dopamine receptor. Recently, a D3 dopamine receptor was identified that is insensitive to guanine nucleotides and exhibits an unusual distribution in the brain. When this receptor is expressed in Chinese hamster ovary cells, quinelorane has higher affinity for the D3 receptor than the D2 receptor. To further define the pharmacology of quinelorane, we have synthesized [3H]-quinelorane and examined its binding to sections of rat brain in vitro. [3H]-quinelorane bound with high affinity (KD = 1.8 nM) and exhibited very low nonspecific binding. D2 selective antagonists, such as (+)butaclamol and spiperone, were potent inhibitors of binding while the D1 antagonist SCH23390 was significantly less potent. A majority of the binding was inhibited in a concentration-dependent manner by guanylyl-imidodiphosphate with a maximal inhibition at concentrations of 1 microM and greater. Autoradiographic studies were performed in the presence and absence of 10 microM Gpp(NH)p. Binding in D2 containing regions, such as the caudate-putamen, was completely inhibited by guanylyl-imidodiphosphate although binding in D3 containing areas, such as the islands of Calleja, was unaffected. Therefore, [3H]-quinelorane is an excellent agonist radioligand for the localization of D2 and D3 receptors in rat brain.

Animals↗
PubMed1994

Relationship between sigma-like site and progesterone-binding site of adult male rat liver microsomes.

An increasing amount of evidence suggests that the sigma (sigma) sites, putative targets for a variety of psychotomimetic and antipsychotic drugs, exist not only in the brain but also in various peripheral organs. However, there are many ambiguities as to their biological roles, subcellular distributions, endogenous ligands and so on. We therefore performed our study for clarification of some of these ambiguities. As a result, we demonstrated that adult male rat liver microsomes, especially smooth endoplasmic reticulum, possessed a saturable haloperidol-binding site closely resembling the sigma site, with a high affinity (Kd 1.0 +/- 0.3 nmol/L) and high capacity (Bmax 9.3 +/- 1.5 pmol/mg protein) and with the rank order of affinity of the ligands: haloperidol > reduced haloperidol > clorgyline > ifenprodil > 1,3-di(2-tolyl)guanidine, (-)-butaclamol > GBR-12909 > SKF-525A > progesterone > 5 alpha-dihydrotestosterone > R(+)-3- (hydroxyphenyl)-N-propylpiperidine > testosterone >> corticosteroids, estradiol-17 beta, cholesterol and neuroactive compounds displaying high affinities for other neurotransmitter receptors such as dopamine D2, serotonin (5-HT1A and 5-HT2) and alpha 1-adrenergic and GABAA receptors. This rank order showed a high correlation (r = 0.908) with that of a large portion (approximately 85%) of specific progesterone-binding site (Kd 31.0 +/- 3.5 nmol/L, Bmax 5.7 +/- 0.2 pmol/mg protein) of the same source. Therefore, these two sites were suggested to be the same or closely related. Furthermore, we provide a strong suggestion that these sites neither are identical with some subforms of the microsomal cytochromes P-450 or other steroid/drug-metabolizing enzymes nor participate universally and directly in the progesterone-metabolizing processes.

Animals↗
PubMed1994

Primary structure and functional characterization of a Drosophila dopamine receptor with high homology to human D1/5 receptors.

Members of the superfamily of G-protein coupled receptors share significant similarities in sequence and transmembrane architecture. We have isolated a Drosophila homologue of the mammalian dopamine receptor family using a low stringency hybridization approach. The deduced amino acid sequence is approximately 70% homologous to the human D1/D5 receptors. When expressed in HEK 293 cells, the Drosophila receptor stimulates cAMP production in response to dopamine application. This effect was mimicked by SKF 38393, a specific D1 receptor agonist, but inhibited by dopaminergic antagonists such as butaclamol and flupentixol. In situ hybridization revealed that the Drosophila dopamine receptor is highly expressed in the somata of the optic lobes. This suggests that the receptor might be involved in the processing of visual information and/or visual learning in invertebrates.

Amino Acid Sequence↗
PubMed1994

Expression and pharmacological characterization of the human D3 dopamine receptor.

