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PubMed1998

Central administration of dopamine D3 receptor antisense to rat: effects on locomotion, dopamine release and [3H]spiperone binding.

A 15-mer, all-phosphorothioate-modified antisense oligodeoxynucleotide (ASO) targeted against rat dopamine D3 receptor mRNA (4 microM, 5 days) significantly reduced (28%) the amount of binding sites labelled with [3H]spiperone in monolayer cultured Chinese hamster ovary (CHO) cells transfected with the complementary desoxyribonucleic acid (cDNA) for the rat D3 receptor. In contrast, D3-ASO treatment did not reduce the amount of bound [3H]spiperone in CHO cells transfected with D2 receptor cDNA. Intracerebroventricular infusion of D3-ASO (osmotic minipump, 10 microg/microl/h, 7 days) influenced dopamine receptor density in the limbic forebrain such that the upper part of the dopamine/[3H]spiperone displacement curve--tentatively representing the D3 receptor--was altered significantly. Spontaneous locomotor activity of non-habituated rats was increased significantly in D3-ASO-treated animals; in addition, in vivo microdialysis revealed a moderate increase in dopamine release in the nucleus accumbens in these animals. In all experiments, an oligodeoxynucleotide comprising the same nucleotides as the antisense sequence, but in random order, was used as control. It is concluded that the antisense strategy is useful for investigating the functional role of dopamine D3 receptors and that the dopamine D3 receptor is involved in rat locomotor behaviour.

Animals↗
PubMed1986

Hyperprolactinaemia does not alter specific striatal 3H-spiperone binding in the rat.

We have investigated the effect of single injections (1 mg/animal i.v.) of prolactin or vehicle, and repeated depot (0.125-1.0 mg/animal/day) or bolus (1.0 mg/animal/day) administration of prolactin or vehicle for 6 days to adult male rats. The density (Bmax) and affinity (Kd) of specific striatal [3H]spiperone binding was not changed by any of the prolactin treatment schedules used. Allogeneic transplants of anterior pituitary glands resulted in an increased concentration of circulating prolactin but did not alter the density or affinity of specific striatal [3H]spiperone binding in male rats, measured 2 weeks following the operation. Prolactin did not displace specific striatal [3H]spiperone binding when incorporated in vitro. Any effect of prolactin on striatal dopamine receptor function appears to be exerted only by high, non-physiological concentrations, and such effects are difficult to reproduce.

Animals↗
PubMed1983

Guanine nucleotides reveal differential actions of ergot derivatives at D-2 receptors labelled by [3H]spiperone in striatal homogenates.

The specific binding of [3H]spiperone (35 pM), as defined by the D-2 antagonist sulpiride, was potently displaced by ergot derivatives of both the ergoline and ergopeptine type, and by dopamine agonists and antagonists. The potency of the ergot derivatives ranged widely from an IC50 value of 3 nM for bromocriptine to a value of 1000 nM for the partial ergoline, LY-141865. GTP and its stable analogue, guanyl-5'-yl-imidodiphosphate (Gpp(NH)p), did not affect the affinity (100 pM) or density (30 pmol/g wet wt) of [3H]spiperone binding sites, but did decrease the potency of a number of ergoline compounds including pergolide, lergotrile and LY-141865, as well as dopamine agonists to displace [3H]spiperone binding. The affinities of the ergopeptines, bromocriptine and dihydroergocryptine, and of the isolysergic acid ergoline, lisuride, and dopamine antagonists were unaltered by the presence of guanine nucleotides. The effect was specific for guanine nucleotides, with near maximal effects on agonist affinity observed in the presence of a 100 microM concentration of nucleotide. The relative decrease in affinity found in the presence of GTP or Gpp(NH)p varied widely for individual ergot derivatives and dopamine agonists. The largest decrease was seen with dopamine itself, and agonists such as the tetralins and with LY-141865. Many ergolines had shifts in potency between those seen for agonists and antagonists, suggesting a partial agonist action at D-2 receptors. Guanine nucleotide sensitivity may represent a valuable in vitro method for studying the agonist/antagonist properties of dopaminergic drugs, such as the semi-synthetic ergoline compounds.

