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PubMed1981

Optimal conditions for [3H]apomorphine binding and anomalous equilibrium binding of [3H]apomorphine and [3H]spiperone to rat striatal membranes: involvement of surface phenomena versus multiple binding sites.

I. Binding of [3H] apomorphine to dopaminergic receptors in rat striatum was most reproducible and clearly detectable when incubations were run at 25 degrees C in Tris-HCl buffer, pH 7.5, containing 1 mM-EDTA and 0.01% ascorbic acid, using a washed total-membrane fraction. The receptor binding was stereospecifically inhibited by (+)-butaclamol, and dopamine agonists and antagonists showed high binding affinity for these sites. Unlabelled apomorphine inhibited an additional nonstereospecific binding site, which was unrelated to dopamine receptors. EDTA in the incubation mixture considerably lowered nonstereospecific [3H]apomorphine binding, apparently by preventing the complexation of the catechol moiety with metal ions which were demonstrated in membrane preparations. Stereospecific [3H]apomorphine binding was not detectable in the frontal cortex, whereas in the absence of EDTA much saturable nonstereospecific binding occurred. II. Kinetic patterns of stereospecific [3H]spiperone and [3H]apomorphine binding to rat striatal membranes and the inhibition patterns of a dopamine antagonist and an agonist were evaluated at different temperatures in high-ionic-strength Tris buffer with salts added and low-ionic-strength Tris buffer with EDTA. Apparent KD values of spiperone decreased with decreasing tissue concentrations. KD values of both spiperone and apomorphine were little influenced by temperature changes. Scatchard plots of the stereospecific binding changed from linear to curved; the amount of nonstereospecific binding of the 3H ligands varied considerably, but in opposite directions for spiperone and apomorphine in the different buffers. In various assay conditions, interactions between agonists, and between antagonists, appeared fully competitive, but agonist-antagonist interactions were of mixed type. The anomalous binding patterns are interpreted in terms of surface phenomena occurring upon reactions of a ligand with complex physicochemical properties and nonsolubilized sites on membranes suspended in a buffered aqueous solution. It is concluded that anomalous binding patterns are not necessarily an indication of binding to multiple sites or involvement of distinct receptors for high-affinity agonist and antagonist binding.

Animals↗

PubMed1981

Discrimination of multiple [3H]5-hydroxytryptamine binding sites by the neuroleptic spiperone in rat brain.

Certain neuroleptic drugs, such as spiperone and (+) butaclamol, can discriminate between two populations of [3H]5-hydroxytryptamine ([3H]5-HT) binding sites in rat brain. The butyrophenone neuroleptic spiperone shows the greatest selectivity for these two binding sites, having at least a 3000-fold difference between its dissociation constants (2-12 nM versus 35,000 nM) for the high- and low-affinity sites, respectively. Inhibition of [3H]5-HT binding by spiperone in rat frontal cortex and corpus striatum yields distinctly biphasic inhibition curves with Hill slopes significantly less than unity. Results from nonlinear regression analysis of these inhibition studies were consistent with a two-site model in each brain region. In the frontal cortex the high-affinity neuroleptic sites comprised about 60% of the total [3H]5-HT binding sites whereas in the corpus striatum they accounted for only 20% of the sites. Furthermore, saturation studies of [3H]5-HT binding assayed in the absence or presence of 1 microM-spiperone (a concentration that completely blocks the high-affinity site while having minimal activity at the low-affinity site) reveal a parallel shift in the Scatchard plot with no change in the dissociation constant of [3H]5-HT, but a significant decrease (64% in frontal cortex or 28% in corpus striatum) in the number of specific binding sites. These observations are consistent with the existence of at least two populations of [3H]5-HT binding sites having a differential regional distribution in rat brain.

Animals↗

PubMed1983

Dual effects of ascorbate on serotonin and spiperone binding in rat cortical membranes.

