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At least 127 records · Page 7Linked to original sources
PubMed1995

Effect of a corn diet during development on [3H]-spiperone binding in the brain of rats at the perinatal stage.

A model of undernutrition based on feeding with a corn-diet (tryptophan deficient) was used to study maturation and physiology of the rat brain 5-HTergic system. Previously, using that model, we observed a decrease in 5-HT uptake in rat brain slices, assuming that some compensatory mechanisms could be implicated at the synaptic level on those conditions. Body, brain weight, and total [3H]-spiperone binding were recorded at two fetal ages and newborn pups from mothers were fed with a corn-diet and with a corn-lysine diet. Significant decreases in body weight and in [3H]-spiperone binding were observed at all ages studied in the corn-based diet groups with respect to controls at the first postnatal day of age, whereas at the 18th gestation day, the [3H]-spiperone binding was higher in the protein restricted and corn-lysine supplemented group than in the control group. Results suggested that expression of 5-HT receptors and possibly their synthesis may be limited at the synaptic level on undernutrition conditions.

Aging↗
PubMed1985

Binding of [3H]flunitrazepam and [3H]spiperone to melanoma cell membrane preparations.

Binding of [3H]flunitrazepam and [3H]spiperone to membrane preparations isolated by high speed centrifugation of hamster, rabbit and human melanoma cell homogenates was analyzed. All melanoma cell types expressed a high density of specific binding sites for [3H]flunitrazepam (3-4 pmol/mg protein) with a high affinity (Kd about 30 nM). This binding was independent of melanin content of cells and could be classified, based on competition experiments, as a Ro 5-4864-like binding type. Specific [3H]spiperone binding to these cell lines clearly revealed at least two types of binding sites: a low affinity, high capacity type of binding site (Kd greater than 100 nM, Bmax about 50 pmol/mg protein) and a high affinity, low capacity binding site (Kd less than 1 nm, Bmax 30 fmol/mg protein). Binding of spiperone to the low affinity, high capacity site appeared displaceable by NM 113 and dependent on melanin content of the cells and probably represents binding to melanin. Analysis of drug binding to melanoma membrane cell preparations and correlation with drug effects should include the possible involvement of binding to melanin.

Animals↗
PubMed1982

The low affinity component of [3H]spiperone binding reflects association to a non-dopaminergic, neuroleptic site.

The pharmacological properties of a low affinity site labelled by [3H]spiperone in membranes prepared from the rat nucleus accumbens were examined by investigating the ability of dopaminergic agonists, antagonists and various other drugs to displace the binding of 2 nM [3H]spiperone. Neuroleptic drugs were the most potent displacers of binding, and dopaminergic agonists, except for bromocryptine and lergotrile, had inhibition constants greater than 1 microM. The majority of drugs studied exhibited a high selectivity for the high affinity site labelled by [3H]spiperone and low affinity sites probably represent a non-specific, non-dopaminergic site for neuroleptic drugs.

Animals↗
PubMed1991

Distribution of dopaminergic receptors in the primate cerebral cortex: quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390.