Animals↗
PubMed1977

Lack of stimulation by high amphetamine doses following a low dose of spiperone.

The locomotor stimulant and stereotypic effects of amphetamine were investigated in rats pretreated with the specific dopaminergic blocker spiperone (0.25 mg/kg). Amphetamine doses from 8.0 to 64.0 mg/kg failed to stimulate behavior significantly and consistently after spiperone treatment. These results suggest the possibility of non-competitive antagonism by spiperone at dopaminergic synapses.

Animals↗
PubMed1981

Potentiation by spiperone and other butyrophenones of fluid secretion by isolated salivary glands of ixodid ticks.

Isolated salivary glands from the ixodid tick, Amblyomma hebraeum Koch are stimulated to secrete fluid when exposed to dopamine (DA), the maximum response occurring at 10(-6) M. Spiperone, and a number of other butyrophenone derivatives, although lacking intrinsic activity, are able to potentiate the secretion elicited by supramaximal concentrations of DA; this potentiation by spiperone is evident at concentrations in the femtomolar range. Tranylcypromine, a potent, competitive inhibitor of monoamine oxidase (MAO) in tick salivary gland homogenates, has both intrinsic activity and potentiates DA-induced salivation. The fact that spiperone potentiates ergometrine-induced salivation that the prime mechanism of the butyrophenone effect is not by inhibiting catecholamine catabolism. The results also suggest that the receptor for DA and that for butyrophenones are distinct sites. Droperidol, benperidol and bromperidol, all potent neuroleptic drugs, failed (at 10(-9) M) to potentiate salivation. By contrast, R951, R27275 and R1187 (all at 10(-9) M) were very effective potentiators on the salivary gland system, despite the fact that they lack the basic structural requirements for neuroleptic activity. These results suggest that the butyrophenone site in tick salivary glands is different from butyrophenone binding sites in mammalian CNS.

Animals↗
PubMed1982

[3H]N-propylapomorphine and [3H]spiperone binding in brain indicate two states of the D2-dopamine receptor.

[3H]N-propylapomorphine ([3H]NPA) a dopaminergic catecholamine derivative, labels a sub-set of D2-dopamine receptors in bovine caudate particulate preparation. [3H]Spiperone, a dopamine receptor antagonist, labels twice as many sites as [3H]NPA. Dopaminergic ergots and potent neuroleptics compete for both radioactive ligands with similar high affinities. Catecholamines and catecholamine derivatives compete more potently for [3H]NPA binding than for [3H]spiperone binding. Guanyl nucleotides reduce both [3H]NPA binding and the high affinity phase of catecholamine and catecholamine derivative competition for [3H]spiperone binding. These results are similar to binding results reported in studies of two-state receptors linked to adenylate cyclase such as the beta-adrenergic receptors. These observations indicate that the D2-dopamine receptor in the brain may exist in two states and may be inversely coupled to brain adenylate cyclase activity.

Animals↗
PubMed1984

[3H]spiperone binding in the nigrostriatal system in human brain.

The characteristics of [3H]spiperone binding in human brain were compared in three areas of the nigrostriatal pathway: areas containing the nerve terminals (caudate nucleus, putamen and pallidum); the area containing the cell bodies (substantia nigra pars compacta); the area containing the dendrites (pars reticulata). The affinity constants were calculated from saturation binding curves and from the kinetics of association and dissociation. The pharmacological profiles of the receptors was also established by displacement studies. The affinity constants and pharmacological profiles were similar in the striatum and the substantia nigra, although the latter contained a much smaller number of sites. In the substantia nigra, however, curved Scatchard plots were obtained, indicating that a second lower affinity site binding [3H]spiperone was also present. A considerable proportion (50%) of [3H]spiperone binding to nigral membranes could be displaced by the serotonin antagonist cinanserine , compared to the striatum (20%). The effect of post-mortem conditions on binding levels was studied in the rat. A loss of 20% occurred during the first hours after death, but was stable by 6 h until at least 24 h.