Ascorbate-induced lipid peroxidation, as measured by malonyldialdehyde (MDA) production, caused irreversible decreases in Bmax of both [3H]5-HT and [3H]spiperone binding. CaCl2 (4 mM) inhibited ascorbate-induced MDA formation at ascorbate concentrations greater than 0.57 mM, but not at less than or equal to 0.57 mM. Under the standard assay conditions (5.7 mM ascorbate and 4 mM CaCl2), CaCl2 inhibited the MDA production caused by ascorbate by 88%, and the loss in [3H]5-HT binding by 57%. Ascorbate still decreased [3H]5-HT binding when lipid peroxidation was completely inhibited by EDTA. This additional effect of ascorbate was reversible after washing the membranes. Other reducing agents (dithiothreitol, glutathione, and metabisulfite) also decreased the binding of [3H]serotonin. In contrast, [3H]spiperone binding was not affected by ascorbate in the absence of lipid peroxidation or by other reducing agents. These experiments demonstrate that ascorbate has a dual and differential effect on serotonin binding sites. First, ascorbate-induced lipid peroxidation irreversibly inactivates both [3H]5-HT and [3H]spiperone binding. Second, independent of lipid peroxidation, there is a direct, reversible effect of ascorbate on [3H]serotonin but not on [3H]spiperone binding, which is probably due to the difference in the biochemical nature of the two serotonin binding sites.

Animals↗

PubMed1987

Relationship between dopamine receptor occupation by spiperone and acetylcholine levels in the rat striatum after long-term haloperidol treatment depends on dopamine innervation.

The effect of chronic neuroleptic treatment on the relationship between the blockade of dopamine (DA) receptors by the neuroleptic drug spiperone and the decline in acetylcholine (ACh) levels was determined in the rat striatum in vivo. In rats, a unilateral lesion of the nigrostriatal pathway was produced with 6-hydroxydopamine. The rats were treated for 6 weeks with haloperidol (twice a day at 1 mg kg-1). Partial and complete receptor occupation was determined with radioactive spiperone (a D2 antagonist), given in various doses of different specific activity 2 h before death. ACh, choline, and radioactivity contents were measured in the same striatum. Following long-term haloperidol treatment, an increase in the maximal number of binding sites for spiperone was found. Virtually identical negative (linear) correlations between striatal ACh content and the number of receptors occupied by spiperone were found in saline- or subchronic haloperidol-treated rats when DA innervation was intact. The slope of the line describing the decrease in ACh content per occupied receptor, however, was much lower in haloperidol-treated rats than in saline-treated animals. After lesioning of the dopaminergic pathway, there was no longer a correlation between the receptor occupation and ACh levels in the striatum. These results show that receptor occupation by a neuroleptic correlates highly with function only when dopaminergic innervation is intact. Also, it appears that there is no fixed number of striatal ACh molecules per DA receptor, and, finally, that in vivo receptor detection methods distinguish differences in receptor density (as do in vitro techniques).

Acetylcholine↗

PubMed2003

In vivo evidence for dopamine-mediated internalization of D2-receptors after amphetamine: differential findings with [3H]raclopride versus [3H]spiperone.

Competition with endogenous dopamine (DA) is usually invoked to explain changes in [(11)C]raclopride binding observed after amphetamine administration in animals and humans. This account has recently been questioned because a number of inconsistencies have been reported that contradict it. In the present study, we investigated whether the decrease in [(3)H]raclopride binding observed in the rat striatum after an amphetamine challenge reflects true competition with endogenous DA or agonist-mediated internalization of D(2)-receptors. We found that the amphetamine-induced decrease in [(3)H]raclopride binding is caused by a decrease in D(2)-receptor density (B(max)) with no change in affinity (K(d)). In contrast, in the same tissue, neither the B(max) nor the K(d) were affected when measured with [(3)H]spiperone. Challenge with amphetamine not only decreased the number of D(2)-receptors but also eliminated the proportion (22%) of receptors usually in the high-affinity state. The addition of Gpp(NH)p had no effect on B(max), suggesting that these receptors were not just noncompetitively bound with dopamine at the cell-surface. Subcellular fractionation studies showed that amphetamine treatment led to a decrease in radioligand binding in the cell-surface fraction for both [(3)H]raclopride and [(3)H]spiperone; however, in the case of [(3)H]spiperone, this was accompanied by a compensatory increase in binding in the intracellular compartment, whereas no increase was seen with [(3)H]raclopride. These data suggest that amphetamine releases dopamine, which binds to the high-affinity state of the D(2)-receptor, leading to its sequestration in some intracellular compartment; in this compartment, sequestered receptors are inaccessible to [(3)H]raclopride binding but can still be bound by [(3)H]spiperone.