A widespread distribution of dopamine D1 receptors in the neocortex is well recognized. However, the presence of dopamine D2 receptors in this structure has only recently been established [Martres et al. (1985) Eur. J. Pharmac. 118, 211-219; Lidow et al. (1989) Proc. natn. Acad. Sci. U.S.A. 86, 6412-6416]. In the present paper, a highly specific antagonist, [3H]raclopride, was used for autoradiographic determination of the distribution of D2 receptors in 12 cytoarchitectonic areas of the frontal, parietal, and occipital lobes of the rhesus monkey. A low density of D2-specific [3H]raclopride binding (1.5-4.0 fmol/mg tissue) was detected in all layers of all cortical areas studied. Throughout the entire cortex, the highest density of binding was consistently found in layer V. This is a unique distribution not observed so far for any other neurotransmitter receptor subtype in monkey cerebral cortex, including D1 receptor. In addition, a comparison was made of the distribution of [3H]raclopride and [3H]spiperone, which has been commonly used in previous attempts to label cortical D2 receptors. We found marked differences in the distribution of these two radioligands. In the prefrontal cortex, the pattern of [3H]spiperone binding in the presence of ketanserin resembled the combined distribution of 5-HT1C serotoninergic and alpha 2-adrenergic sites as well as D2 receptors. Thus, [3H]raclopride provides a better estimation of the D2 receptor distribution than does [3H]spiperone. The distribution of D2-specific binding of [3H]raclopride was also compared with the D1-specific binding of [3H]SCH23390 in the presence of mianserin to block labeling to 5-HT2 and 5-HT1C sites. The density of D1-specific [3H]SCH23390 binding was 10-20 times higher than that of D2-specific [3H]raclopride binding throughout the cortex. The densities of both [3H]raclopride and [3H]SCH23390 binding sites display a rostral-caudal gradient with the highest concentrations in prefrontal and the lowest concentrations in the occipital cortex. However, the binding sites of these two ligands had different laminar distributions in all areas examined. In contrast to preferential [3H]raclopride binding in layer V, a bilaminar pattern of [3H]SCH23390 labeling was observed in most cytoarchitectonic areas, with the highest concentrations in supragranular layers I, II and IIIa and infragranular layers V and VI. Whereas [3H]raclopride binding was similar in all cytoarchitectonic areas, [3H]SCH23390 exhibited some region-specific variations in the primary visual and motor cortex. The different regional and laminar distributions of D1 and D2 dopaminergic receptors indicates that they may subserve different aspects of dopamine function in the cerebral cortex.

Animals↗
PubMed1993

Tyr-MIF-1 attenuates development of tolerance to spiperone-induced catalepsy in rats.

Because the tripeptide MIF-1 (Pro-Leu-Gly-NH2) is known to attenuate the effects of neuroleptic-induced catalepsy as well as neuroleptic-induced proliferation of dopamine (DA) receptors, we studied the related naturally occurring peptide, Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) for similar properties. Male rats were treated SC for 11 consecutive days with either the DA D1 receptor antagonist SCH 23390 HCl (0.50 mg/kg per day), the DA D2 receptor antagonist spiperone HCl (0.30 mg/kg per day), or vehicle. Half the rats were cotreated daily with Tyr-MIF-1 (1.0 mg/kg per day). The cataleptic effects of SCH 23390 were not altered by Tyr-MIF-1. Tolerance to SCH 23390-induced catalepsy did not develop during the 11-day treatment, and Tyr-MIF-1 had no effect on SCH 23390-induced catalepsy. However, tolerance developed to spiperone-induced catalepsy, and Tyr-MIF-1 attenuated this development of tolerance (p < 0.001). Locomotor and stereotyped activities of the DA D1 and D2 agonists, SKF 39393 (3.0 mg/kg) and quinpirole (3.0 mg/kg) were not affected by Tyr-MIF-1 after treatment with the DA antagonists was discontinued. Tyr-MIF-1 did not alter the Bmax or Kd for in vitro binding of [3H]SCH 23390 and [3H]spiperone to homogenates of the striatum. These findings indicate that Tyr-MIF-1 is able to selectively affect the development of receptor tolerance to a DA D2 receptor antagonist, and that this effect is unrelated to changes in affinity or numbers of D2 receptors.

Amino Acid Sequence↗
PubMed2000

Multistep solution-phase parallel synthesis of spiperone analogues.

A flexible, multistep parallel synthesis of spiperone analogues is described. A library of 4-substituted piperidines, assembled utilizing reductive amination and acylation protocols, was alkylated either homogeneously or heterogeneously, exploiting a product release only concept, to afford an oxa-series of spiperone analogues. Screening of the products at 5-HT2 and D2 receptors revealed 5-HT2A antagonists with improved selectivity compared to spiperone and AMI-193.

Antipsychotic Agents↗
PubMed1989

3-(2'-[18F]fluoroethyl)spiperone: in vivo biochemical and kinetic characterization in rodents, nonhuman primates, and humans.