Aged↗
PubMed1984

[3H]spiperone binding, dopamine and HVA concentrations in Parkinson's disease and supranuclear palsy.

The density of D2-type dopamine receptors, measured by the binding of [3H]spiperone was normal in the substantia nigra, caudate nucleus and nucleus accumbens of Parkinsonian subjects and above control levels in the putamen, in spite of massive lesions of the dopaminergic neurons. Dopamine levels were reduced in the putamen, caudate nucleus, and nucleus accumbens by 97, 85 and 68%, respectively and by 78 and 93% in the pars compacta and pars reticulata of the substantia nigra. HVA levels were much less affected suggesting that increased activity of the remaining dopaminergic neurons compensated to some extent for the lesions. Neuroleptic treatment and the presence of dementia in the Parkinsonian subjects affected [3H]spiperone binding and dopamine concentrations. Dopamine and HVA levels in the striatum of subjects with supranuclear palsy indicate that the nigrostriatal system was lesioned to the same degree in this disease as in idiopathic Parkinsonism, but spiperone binding was reduced by half in all the structures studies.

Aged↗
PubMed1984

Selective and stereospecific interactions of R-SK & F 38393 with [3H]piflutixol but not [3H]spiperone binding to striatal D1 and D2 dopamine receptors: comparisons with SCH 23390.

Four benzazepine derivatives, racemic SK&F 38393, its resolved R- and S-enantiomers, and SCH 23390 have been investigated for their interactions with striatal D1 and D2 dopamine receptors, as indexed by the binding of [3H] piflutixol and [3H]spiperone respectively. For the agonist SK&F 38393, its R-enantiomer was active in displacing [3H] piflutixol while its S- antipode was 100 fold less potent. In contrast, both enantiomers showed similar and negligible activity to displace [3H]spiperone. SCH 23390, an antagonist analogue with an R-configuration, potently displaced [3H] piflutixol but not [3H]spiperone. R-SK&F 38393 and SCH 23390 may help clarify the structural requirements for, and functional consequences of, selective actions at the D1 dopamine receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Uptake of 3H-spiperone by lymphocytes in schizophrenia.

Uptake of 3H-spiperone into lymphocytes obtained from control subjects (N = 22), chronic schizophrenics (N = 20), relatives with psychiatric disorder (N = 11) and unaffected relatives (N = 17) was studied. No differences were observed in spiperone uptake among any of the groups examined. Although previous investigations reported marked differences in 3H-spiperone uptake between schizophrenic and control subjects, we were unable to replicate their findings: the failure to replicate those of Bondy and colleagues may well be due to our inability to duplicate in our laboratory the exact biochemical methodology described by these investigators. Saturation curves could not be determined for most subjects. In addition, chronicity of illness and long-term exposure to neuroleptic medication among the schizophrenic subjects may partially account for the contradictory results reported by different investigators.

Adult↗
PubMed1992

The sequestration of [3H]spiperone by lymphocytes in schizophrenics and their first-degree relatives: a limited vulnerability marker?

The sequestration of [3H]spiperone by lymphocytes was studied in preserved cells obtained from 22 schizophrenic subjects and 40 of their relatives, and the results were compared with those obtained from 25 healthy control subjects. Mean displaceable sequestration values, obtained from measurements made at a single radioligand concentration (1nM) which optimised the relative contribution of "high affinity" sequestration, were found to be similar for all groups of subjects. Furthermore, displaceable spiperone sequestration was abnormally high in only a small proportion of the schizophrenics (13.6%) and their relatives (5%). There was no evidence that either exposure to neuroleptic medication or duration of illness had an effect on sequestration values. The results suggest that, at least until the required experimental conditions are better established, [3H]spiperone sequestration by lymphocytes does not offer a useful vulnerability marker for schizophrenia.

Adolescent↗
PubMed1979

Alterations in [3H]spiperone binding in human caudate nucleus, substantia nigra and frontal cortex in the Shy-Drager syndrome and Parkinson's disease.

