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At least 217 records · Page 12Linked to original sources
PubMed1985

Effects of dopamine superfusion on the activity of rabbit carotid chemoreceptors in vitro.

The effect of different concentrations (0.001, 0.01, 0.1 and 1 mM) of dopamine on chemo-afferent activity was studied in the rabbit carotid body superfused in vitro. Excitation was the sole effect observed: it was always present for dopamine tests at 0.1 and 1 mM but was found in only 4 out of 9 tests at 0.01 mM and in 1 out of 5 tests at 0.001 mM. By comparison with a natural stimulus like hypoxia, dopamine excitation was delayed and had a much slower time course. Dopamine antagonists, (+)-butaclamol and haloperidol did not affect the responses to dopamine and to hypoxia. The results were not significantly altered when CO2 was added to the superfusing medium. It is concluded that dopamine is not a likely excitatory transmitter for chemoreception in the rabbit carotid body.

Animals↗
PubMed1983

[3H]spiroperidol binding in crude membrane suspensions of gill tissue from the marine mussel, Mytilus californianus.

Saturable, high-affinity binding sites for [3H]spiroperidol can be demonstrated in crude suspensions of mussel gill tissue. This binding shows stereospecificity toward the d- and l-isomers of butaclamol. Competition studies show that both dopamine and serotonin can displace [3H]spiroperidol from binding sites at nanomolar concentrations. Evidence is presented that suggests that the [3H]spiroperidol-binding sites can be divided into two distinct groups: those with high affinity for dopamine and those with high affinity for serotonin.

Animals↗
PubMed2004

The effects of dopamine receptor agonists and antagonists on the secretory rate of cockroach (Periplaneta americana) salivary glands.

The acinar salivary glands of the cockroach, Periplaneta americana, are innervated by dopaminergic and serotonergic nerve fibers. Serotonin stimulates the secretion of protein-rich saliva, whereas dopamine causes the production of protein-free saliva. This suggests that dopamine acts selectively on ion-transporting peripheral cells within the acini and the duct cells, and that serotonin acts on the protein-producing central cells of the acini. We have investigated the pharmacology of the dopamine-induced secretory activity of the salivary gland of Periplaneta americana by testing several dopamine receptor agonists and antagonists. The effects of dopamine can be mimicked by the non-selective dopamine receptor agonist 6,7-ADTN and, less effectively, by the vertebrate D1 receptor-selective agonist chloro-APB. The vertebrate D1 receptor-selective agonist SKF 38393 and vertebrate D2 receptor-selective agonist R(-)-TNPA were ineffective. R(+)-Lisuride induces a secretory response with a slower onset and a lower maximal response compared with dopamine-induced secretion. However, lisuride-stimulated glands continue secreting saliva, even after lisuride-washout. Dopamine-induced secretions can be blocked by the vertebrate dopamine receptor antagonists cis(Z)-flupenthixol, chlorpromazine, and S(+)-butaclamol. Our pharmacological data do not unequivocally indicate whether the dopamine receptors on the Periplaneta salivary glands belong to the D1 or D2 subfamily of dopamine receptors, but we can confirm that the pharmacology of invertebrate dopamine receptors is remarkably different from that of their vertebrate counterparts.

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

Effects of dopamine and dopamine-active compounds on oxytocin and vasopressin production in rat neurohypophyseal tissue cultures.

The effects of dopamine (DA) or DA-active drugs on the synthesis of neurohypophyseal (NH) hormones were studied in 13-14 day cultures of isolated NH tissue from rats. The following DA-active compounds were used (10(-6) M in each medium): DA, apomorphine (APM), Pro-Lys-Gly (PLG), butaclamol (B), haloperidol (HP), chlorpromazine (CPZ) and sulpiride (SP). The oxytocin (OT) and vasopressin (VP) contents of the condensed media were determined by RIA after a 1 or 2 h incubation. Significantly increased contents of OT and VP were detected in the tissue culture media following DA, APM or PLG administration. This elevation of NH hormone production could be blocked by previous administration of B or the DA receptor antagonists HP, CPZ or SP. The application of B after DA agonists proved ineffective. The results indicate that NH hormone production can be directly influenced by the DA-ergic system. The DA-ergic control of NH hormone secretion in rats can occur independently of the hypothalamus, at the level of the posterior pituitary.