3-(2'-[18F]fluoroethyl)spiperone (FESP), a recently developed dopamine D2-receptor binding radiopharmaceutical, was used for dynamic characterization of dopamine-receptor binding in Macaca nemestrina monkeys and humans with positron emission tomography (PET). FESP in vitro binding properties to the dopamine receptor (IC50 = 1.5 nM) are similar to those of spiperone. Serial PET scans in monkeys after intravenous bolus injection of FESP revealed specific radioactivity accumulation in striatum (rich in dopamine D2-receptors), whereas radioactivity concentration declined after 20 min in frontal cortex (serotonin receptors) and more rapidly in cerebellum (nonspecific binding). Specific dopamine D2-receptor binding was saturated with increasing concentrations of radioligand (specific activity range: 1-10,000 Ci/mmol), was stereospecifically blocked with (+)butaclamol (0.5 mg/kg), and showed only partial displacement with spiperone (200 micrograms/kg, i.v. administration 90 min after FESP injection). From PET experiments with FESP in humans, it is possible to visualize accumulation of radioactivity in striatum in a manner similar to that observed in monkeys and, ex vivo, in rodents (adult male Sprague-Dawley rats). Biochemical analyses in rat brain revealed that the activity (approximately 90%) in striatum was unmodified FESP up to 4 h after injection. On the other hand, FESP was metabolized peripherally (rat greater than monkey greater than human), with only 11% of plasma radioactivity remaining as intact FESP in rodents and 54% in humans after 2 h. Based on these interspecies scaling pharmacokinetic data, it is unequivocal that FESP peripheral metabolites do not significantly contribute to the accumulated radioactivity in striatal tissue. Therefore, it is concluded that FESP is suitable for the quantitative estimation of dopamine D2-receptor sites using PET.

Animals↗
PubMed1997

Inhibition of the constitutive activity of human 5-HT1A receptors by the inverse agonist, spiperone but not the neutral antagonist, WAY 100,635.

At recombinant human 5-hydroxytryptamine (5-HT)5-HT1A receptors expressed in Chinese hamster ovary cells (CHO-5-HT1A), 5-carboxamidotryptamine (5-CT), acted as a full agonist (relative to 5-HT = 100%) for stimulation of receptor-mediated [35S]-GTP gamma S (guanylyl 5'-[gamma-thio]-tryphosphate) binding. In contrast, spiperone inhibited basal [35S]-GTP gamma S binding by 30.2% (IC50 = 55.5 nM) in CHO-5-HT1A membranes but not in control untransfected membranes. The antagonist, N-[2-[4-(2-methoxyphenyl) -1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclohexane-carboxamide (WAY 100,635), blocked both 5-CT-induced stimulation and spiperone-induced inhibition of [35S]-GTP gamma S binding without itself modifying [35S]-GTP gamma S binding. It is concluded that, in this heterologous expression system, 5-HT1A receptors display 'constitutive' activation of G-proteins and that spiperone displays inverse agonist activity whereas WAY 100,635 acts as a 'neutral' antagonist at this site.

Animals↗
PubMed1995

[3H]nemonapride and [3H]spiperone label equivalent numbers of D2 and D3 dopamine receptors in a range of tissues and under different conditions.

[3H]Nemonapride and [3H]spiperone are very widely used to study dopaminergic systems in vitro and in vivo, but it has been reported that [3H]nemonapride and [3H]spiperone give markedly different Bmax values for preparations of D2 dopamine receptors from recombinant cell lines or animal tissues. We have used the two radioligands in parallel to study a range of dopamine receptors [D2(short), D2(long), and D3] in different buffers. Bmax values derived using either radioligand differ by an average of < 20%, independent of receptor type or buffer conditions. All competition experiments show that the two ligands compete at a single site. It seems that [3H]spiperone and [3H]nemonapride do not differentiate between different forms or populations of D2-like receptors.