[3H]Spiperone binding was investigated in the caudate nucleus, substantia nigra (s. nigra) and frontal cortex of control subjects and of patients with Parkinson's disease and the Shy-Drager syndrome. Binding sites for [3H]spiperone were interpreted as dopamine receptors in caudate and s. nigra, and as 5-hydroxytryptamine (5-HT) receptors in frontal cortex. Scatchard analysis showed that the Bmax (maximal number of binding sites) in caudate was similar in the 3 groups, whereas in s. nigra the Bmax was reduced by approximately 60% in both Parkinsons disease and Shy-Drager syndrome. The dissociation constant (Kd) for [3H]spiperone binding in s. nigra was similar in the 3 groups. In caudate nucleus, the Kd was similar in control and Parkinson groups; however, there was a significant increase in the dissociation constant in the caudate nucleus from cases of Shy-Drager syndrome. No differences in binding characteristics were observed in the frontal cortex. These results are taken to reflect a loss of dopamine receptor sites in the s. nigra in both Parkinson's disease and Shy-Drager syndrome, and a reduced affinity of dopamine receptor sites in the caudate nucleus in Shy-Drager syndrome.

Binding Sites↗
PubMed1983

Effects of a series of substituted benzamides on rat prolactin secretion and 3H-spiperone binding to bovine anterior pituitary membranes.

The potency of seven substituted benzamide drugs (AHR-5531B, AHR-5645B, AHR-6092, AHR-8764, bromopride, sultopride and tiapride) to stimulate rat prolactin (PRL) secretion in vivo was found to be three orders of magnitude greater than that of non-benzamide neuroleptic drugs relative to their respective abilities to inhibit 3H-spiperone binding to bovine anterior pituitary membranes. Nevertheless, the IC50 values for the inhibition of 3H-spiperone binding by the seven substituted benzamide drugs was significantly correlated with their high potency to stimulate rat PRL secretion in vivo. Further, the slope of the regression line for these substituted benzamides paralleled that of a series of butyrophenone, phenothiazine, morphanthridine and dibenzodiazepine neuroleptic drugs. Two benzamide (sulpiride and metoclopramide) and three non-benzamide neuroleptic drugs gave intermediate results. This data suggests that blockade of different subgroups of dopamine receptors in the anterior pituitary gland labeled by 3H-spiperone may be responsible for the in vivo stimulation of PRL secretion by the benzamide and non-benzamide neuroleptic drugs.

Animals↗
PubMed1984

Contamination of serotonin-2 binding sites by an alpha-1 adrenergic component in assays with (3H)spiperone.

(3H)Spiperone binds to two sites in mouse cortical membranes. These binding sites are discriminated by methysergide and prazosin, but not by butaclamol, lysergic acid diethylamide, or ketanserin. One of these sites is serotonergic in nature and is the authentic S-2 binding site. The other component is adrenergic and corresponds to the alpha-1 adrenoreceptor. This alpha-1 component may be present in other S-2 binding assays using (3H)spiperone, or (3H)ketanserin. No (3H)spiperone binding to dopaminergic D-2 sites was found in mouse cortex. Methods of avoiding alpha-1 contamination of S-2 binding assays are suggested.

Animals↗
PubMed1984

The effects of exercise training on [3H]-spiperone binding in rat striatum.

Thirty male Sprague-Dawley rats 100 days of age were divided into three groups: interval trained, endurance trained, and pair-weighted controls. Both trained groups ran up to one hour per day, 6 days per week for 12 weeks. The interval trained group ran up to 20 repeat intervals at 54 meters per minute for 30 seconds, while the endurance trained group ran at 27 meters per minute for 60 minutes. The animals were sacrificed, and the effects of aerobic training were documented by measuring cytochrome oxidase activity in the mixed quadriceps muscles. The cytochrome oxidase activity of the interval and endurance trained groups increased 49%, and 31% respectively, above the control group. [3H]-spiperone was used to label dopamine receptors in the striatum. The endurance group was not significantly different from the interval group in [3H]-spiperone receptor binding, so the two exercise groups were combined to form one group of runners. The runners had significantly higher [3H]-spiperone receptor binding than the controls, F(1,26) = 4.87, p less than 0.05. The mean and standard error for receptor binding was 89 +/- 13 fmoles/mg protein for the runners and 60 +/- 5 fmoles/mg protein for the controls.