Amphetamine↗

PubMed1980

Effect of chronic sulpiride on striatal spiperone binding.

Increased 3H-spiperone binding after chronic neuroleptic treatment has been proposed as a molecular model of tardive dyskinesia. Sulpiride has been claimed to be an atypical neuroleptic that might not produce tardive dyskinesia. The effect of chronic sulpiride was, therefore, compared to that of chronic haloperidol on striatal 3H-spiperone binding. 3 weeks of haloperidol feeding caused a 28% increase in 3H-spiperone binding, whereas even very high dose sulpiride had no effect on spiperone binding. These findings support the concept that sulpiride may be a unique neuroleptic with regard to long-term effects on dopamine receptors.

Animals↗

PubMed2002

Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists.

The structures of ketanserin (1) and spiperone (2) were examined in detail to determine the role of various substituent groups on 5-HT(2A) receptor affinity and selectivity. It was found that the presence of the quinazoline ring of ketanserin detracts from selectivity and that various ring-opened analogs displayed ketanserin-like affinity and up to 30-fold enhanced selectivity. The triazaspirodecanone portion of spiperone is a major determinant of its 5-HT affinity and selectivity. The conformational rigidity imposed by the ring, as well as the nature of the N(1)-substituent, are important factors in controlling binding at 5-HT(2A), 5-HT(2C), 5-HT(1A), and dopamine D2 receptors. Replacement of the N(1)-phenyl ring of spiperone with a methyl group (KML-010; 48) resulted in a compound that binds at 5-HT(2A) receptors with slightly lower affinity than spiperone, but that lacked affinity (Ki >10,000 nM) for 5-HT(2C) and 5-HT(1A) receptors and binds with 400-fold reduced affinity at D2 receptors.

Animals↗

PubMed1989

Two classes of [3H]spiperone binding sites in bovine neurohypophysis: D-2 receptors and putative 5-HT2 receptors.

Binding of [3H]spiperone was studied in membranes obtained from bovine neurohypophyses devoid of intermediate lobe tissue. Non-linear Scatchard plot suggested the presence of more than a single class of binding sites. Competition experiments using ketanserin, a ligand selective for 5-HT2 receptors, were carried out to ascertain whether serotonergic, in addition to dopaminergic receptors, might be responsible for the heterogeneity of [3H]spiperone binding. Computer-assisted modeling suggested the presence of two classes of binding sites for ketanserin (Kd = 1.6 +/- 0.2 and 366.7 +/- 20.5 nM, respectively). The Kd value for ketanserin binding to the high-affinity sites, as well as the Kd of [3H]spiperone for these sites suggested by the 2 sites model indicate that they represent serotonin 5-HT2 receptors. The [3H]spiperone Kd at the ketanserin low-affinity sites (65 +/- 7 pM) and the rank order of inhibitory potencies for several antagonists show that the low-affinity sites represent dopamine D-2 receptors.

Animals↗

PubMed1994

Labelling of D2-dopaminergic and 5-HT2-serotonergic binding sites in human trophoblastic cells using [3H]-spiperone.