Animals↗
PubMed1978

Selective labeling of alpha-adrenergic receptors in caudate nucleus by [3H] dihydroergocryptine in the presence of spiperone-blocked dopamine receptors.

Because it was known that [(3)H]dihydroergocryptine can label alpha-adrenergic receptors as well as dopamine receptors, this study was done to establish the conditions under which [(3)H]dihydroergocryptine would be a reliable ligand for selective labeling of alpha-adrenergic receptors. The calf caudate was chosen because it contains both dopamine and adrenergic receptors, and 5 nM spiperone (spiroperidol) was used to block the neuroleptic/dopamine receptors. Thus, in the presence of spiperone, [(3)H]dihydroergocryptine exhibited saturable binding with a K(d) of 0.73 nM and a total number of sites of 150 fmol/mg of protein. The catechol neurotransmitters competed for [(3)H]dihydroergocryptine binding in the potencies order epinephrine > (-)-norepinephrine > dopamine, indicating that [(3)H]dihydroergocryptine (in the presence of 5 nM spiperone) was revealing alpha receptors. The alpha-adrenergic antagonists also competed for binding in the appropriate order: phentolamine > phenoxybenzamine > dibenamine. Finally, chlorpromazine was more potent than haloperidol in competing for [(3)H]dihydroergocryptine, also in accord with the properties of alpha receptors. These results with [(3)H]dihydroergocryptine as an alpha-adrenergic receptor ligand correlate well with those published by others for [(3)H]WB-4101.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Nad-299 antagonises 5-HT-stimulated and spiperone-inhibited [35S]GTPgammaS binding in cloned 5-HT1A receptors.

In Chinese Hamster Ovary (CHO) cells expressing cloned human 5-hydroxytryptamine1A A (5-HT1A) receptors, (R)-3-N,N-dicyclobutylamino-8-fluoro-[6-3H]-3,4-dihydro-2H-1-benzopyan-5-carboxamide ([3H]NAD-299) exhibited high affinity (Kd = 0.16 nM) and labeled 34% more receptors than 8-hydroxy-2-([2,3-3H]di-n-propylamino)tetralin ([3H]8-OH-DPAT). NAD-299 behaved as a silent antagonist in [35S]GTPgammaS binding similar to N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide (WAY-100635) and (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)UH-301). 5-HT and 5-carboxamidotryptamine (5-CT) stimulated [35S]GTPgammaS binding 2.5-fold while spiperone and methiothepin inhibited [35S]GTPgammaS binding 1.4-fold. Furthermore, NAD-299 antagonised both the 5-HT stimulated and the spiperone inhibited [35S]GTPgammaS binding to basal levels. The KiL/KiH ratios for spiperone (0.66), methiothepin (0.39), WAY-100635 (0.32), (S)UH-301 (0.94), NAD-299 (1.29), NAN-190 (1.23), (S)pindolol (5.85), ipsapirone (13.1), buspirone (24.6), (+/-)8-OH-DPAT (47.3), flesinoxan (55.8), 5-HT (200) and 5-CT (389) correlated highly significantly with the intrinsic activity obtained with [35S] GTPgammaS (r = 0.97).

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1981

Comparison of the binding of [3H]spiperone and [3H]domperidone in homogenates of mammalian retina and caudate nucleus.

The specific binding of [3H]spiperone and [3H]domperidone, as defined by 1 microM-(+)butaclamol, was compared in homogenates of bovine retina and caudate nucleus. Scatchard analyses of saturation data for [3H]spiperone binding yielded dissociation constants (Kd) of 0.35 nM in the retina and 0.64 nM in the caudate nucleus. Comparison of the maximum number of binding sites (Bmax) present in each tissue indicated that the density of sites in bovine caudate nucleus (270 fmol/mg protein) was approximately three times higher than in bovine retina (92 fmol/mg protein). This difference was even more marked in guinea pig tissues, with a ratio of 7:1 between corpus striatum and retina. The pharmacological analysis of [3H]spiperone binding in both the bovine retina and caudate nucleus indicated an interaction with dopaminergic rather than serotonergic sites. However, inhibition curves obtained to dopaminergic agonists in the bovine retina were significantly steeper than those observed in the bovine caudate nucleus, as reflected in the greater Hill coefficients obtained for these agents in the retina. Furthermore, only a small amount of specific [3H]domperidone binding was observed in either the bovine caudate nucleus or the guinea pig striatum, whilst no specific [3H]domperidone binding was detectable in homogenates of either bovine or guinea pig retina. These data suggest that the retina possesses only a small population of dopaminergic D2 sites and that these binding sites may differ from those present in the caudate nucleus.