Animals↗
PubMed1987

Comparison of 3H-spiperone binding in caudate nuclei of rabbits and rats.

3H-Spiperone binding and inhibition by competing ligands were studied in caudate nucleus homogenates from Sprague-Dawley rats and New Zealand albino rabbits. 3H-Spiperone binding sites were very similar in the two species and had pharmacological profiles characteristic of D2-dopamine receptors, in accordance with previous reports. However, differences occurred between the species in the potencies with which dopaminergic ergots and other drugs interacted with these binding sites and with regard to the compounds used to define specific binding. These findings suggest that slight differences in relative proportions of subtypes of 3H-spiperone binding sites, or of neuroleptic potencies at these subtypes, may exist between rabbits and rats.

Animals↗
PubMed1992

Dopamine receptors in human foetal brains: characterization, regulation and ontogeny of [3H]spiperone binding sites in striatum.

Eighteen corpora striata from normal human foetal brains ranging in gestational age from 16 to 40 weeks and five from post natal brains ranging from 23 days to 42 years were analysed for the ontogeny of dopamine receptors using [3H]spiperone as the ligand and 10 mM dopamine hydrochloride was used in blanks. Spiperone binding sites were characterized in a 40-week-old foetal brain to be dopamine receptors by the following criteria: (1) It was localized in a crude mitochondrial pellet that included synaptosomes; (2) binding was saturable at 0.8 nM concentration; (3) dopaminergic antagonists spiperone, haloperidol, pimozide, trifluperazine and chlorpromazine competed for the binding with IC50 values in the range of 0.3-14 nM while agonists--apomorphine and dopamine gave IC50 values of 2.5 and 10 microM, respectively suggesting a D2 type receptor. Epinephrine and norepinephrine inhibited the binding much less efficiently while mianserin at 10 microM and serotonin at 1 mM concentration did not inhibit the binding. Bimolecular association and dissociation rate constants for the reversible binding were 5.7 x 10(8) M-1 min-1 and 5.0 x 10(-2) min-1, respectively. Equilibrium dissociation constant was 87 pM and the KD obtained by saturation binding was 73 pM. During the foetal age 16 to 40 weeks, the receptor concentration remained in the range of 38-60 fmol/mg protein or 570-1080 fmol/g striatum but it increased two-fold postnatally reaching a maximum at 5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

3H-spiperone binding to peripheral mononuclear cells in psychiatric in-patients.

1. There is an ongoing controversy, if increased binding of 3H-spiperone to lymphocytes might discriminate between schizophrenia and other psychiatric diseases or even be a genetic vulnerability marker for schizophrenia, or predict the response to neuroleptic treatment. 2. Some critical methodological details which might contribute to this controversy are described. 3. 3H-spiperone binding was evaluated in 31 patients with schizophrenia, 7 patients with schizoaffective disorder, bipolar type, 6 patients with a manic episode and 6 patients with a depressive episode of bipolar major affective disorder (DSM-III-R criteria), and in 19 healthy subjects. 4. There were no significant differences in characteristic binding parameters (KD, Bmax) between all groups of psychiatric in-patients and in comparison to healthy subjects. Moreover, there was no relation of binding parameters to any of the subtypes of schizopherenia or to the course of illness according to DSM-III-R-criteria. 5. Neuroleptic treatment or clinical response to treatment had no consistent effect on binding parameters intra-individually. 6. In summary, 3H-spiperone binding to lymphocytes failed to differentiate between the diagnostic subgroups (DSM-III-R) and between treatment responders and non-responders in our sample of patients.

Adult↗