We previously reported that dopamine (DA) inhibited the release of human placental lactogen (hPL) from human placental cells. We also demonstrated the presence of D2-dopamine receptors in membrane preparations of human term placenta. The aim of the present study was to characterize these D2 receptors on freshly isolated human trophoblastic cells. The binding of [3H]-spiperone to these cells showed a curvilinear Scatchard plot suggesting the presence of two classes of binding sites (Kd1 = 1.26nM; Kd2 = 44.3nM). Competition experiments showed the following inhibitory binding potencies: serotonin-2 (5-HT2) > or = D2 >>> alpha-adrenergic, beta-adrenergic, D1-dopamine, thus suggesting the presence of 5-HT2 binding sites. We have examined this possibility by blocking [3H]-spiperone binding to 5-HT2 receptors in the presence of 50nM ketanserin, a selective antagonist of 5-HT2 sites. Under this condition, the linear Scatchard plot obtained suggested a single population of homogeneous binding sites for [3H]-spiperone with a Kd of 0.55nM. To further characterize placental D2 receptors we conducted binding experiments with [3H]-raclopride, an more selective D2 antagonist. The linear Scatchard plot obtained with this ligand suggested one class of binding sites for [3H]-raclopride (Kd = 6nM) with the following inhibitory potencies: D2 >>> beta-adrenergic >> 5-HT2, D1, alpha-adrenergic. These results suggest an important paracrine function for DA in human placenta and show for the first time that [3H]-spiperone binds putative 5-HT2 receptors in human placenta.

Humans↗

PubMed1987

Ascorbic acid reduces accumulation of [3H]spiperone in mouse striatum in vivo.

[3H]Spiperone was administered (20 microCi/kg, 0.0003 mg/kg, sc) to mice. In agreement with other published reports, 2 hr later the accumulation of tritium was three to four times greater in the corpus striatum than in the cerebellum. Ascorbic acid (100, 1000, 2000 mg/kg, ip, 30 min) reduced the 2-hr accumulation in the corpus striatum 16, 42, and 63%, respectively, with only the highest dose producing any significant (18%) reduction in the cerebellum. The effect was still evident in striatum 18 hr after a single dose of 1000 mg/kg. Striatal minces taken from mice treated 1 or 2 hr earlier with ascorbic acid (2000 mg/kg, ip) showed no reduction in [3H]spiperone binding. However, preincubation of striatal minces for 2 hr with ascorbic acid (10(-3) M) produced an 82% reduction in specific binding while not having any effect on nonspecific binding. While it cannot be certain that the reduction of striatal [3H]spiperone concentrations after ascorbic acid in vivo was not a result of some nonspecific alteration in the pharmacokinetics of [3H]spiperone, the in vitro observation strongly suggests that it resulted from an alteration of binding characteristics at the receptor level.

Animals↗

PubMedDate not supplied

Spiperone-induced endothelium-dependent relaxation of porcine coronary artery: an investigation into the underlying mechanism.

In pig coronary artery rings contracted by the thromboxane analogue U 46619 (9,11-dideoxy-11 alpha, 9 alpha-epoxy-methano-prostaglandin F 2 alpha), spiperone induced a relaxation which, at 30 mumol/l, corresponded to a complete reversal of the U 46619-induced contraction. The concentration-response curve for spiperone was bell-shaped. The second phase, i.e. the reduction of the relaxant effect (at concentrations above 30 mumol/l) was due to a contractile effect which was the only response in (1) endothelium-denuded arteries, (2) arteries treated with gossypol or methylene blue, or (3) arteries not precontracted with U 46619. Suramin and reactive blue 2 antagonized the relaxing effect, whereas metitepine, spiroxatrine, propranolol, idazoxan, flupenthixol, atropine and 8-phenyltheophylline did not. The endothelium-independent contraction was not reduced by metitepine. In strips of arteries with intact endothelium, incubated with [3H]adenosine and subsequently superfused with physiological salt solution containing dipyridamole, spiperone evoked an increase in tritium overflow above basal efflux. The present results are compatible with the hypothesis that spiperone releases ATP from the pig coronary artery. ATP, in turn, seems to activate endothelial P2 purinoceptors, leading to the release of endothelium-derived relaxing factor (NO) with a subsequent vascular relaxation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1984

Estimation of the apparent affinity of the striatal dopamine receptors for the radioligand[3H]spiperone [( 3H]spiroperidol).