Animals↗
PubMed2003

Analysis of two D1-like dopamine receptors from the honey bee Apis mellifera reveals agonist-independent activity.

Dopamine is found in many invertebrate organisms, including insects, however, the mechanisms through which this amine operates remain unclear. We have expressed two dopamine receptors cloned from honey bee (AmDOP1 and AmDOP2) in insect cells (Spodoptera frugiperda), and compared their pharmacology directly using production of cAMP as a functional assay. In each assay, AmDOP1 receptors required lower concentrations of dopamine and 6,7-ADTN for maximal activation than AmDOP2 receptors. Conversely, butaclamol and cis(Z)-flupentixol were more potent at blocking the cAMP response mediated through AmDOP2 than AmDOP1 receptors. Expression of AmDOP1, but not AmDOP2, receptors significantly increased levels of cAMP even in the absence of ligand. This constitutive activity was blocked by cis(Z)-flupentixol. This work provides the first evidence of a constitutively activated dopamine receptor in invertebrates and suggests that although AmDOP1 and AmDOP2 share much less homology than their vertebrate counterparts, they display a number of functional parallels with the mammalian D1-like dopamine receptors.

Animals↗
PubMed2002

Decreased [(3)H]spiperone binding in the anterior cingulate cortex of schizophrenia patients: an autoradiographic study.

Abnormalities in the anterior cingulate cortex have been reported in patients with schizophrenia, and have been implicated in the pathophysiology of this disorder. In the present study, we have examined antipsychotic-sensitive binding sites in the left anterior cingulate cortex of schizophrenia patients and controls. Using quantitative autoradiography and [(3)H]spiperone as a ligand, both saturation and competition experiments were performed in post-mortem brain tissue obtained from six schizophrenia and six control cases. Saturation experiments revealed that the maximum number of [(3)H]spiperone binding sites was significantly reduced by 31% in the schizophrenia group as compared to the control group (65.3+/-5.6 fmol/mg tissue versus 94.2+/-7.3 fmol/mg tissue). Increased dissociation constant was also observed in the schizophrenia group (2.2+/-0.4 nM versus 1.3+/-0.2 nM), but was not statistically significant (P=0.07). Competition experiments were performed in order to examine the pharmacological profile of [(3)H]spiperone binding, and revealed that: (i) displacement of [(3)H]spiperone binding by clozapine and mianserin was significantly reduced in the schizophrenia group as compared to the control group (-26% and -16% respectively); (ii) the order of displacement potency of the drugs tested was: haloperidol>mianserin>butaclamol approximately risperidone>clozapine>2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene. Our results suggest a reduction of antipsychotic-sensitive binding sites in the anterior cingulate cortex of patients with schizophrenia. Such abnormality could lead to an imbalance in neurotransmitter regulation in the anterior cingulate cortex which may contribute to the emergence of some symptoms of schizophrenia.

Adult↗
PubMed2000

Novel regulation of p38gamma by dopamine D2 receptors during hypoxia.

The p38 signalling pathway is part of the MAPK superfamily and is activated by various stressors. Our previous results have shown that two p38 isoforms, p38alpha and p38gamma, are activated by hypoxia in the neural-like PC12 cell line. PC12 cells also synthesize and secrete catecholamines, including dopamine, in response to hypoxia. We have now used this system to study the interaction between D2-dopamine receptor signalling and the p38 stress-activated protein kinases. Our results show that two D2 receptor antagonists, butaclamol and sulpiride, enhance hypoxia-induced phosphorylation of p38gamma, but not p38. This effect persists in protein kinase A (PKA)-deficient PC12 cells, demonstrating that p38gamma modulation by the D2 receptor is independent of the cAMP/PKA signalling system. We further show that removal of extracellular calcium blocks the hypoxia-induced increase in p38gamma activity. These results are the first to demonstrate that p38gamma can be regulated by the D2 receptor and calcium following hypoxic exposure.

Animals↗
PubMed1984

Design, synthesis, and X-ray data of novel potential antipsychotic agents. Substituted 7-phenylquinolizidines: stereospecific, neuroleptic, and antinociceptive properties.