Binding of dopamine receptor ligands to human D2 and D3 receptors was characterized in Chinese hamster ovary (CHO) cells using the dopamine D2 receptor antagonist [125I] iodosulpiride. Only limited binding selectivity was observed for known dopamine D2 receptor antagonists from a variety of chemical classes, which included haloperidol, chlorpromazine, sulpiride, pimozide and cis flupenthixol. The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. There was no evidence of functional coupling of the hD3 receptor to adenylate cyclase, arachidonic acid release, phospholipase C activation, K+ currents or calcium mobilization in any of the cell lines examined. Furthermore, guanine nucleotides failed to inhibit the binding of [3H] N-0437 to hD3 receptors in any of the three cell lines. There may be a number of explanations for these results. These cell lines may not have the appropriate G-protein or secondary messenger systems that are coupled to the hD3 receptor in situ. Alternatively, this receptor may couple by a mechanism that is as yet undefined. The finding that a wide range of structurally diverse human dopamine D2 (hD2) receptor agonists have an apparent hD3 selectivity may imply that the hD3 receptor exists predominantly in a high affinity state.

Animals↗
PubMed1994

Pharmacological and functional characterization of D2, D3 and D4 dopamine receptors in fibroblast and dopaminergic cell lines.

In order to study the properties of the D2-like dopamine receptors, D2, D3 and D4 clones were transfected into mouse Ltk- fibroblasts, CCL1.3, and a neuronal mesencephalic cell line, MN9D. Most of the derived antagonist and agonist inhibition constants were the same for a given receptor in either cell line as determined by saturation and competition binding experiments. The rank order potencies for antagonists are: eticlopride, D2 > D3 > D4; YM-09151-2, D2 = D4 > D3; spiperone, D2 = D3 > D4; (+)-butaclamol, D2 > D3 > D4; clozapine, D4 > D2 > D3; and for agonists, quinpirole, D3 = D4 > D2; 7-hydroxy-2-(di-n-propyl)-aminotetralin, D3 > D2 = D4. Functionally, D2 stimulation increases inositol phosphate levels in CCL1.3 cells but not in MN9D, whereas D2 activation inhibits forskolin-stimulated cyclic AMP levels in both cell lines. D4 stimulation has no effect on inositol phosphate metabolism in either cell type, but inhibits adenylate cyclase in MN9D cells. Both the D2 and D4 mediated decreases in cyclic AMP can be blocked by preincubation with pertussis toxin. D3 does not couple to these pathways in either cell line. Reverse transcription/polymerase chain reaction techniques were used to determine the availability of cellular signalling systems. Both CCL1.3 and MN9D cells have high levels of G alpha i2 expression, whereas neither cell expresses G alpha i1 or G alpha i3. These data imply that the D2 receptor couples to the G alpha i2 subtype in both cell lines, whereas D4 does not.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗
PubMed1996

Differential coupling of rat D2 dopamine receptor isoforms expressed in Spodoptera frugiperda insect cells.

By using a baculovirus expression system, the two isoforms of the rat D2 dopamine receptor were expressed at densities ranging up to 15 pmol/mg of protein. D2L and D2S dopamine receptors expressed in aline of Spodoptera frugiperda (Sf9) insect cells Sf9cells, displayed high affinity for the antagonists spiroperidol and (+)-butaclamol and the agonist N-propylnorapomorphine. Antisera raised against the D2 receptor immunoprecipitated binding sites for a radiolabeled D2 antagonist from solubilized extracts of infected Sf9cells. In immunoblots of Sf9cells infected with recombinant D2 baculovirus, these antisera recognized a major species of protein of approximately 46 kDa. Photoaffinity-labeling of infected Sf9cells using N-(p-azido-m-[125I]iodophenethyl)spiperone also identified a protein of this size, suggesting that D2 receptors expressed in Sf9cells are largely unglycosylated. In cells expressing receptors at a density greater than 1 pmol/mg, GTP-sensitive, high-affinity binding of agonists was not detected in studies of the inhibition of the binding of a radiolabeled D2 antagonist. When expression levels were under 1 pmol/mg, the binding of agonists was sensitive to the addition of guanine nucleotides, indicating that D2 receptors were coupled to endogenous G proteins. Endogenous G proteins enable both isoforms of D2 receptors to couple to the inhibition of adenylyl cyclase activity. The high-affinity state of the D2 receptor was directly measured using a radiolabeled agonist. Although the density of receptors increased with longer times after infection, the density of high-affinity sites reached a maximum of approximately 40 fmol/mg 30 to 36 hr after infection. Coexpression of D2 receptors and G protein subunits in Sf9cells dramatically increased the density of high-affinity sites, whereas the total density of receptors was unchanged, confirming that D2 receptors in Sf9 cells can exist in the high-affinity-coupled state, but that appropriate G proteins are expressed at relatively low levels. The density of D2S receptors converted to a coupled, agonist-preferring state when coexpressed with G proteins subunits (alpha i1, beta 1 and gamma 2) was 5 times greater than that of D2L receptors expressed under the same conditions, consistent with the hypothesis that D2 dopamine receptor isoforms differentially couple to alpha i1.