The characteristics of the receptor population labeled by the ligand [3H]spiperone were determined by several experimental procedures. Varying the assay volumes, and hence both the receptor and ligand concentrations, did not alter the specificity for the dopamine (DA) receptor. The density of binding sites estimated from saturation analyses varied little (6%) over a greater than 50-fold tissue concentration range. In contrast, variation in tissue concentration did alter the apparent affinity of [3H]spiperone for the DA receptors more than 16-fold, as determined from saturation analyses. This was most marked at large receptor or tissue concentrations. The standard correction for depletion of the free ligand by that bound to the receptors reduced the range to threefold or 200%. Two separate measurements of the DA receptor affinity, using the rates of association and dissociation and the shift in Ki for DA, gave affinity measurements in the same range as that obtained using low concentrations of receptors in saturation analyses. Therefore, three separate estimates for the affinity of [3H]spiperone binding to the striatal DA receptors agreed that it is probably in the range of 10-15 pM, and single saturation experiments reach this level when the tissue concentration is very low, ie, less than 15 micrograms protein per 1 ml assay volume.

Animals↗

PubMed2003

Dopamine displaces [3H]domperidone from high-affinity sites of the dopamine D2 receptor, but not [3H]raclopride or [3H]spiperone in isotonic medium: Implications for human positron emission tomography.

Because the high-affinity state of the dopamine D2 receptor, D2High, is the functional state of the receptor, has a role in demarcating typical from atypical antipsychotics, and is markedly elevated in amphetamine-sensitized rats, it is important to have a method for the convenient detection of this state by a ligand. The present data show that, in contrast to [(3)H]spiperone or [(3)H]raclopride, [(3)H]domperidone labels D2High sites in the presence of isotonic NaCl in either striatum or cloned D2Long receptors, yielding a dopamine dissociation constant (1.75 nM) in agreement with that found with [(3)H]dopamine. Increased labeling of D2High sites occurred with [(3)H]domperidone after severe disruption of the cells, suggesting that [(3)H]domperidone has better access to the D2 receptor from the cytoplasmic aspect of the cell membrane. The density of the [(3)H]domperidone-labeled D2 receptors was the same as that of the [(3)H]raclopride-labeled D2 receptors, but twice the density of [(3)H]spiperone sites for human cloned D2Long receptors, compatible with the monomer-dimer concept of the D2 receptor. [(3)H]domperidone readily labels the D2High sites in postmortem human brain homogenates. Although [(3)H]spiperone or [(3)H]raclopride can occupy D2High sites, the inability of 1-10 nM dopamine to displace these ligands under isotonic conditions suggests that these ligands may not be suitable for monitoring the physiological high-affinity state of the dopamine D2 receptor by means of [(11)C]methylspiperone or [(11)C]raclopride in humans.

Animals↗

PubMed1982

The effect of chronic bromocriptine and L-dopa on spiperone binding and apomorphine-induced stereotypy.

Chronic treatment with dopamine (DA) agonists has been reported in various paradigms to cause supersensitivity of DA receptors or, contradictorily, subsensitivity of DA receptors. The present study administered 15 mg/kg bromocriptine for 7 days and measured both striatal spiperone binding and apomorphine (AP)-induced stereotypy. A significant decrease in AP-induced stereotypies was observed after chronic bromocriptine treatment, but without a significant parallel decrease in striatal spiperone binding. These results probably do not represent a true agonist-induced subsensitivity, but possibly show that residual bromocriptine in vivo may antagonize AP-induced stereotypy. Since some reports have suggested that L-Dopa may specifically reverse the increases in DA receptor number induced by chronic haloperidol, we also studied the effect of 7 days of L-Dopa treatment after 6-week chronic haloperidol treatment of mice. While chronic haloperidol significantly increased striatal spiperone binding, subsequent L-Dopa treatment did not reverse this biochemical supersensitivity. It is concluded that agonist induction of subsensitivity in the DA system is difficult to reproduce and may depend on highly specific dosage conditions and treatment schedules.