The semirigid 7-phenylquinolizidine system was selected for the design of new potential antipsychotic agents because it fulfills earlier considerations on the minimal structural and steric requirements necessary to attain a high affinity to the dopamine receptors and, in addition, leaves open many opportunities for variations. Whereas the initial compound 5a, modeled after the structure of butaclamol, was virtually inactive, the introduction of substituents on the phenyl ring and of further optional structural elements improved the dopamine antagonistic properties by supplying additional binding forces. Initially, a compound in the potency range of chlorpromazine was obtained: (9aH)-2-tert-butyl-7-(2,4-dichlorophenyl)octahydro-2H-qui nolizin-2-ol (5e). By the optical resolution of 5c, it was demonstrated that the biological activity resides in the (-) enantiomer. The absolute configuration of (-)-5e was determined by single-crystal X-ray analysis to be 2S,7R,9aR. Further variations of the optional structural elements led to the unexpected finding of compounds with strong antinociceptive properties, e.g., (2R,7S,9aS)-2-butylocta-hydro-7-phenyl-2H-quinolizin-2 -yl acetate [(+)-26]. Interestingly, this compound belongs to the enantiomeric series opposite to that of the neuroleptic-like (-)-5e.

Analgesia↗
PubMed2000

7-Methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine: a new heterocyclic system and a new lead compound for dopamine receptor antagonists.

Partially hydrogenated derivatives of the new heterocyclic ring systems benz[d]indolo[2,3-g]azecine and bisindolo[3,2-d][2, 3-g]azecine were synthesized starting from lactones and amines via the described synthetic methods. In binding assays with rat striatal receptors, 7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2, 3-g]azecine (LE 300) proved to be of high affinity for the D(1) binding site (K(i) = 0.08 nmol for displacement of [(3)H]SCH23390), being superior in this assay to standards such as butaclamol and SCH23390. This compound was characterized as a dopamine antagonist by conditioned avoidance response test with mice. Thus, LE 300 represents the lead of a new class of dopamine antagonists for future investigations.

Animals↗
PubMed1978

Neuroleptic-induced attenuation of brain stimulation reward in rats.

In 30-min free-operant tests, the dopamine receptor blockers pimozide (.125, .25, and .50 mg/kg) and (+)-butaclamol (.1, .2, and .4 mg/kg) attenuated lever pressing for lateral hypothalamic brain stimulation. When discrete self-stimulation trials were offered in a straight alleyway, pimozide increased start box latencies, slowed running speeds, and reduced lever-pressing rates. However, performance early in both lever-pressing and runway sessions was normal; performance deteriorated as testing progressed, following patterns that paralleled those seen when animals were tested with reductions in the amplitude of stimulating current. Spontaneous recovery was obtained in both situations; experimenter-imposed 10-min time-outs caused renewed lever pressing and running. In contrast, alpha-noradrenergic receptor blockade by phenoxybenzamine (5, 10, and 20 mg/kg) failed to produce extinction-like response patterns. These data support the view that central dopaminergic systems are important components of the neural mechanisms mediating reward.

Animals↗
PubMed1982

Calcium alters the sensitivity of intact horizontal cells to dopamine antagonists.

Horizontal cells of the carp retina possess dopamine receptors linked to adenylate cyclase. Isolated, intact horizontal cells respond to micromolar concentrations of dopamine, whereas nanomolar concentrations of haloperidol, (+)-butaclamol, and flupenthixol block the dopamine response. Preincubation in Ringer's solution containing increased levels of Ca2+ (5-110 mM) decreases the sensitivity of the cells to these antagonists by 1,000-10,000 times. Dopamine sensitivity of the cells is not affected by Ca2+ levels in the preincubation medium. Preincubation of the cells in Ringer's solution containing 500 microM L-glutamate, an agent that increases intracellular Ca2+ levels in intact horizontal cells, also decreases the sensitivity of the cells to haloperidol. These data suggest that antagonist sensitivity of intact horizontal cells may be regulated by intracellular Ca2+.

Animals↗
PubMed1999

Serotonergic agonists behave as partial agonists at the dopamine D2 receptor.