Animals↗
PubMed1982

Ontogenetic development of the striatal [3H]spiperone binding: regulation by sodium and guanine nucleotide in rats.

Ontogenetic development of specific [3H]spiperone binding to crude synaptic membranes and its regulation by Na+ and GTP was investigated in the rat striatum. (d)-Butaclamol more effectively inhibited [3H]spiperone binding than (l)-butaclamol. The ratio of inhibitory activity of (d)- and (l)-butaclamol for [3H]spiperone binding was not different between 1-, 7-, and 70-day-old animals but eight- to ninefold lower at 18 days of gestation than during the postnatal period. A Scatchard plot of specific binding indicated the presence of two types of binding: low-affinity (KD = 1.51 nM) and high-affinity (KD = 0.09 nM) binding on day 70. Only one component (KD = 0.075 nM) was observed on days 1 and 7 and both types of binding were found on day 15. Bmax gradually increased with age and reached a peak on day 30, followed by a decline on days 70 and 360. Na+, 100 mM, significantly increased specific binding on days 1, 7, 15, and 70. GTP, 50 microM, completely reversed the Na+-induced decrease in IC50 of apomorphine on both days 15 and 70, but not on day 7. It is suggested that receptors could recognize ligand stereospecificity on day 1. The density in dopamine receptors in the striatum reaches a peak on day 30, followed by a decrease on days 70 and 360. In addition, regulation by Na+ and GTP in agonist binding to dopamine receptors seems to become functional between 1 and 2 weeks after birth.

Aging↗
PubMed1982

Neurochemical studies of the mesolimbic dopaminergic pathway: [3H]spiperone labels two bindings sites in homogenates of the nucleus accumbens of rat brain.

The binding of [3H]spiperone to membranes of the nucleus accumbens of the rat brain was studied in vitro and found to be of high affinity, rapid, saturable, reversible and stereospecific. Dissociation and saturation experiments indicated the presence of two specific binding sites with apparent dissociation constants of 70 pM and greater than 1 nM. Specific binding with 25 pM [3H]spiperone represented greater than 90% of total binding and was displaced by dopaminergic agonists, neuroleptic drugs and ergot derivatives. The rank order of potency for the ergot derivatives was bromocryptine greater than pergolide greater than lergotrile, and that for D-2 antagonists was domperidone greater than sulpiride greater than molindone greater than metoclopramide. Noradrenergic, histaminergic and serotonergic components of the binding were not detected. [3H]Spiperone binds to high-affinity sites in homogenates of nucleus accumbens, which are likely to be D-2 receptors.

Animals↗
PubMed1985

Occupation of dopamine receptors by N-n-propylnorapomorphine or spiperone and acetylcholine levels in the rat striatum.

In an attempt to quantify the interactions between dopaminergic and cholinergic processes, the consequences of complete or partial activation (with N-n-propylnorapomorphine) or blockade (with spiperone) of dopamine receptors for the acetylcholine levels in the rat striatum were studied. The number of specific striatal binding sites (receptors) of spiperone was nearly three times that of N-n-propylnorapomorphine (76 and 26 pmol g-1 wet weight, respectively). The agonist produced a significant increase in the striatal levels of acetylcholine, but there was no simple relationship between receptor binding and these levels. A linear negative correlation was found between the striatal levels of acetylcholine and specific spiperone binding, showing that further receptor blockade induces a decrease in acetylcholine levels, which is independent of the receptors already occupied by the antagonist. The results of this study are evidence that one striatal dopamine receptor regulates the metabolism of at least 400 molecules of acetylcholine.