Animals↗
PubMed1980

Brain locations controlling the behavioral effects of chronic amphetamine intoxication.

Rats were administered D-amphetamine repeatedly for 4 days. After day 1 of treatment, the amphetamine-induced increases in ambulation, rearing, and stereotyped activity were augmented. However, after 4 days treatment, the rearing and ambulatory responses became attenuated while the stereotyped activities remained augmented. Micro-injection studies revealed that both the augmentation and attenuation of nonstereotyped ambulation were generated from the nucleus accumbens. The augmentation of stereotyped behaviors was generated from the caudate nucleus. Chronically treated animals who were administered 0.7 but not 1.0 mg/kg apomorphine showed augmented behavioral response. Chronic amphetamine treatment significantly decreased (3H) spiroperidol binding in both the nucleus accumbens and caudate nucleus. However, no effect on the DA-stimulated adenyl cyclase activity was observed in either brain region. It is concluded that repeated D-amphetamine administration selectively augments and attenuates D-amphetamine-induced behaviors and that these selective effects are mediated by different dopamine systems.

Adenylyl Cyclases↗
PubMed1977

The interactions of bromocriptine and lergotrile with dopamine and alpha-adrenergic receptors.

Bromocriptine and lergotrile, which are clinically used as antiparkinsonian (AP) agents, compete for the binding of H3-dopamine, H3-apomorphine, and H3-haloperidol to striatal membrane sites. Lergotrile has a higher affinity for the H3-dopamine binding to bovine striatal membranes than bromocriptine. Lergotrile and bromocriptine are almost equipotent in competing for the binding of H3-apomorphine to rat striatal membranes, but bromocriptine is more potent in competing for the binding of H3-haloperidol than lergotrile. These results indicate that lergotrile and bromocriptine are mixed putative agonist-antagonist with respect to the postsynaptic dopamine receptors. Lergotrile and bromocriptine at higher concentrations inhibit synaptosomal tyrosine hydroxylase activity, and reverse the apomorphine elicited enzyme inhibition. Thus, these ergot alkaloids behave as mixed agonist-antagonist also with respect to the presynaptic dopamine receptors. Bromocriptine and lergotrile, as well as other tested DH-ergot alkaloids and neuroleptics, compete for the binding of the alpha-antagonist H3-WB-4101 to rat cerebral cortical membranes. The displacing potencies of the tested DH-ergot alkaloids and of the neuroleptics indicate that they have a high affinity for the alpha-adrenoreceptors in the CNS.

Acetonitriles↗
PubMed1983

Correspondency between different affinity states and target size of the bovine striatal D2 dopamine receptor.

Target size analysis of the D2 dopamine receptor in the bovine striatum revealed the presence of two populations of this receptor, in terms of apparent molecular size. The size of large target was approximately 150 X 10(4) daltons, while that of small target was 11 X 10(4) daltons. The antagonist [3H]spiperone labeled both large and small sized D2 receptors, while agonist [3H]n-propylapomorphine (NPA) labeled only the former. In addition, the apparent molecular size of a functional unit for the GTP effect was calculated to be 150 X 10(4) daltons, such appearing to be identical to that of large target sized D2 dopamine receptors. Therefore, the large sized D2 receptor, probably an oligomeric complex consisting of D2 receptor recognition protein and guanine nucleotide regulatory protein, has a high affinity for both agonist and antagonist, while the small sized receptor, probably a monomeric or dimeric receptor recognition protein, has a high affinity for only the antagonist.

Acetylcholinesterase↗
PubMed1979

Neuroleptic and dopamine receptors: autoradiographic localization of [3H]spiperone in rat brain.

Rats were administered [3H]spiperone (SP: spiroperidol) by tail vein injection and 2 h later the brain was processed for light microscopic autoradiography. High densities of autoradiographic grains were found in all areas known to have a dopaminergic innervation, including the olfactory tubercles, nucleus accumbens, nucleus caudate-putamen, lateral septum, zona incerta, nucleus subthalamicus, arcuate nucleus, nucleus of the central amygdala, areas in the ventral tegmentum and the claustrum. There were also increased autoradiographic grain densities in other areas such as the midbrain and the frontal cortex indicating that binding occurred to other neurotransmitter receptors besides dopamine receptors. These studies delineate with a high resolution at an anatomical level the major binding sites for neuroleptic drugs in the forebrain. They suggest which areas of the brain are the most involved in neuroleptic drug action and they add further evidence that important regions are those receiving a dense dopaminergic innervation.

Animals↗