RAT dopamine D2short receptors expressed in CHO cells were characterized by activation of [35S]GTPgammaS binding. There were no significant differences between the maximal effects seen in activation of [35S]GTPgammaS binding caused by dopaminergic agonists, but the effects of 5-HT, 8OH-DPAT and 5-methoxytryptamine amounted to 47 +/- 7%, 43 +/- 5% and 70 +/- 7% of the dopamine effect, respectively. The dopaminergic antagonist (+)butaclamol inhibited activations of both types of ligands with equal potency (pA2 = 8.9 +/- 0.1), indicating that only one type of receptor is involved. In competition with [3H]raclopride binding, dopaminergic agonists showed 53 +/- 2% of the binding sites in the GTP-dependent high-affinity state, whereas 5-HT showed only 20 +/- 3%. Taken together, the results indicate that serotonergic agonists behave as typical partial agonists for D2 receptors with potential antiparkinsonian activity.

5-Methoxytryptamine↗
PubMed1983

Specific binding of [11C]spiroperidol in rat brain in vivo.

Spiroperidol labeled with carbon-11, a short-lived positron-emitting radionuclide, was used to determine the time course of specific binding of this radioligand to the neuroleptic receptor in vivo in the rat. The three major bran pools--specifically bound, nonspecifically bound, and free (unbound)--were determined over a 60-mm time course by a rapid filtration technique, utilizing (-)- and (+)-butaclamol pretreatments to assess total and nonspecifically bound activities, respectively, in striatum and cerebellum. The ratio of specifically to nonspecifically bound pools in the striatum was 4.1 at 30 min and 5.1 at 60 min. Thus [11C]spiroperidol may be useful for labeling neuroleptic receptors in vivo for serial studies using positron emission transaxial tomography.

Animals↗
PubMed1984

High- and low-affinity states of striatal D2 receptors are not affected by 6-hydroxydopamine or chronic haloperidol treatment.

Specific D2 binding in rat striatum was characterized and then the effects of chronic disruption of dopaminergic activity on antagonist and agonist binding to these sites were studied. D2 receptors were defined as those sites capable of binding [3H]spiperone in the presence of cinanserin, a 5-HT2 antagonist, but not in the presence of (+)-butaclamol, a D2 and 5-HT2 blocker. Saturation, competition, and kinetic analyses suggested that D2 receptors are a homogeneous population exhibiting more complex interactions with agonists than antagonists. Antagonist binding was monophasic and guanine nucleotide-insensitive whereas agonist binding was biphasic and guanine nucleotide-sensitive. D2 receptor density was elevated by more than 40% following dopamine depletion by 6-hydroxydopamine or chronic receptor blockade by haloperidol. However neither treatment altered the affinities or magnitudes of the high- and low-affinity components associated with agonist binding to the D2 receptor.

Animals↗
PubMed1985

Comparison of three 18F-labeled butyrophenone neuroleptic drugs in the baboon using positron emission tomography.

The butyrophenone neuroleptics spiroperidol, benperidol, and haloperidol were radiolabeled with fluorine-18 and studied in baboon brain using positron emission transaxial tomography (PETT). Pretreatment of the baboon with a high pharmacological dose of (+)-butaclamol reduced the specifically bound component of radioactivity distribution in the striatum to approximately the radioactivity distribution found in the cerebellum. Comparative studies of brain distribution kinetics over a 4-h period indicated that either [18F]spiroperidol or [18F]benperidol may be suitable for specific labeling of neuroleptic receptors. In an 8-h study with [18F]spiroperidol, striatal radioactivity did not decline, suggesting that spiroperidol either has a very slow dissociation rate or that it binds irreversibly to these receptors in vivo. [18F]Haloperidol may not be suitable for in vivo PETT studies, because of a relatively high component of nonspecific distribution and a faster dissociation from the receptor. Analysis of 18F in plasma after injection of [18F]spiroperidol indicated rapid metabolism to polar and acidic metabolites, with only 40% of the total radioactivity being present as unchanged drug after 30 min. Analysis of the metabolic stability of the radioactively labeled compound in rat striatum indicated that greater than 95% of [18F]spiroperidol remains unchanged after 4 h.

Animals↗
PubMed1986

Interactions between vasoactive intestinal peptide and dopamine in the rabbit retina: stimulation of a common adenylate cyclase.