Acetylcholine↗
PubMed1990

Time-related changes in serum perphenazine, striatal 3H-spiperone binding and regional brain acid metabolites of dopamine and 5-hydroxy-tryptamine after a single dose of perphenazine.

A single dose of perphenazine (5.0 mg/kg) was administered intraperitoneally to male Wistar rats. The time-related alterations in serum levels of perphenazine, striatal 3H-spiperone binding ex vivo and the regional brain metabolism of dopamine and 5-hydroxy-tryptamine were studied. Low serum levels of perphenazine were observed together with increased Kd of 3H-spiperone. No significant changes in Bmax were observed. Since Kd of 3H-spiperone binding peaked several hours after the maximal serum levels of perphenazine, perphenazine in serum appeared not to directly reflect the events at the receptor level. The concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy, 4-hydroxyphenylacetic acid (HVA) in the striatum were increased after perphenazine. They were maximal 1-3 h after the drug administration and showed positive correlations (correlation coefficient 0.93 and 0.80, respectively) with the serum levels of perphenazine. Increased levels of HVA were also observed both in the olfactory tubercle and in the frontal cortex. However, in the olfactory tubercle, administration of perphenazine did not significantly increase the DOPAC concentrations. In the olfactory tubercle 5-hydroxyindoleacetic acid (5-HIAA) was decreased 1-24 h after administration of perphenazine. In the striatum and in the frontal cortex only slight changes in 5-HIAA were seen. Thus, in the olfactory tubercle 5-hydroxytryptaminergic mechanisms could modulate the dopaminergic neurotransmission.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1978

Effects of spiperone on self-stimulation and other activities of the Mongolian gerbil.

1 Self-stimulation to lever pressing and capacitance probe touching was obtained in Mongolian gerbils (Meriones unguiculatus) from electrode placements within the medial forebrain bundle. 2 Lever pressing was more sensitive to the decremental effects of a central depressant, pentobarbitone, than capacitance probe touching, suggesting its greater responsiveness to disturbances of motor function. 3 Spiperone (0.005 to 0.05 mg/kg) attenuated capacitance probe touching and lever pressing equally, a finding explained by action on either reward pathways or on the ability to initiate responding. 4 This same dose range of spiperone (0.005 to 0.05 mg/kg) attenuated locomotor activity, whether spontaneous or evoked by non-contingent electrical stimulation, and produced catalepsy. 5 The spiperone-induced attentuation of self-stimulation was not necessarily a result of its action on dopaminergic reward pathways since the effects could equally well be explained by a failure to initiate responding.

Animals↗
PubMed1983

Differential anatomical location of [3H]-N,n-propylnorapomorphine and [3H]-spiperone binding sites in the striatum and substantia nigra of the rat.

Specific [3H]-spiperone and [3H]-N,n-propylnorapomorphine (NPA) binding was measured in striatum and substantia nigra of the rat following unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, kainic acid lesions of the substantia nigra or striatum, and following decortication. Binding sites labelled by [3H]-spiperone in striatum were found to lie on striatal cell bodies and on the terminals of cortico-striate glutamate fibres, but not on presynaptic dopamine terminals. In contrast, binding sites labelled by [3H]-NPA were demonstrated on striatal cell bodies and on the terminals of nigro-striata dopamine fibres, but not on cortical afferents. In substantia nigra, specific [3H]-spiperone binding sites were found only on non-dopamine cell bodies. No clear evidence was found for their existence on dopamine cell bodies, the terminals of strio-nigral fibres or the terminals of cortico-nigral fibres. In contrast, specific binding sites for [3H]-NPA were found on dopamine cell bodies and the terminals of strio-nigral fibres. Localization on non-dopamine cell bodies or on cortico-nigral fibres was not demonstrated. These studies support the concept of differential localization of agonist and antagonist binding sites.

Animals↗