Animals↗

PubMed1978

Subsensitivity of the rat striatal dopaminergic system after treatment with bromocriptine: effects on [3H]spiperone binding and dopamine-stimulated cyclic AMP formation.

Repeated daily administration of the dopamine (DA) agonist bromocriptine (15 mg/kg; s.cut.) to rats led to a time dependent decrease in the in vitro binding of [3H]spiperone to striatal membranes. Kinetic analysis of [3H]spiperone binding after 2 and 7 days of bromocriptine treatment showed a 25-50% reduction in the total number of binding sites with no changein their affinity for spiperone. There was also a decreased accumulation of cyclic AMP (cAMP) in striatal slices in response to DA after bromocriptine treatment. The DA-sensitive adenylate cyclase in striatal homogenates, however, remained unchanged in bromocriptine treated rats. There was also no change in cyclic nucleotide phosphodiesterase activity in striatal tissue after bromocriptine treatment. Furthermore, incubation of striatal slices in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine did not alter the decreased cAMP response to DA after 2 days of bromocriptine treatment. These results suggest that a decreased number of DA receptor sites may be responsible for the reduced cAMP response to DA in striatal slices after bromocriptine treatment.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1983

The relation between spiperone binding, behavioural changes, and in vivo tyrosine hydroxylation in the rat striatum.

Spiperone 0.1-10 mg/kg i.p. increased the accumulation of Dopa in the rat striatum after Dopa decarboxylase inhibition. Approximately 50% of the rats treated with doses 1 mg/kg or higher showed cataleptic symptoms. Binding studies performed on the striatal tissues from these rats showed a dose-dependent lowering of the maximal binding of spiperone. The decrease in B max was significant at doses of spiperone 1 mg/kg or higher. Thus at 1 and 10 mg/kg, significant effects on binding, Dopa accumulation, and behaviour were found to coexist.

Animals↗

PubMed1979

Effect of mazindol on brain dopamine turnover in spiperone-treated rats.

Mazindol, an anorexic drug, caused a large increase in brain 3, 4-dihydroxyphenylacetic acid (DOPAC) concentration in spiperone-pretreated rats. The increase was dose-related over a 1--10 mg/kg dose range of mazindol and was maximum within 1 hour after maxzindol injection into rats pretreated 1 hour previously with spiperone. In spiperone-pretreated rats, mazindol accelerated the disappearance of dopamine after the inhibition of dopamine synthesis by alpha-methyltyrosine. Mazindol apparently resembles amfonelic acid, methylphenidate, and cocaine in facilitating the impulse-mediated release of dopamine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1978

The effect of haloperidol, spiperone and pimozide on the flexor reflex of the hind limb of the spinal rat.

It was found that spiperone and pimozide in doses which themselves do not influence the flexor reflex of the hind limb of the spinal rat inhibit stimulation of this reflex induced by serotoninomimetic drugs (LSD and fenfluramine). Higher doses of spiperone depress the flexor reflex and inhibit the stimulating effect of clonidine. Pimozide has no such effect. Haloperidol in doses which do not influence the action of LSD and fenfluramine produces a depression of the flexor reflex and antagonizes the action of clonidine. Our findings indicate that, irrespective of their antidopamine action, spiperone has a central antiserotonin effect and an antinoradrenaline one, pimozide--an antiserotonin one and haloperidol--an antinoradrenaline one.

Animals↗