Although 3,4-dihydroxyphenylethylamine (dopamine, DA) and vasoactive intestinal peptide (VIP) have been reported to stimulate adenylate cyclase activity in the rabbit retina, possible interactions between VIP-sensitive and DA-sensitive adenylate cyclase systems have not been previously investigated. To elucidate the interactions between these two putative transmitter-stimulated cyclase systems, the effects of VIP, DA, and VIP + DA on the conversion of [alpha-32P]ATP to [32P]cyclic AMP in rabbit retinal homogenates were measured. VIP stimulated adenylate cyclase activity in a biphasic manner, suggesting that two classes of VIP receptors may be involved in the induction of cyclic AMP formation. DA was less potent than VIP, and stimulated cyclase activity with a monophasic dose-response curve. When assayed together, these stimulations were partially nonadditive, implying the existence of a common adenylate cyclase pool that may be stimulated by both putative neurotransmitters. The dopaminergic antagonist (+)-butaclamol completely blocked dopaminergic stimulation, but had no significant effect on VIP-induced stimulation, indicating that VIP interacts with specific VIP receptor sites, which are distinct from the dopaminergic receptor sites. Furthermore, the specific D-2 dopaminergic receptor agonist LY141865 demonstrated no inhibitory effect on adenylate cyclase activity, suggesting that the interaction between the VIP- and DA-sensitive adenylate cyclase systems does not result from a D-2 receptor-mediated cyclase inhibition in the rabbit retina. Finally, at maximally effective concentrations, DA and VIP were less potent than fluoride or forskolin in the stimulation of cyclic AMP formation, suggesting that adenylate cyclase pools that are not sensitive to DA and VIP may also be present in this retina.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1987

Kinetic modeling of receptor-ligand binding applied to positron emission tomographic studies with neuroleptic tracers.

Positron emission tomography (PET) with labeled neuroleptics has made possible the study of neurotransmitter-receptor systems in vivo. In this study we investigate the kinetics of the 3,4-dihydroxyphenylethylamine (dopamine) receptor-ligand binding using PET data from a series of experiments in the baboon with the 18F-labeled drugs spiperone, haloperidol, and benperidol. Models used to describe these systems are based on first-order kinetics which applies at high specific activity (low receptor occupancy). The parameters governing the uptake and loss of drug from the brain were found by fitting PET data from regions with little or no receptor concentration (cerebellum) and from experiments in which specific binding was blocked by pretreatment with the drug (+)-butaclamol. Receptor constants were determined by fitting data from receptor-containing structures. Correcting the arterial plasma activities (the model driving function) for the presence of drug metabolites was found to be important in the modeling of these systems.

Animals↗
PubMed1989

Specific [3H]SCH23390 binding to dopamine D1 receptors in cerebral cortex and neostriatum: role of disulfide and sulfhydryl groups.

Receptor binding studies were performed in cerebral cortex (CTX) and neostriatum (CPU; caudate-putamen) using the dopamine D1 antagonist [3H]SCH23390. Because receptors are of protein nature, we examined the role of disulfide bonds (--SS--) and sulfhydryl groups (--SH) in the specific binding of [3H]SCH23390. Furthermore, membrane preparations contain a certain amount of lipid, so that treatments with --SH and --SS-- reagents could determine whether the fixation of the radioligand was to protein or to the lipid moiety. Pretreatment of CTX and CPU membranes with dithioerythritol, L-dithiothreitol, or 5,5'-dithiobis(2-nitrobenzoic acid), as well as with the alkylating agent N-ethylmaleimide, produced dose-dependent decreases of specific [3H]SCH23390 binding in membrane preparations from both tissues. These changes were not reversible after up to two washes, but could be prevented in part if the treatments were performed in the presence of dopamine. Additional protection experiments were conducted with (+)- and (-)-butaclamol, as well as with (+)- and (-)-SKF38393. A series of saturation experiments (with pretreated membranes in the absence of reactives) demonstrated that the alkylation of --SS-- groups reduced specific [3H]SCH23390 binding mainly through an affinity change, but L-dithiothreitol and 5,5-dithiobis(2-nitrobenzoic acid) decreased the number of binding sites. The affinity of the receptor to agonists was examined with the two enantiomers of SKF38393; the inhibition curves showed that residual binding was not affected and stereospecificity was conserved. The present results provide evidence for the participation of both --SS-- and --SH groups in the recognition site of the dopamine D1 receptor in both the CTX and the CPU.

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