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PubMed1988

Repeated administration of HA-966 and haloperidol to rats: similar tolerance to striatal dopamine accumulation after HA-966 challenge, but dissimilar effects on striatal [3H]spiperone binding.

Repeated administration of 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) to rats induces tolerance, as shown by a decreased, drug-stimulated accumulation of dopamine (DA) in the striatum. In the present study we compared the adaptive response of the striatal dopaminergic system to repeated administration of HA-966 with the adaptive response observed after repeated haloperidol. These treatments deprive dopamine (DA) receptors from their agonist and cause a blockade of DA receptors, respectively. Tolerance to HA-966 was not accompanied by a change in the specific binding of [3H]spiperone to striatal membranes. This is in contrast to the well-documented up-regulation of DA receptors that occurs with tolerance to haloperidol. Repeated haloperidol pretreatment also diminished DA accumulation following a challenge dose of HA-966, to a similar extent as that caused by repeated pretreatment with HA-966. These similar effects of pretreatment with HA-966 or haloperidol on the response to the HA-966 challenge are in line with, and strengthen, the idea that an increased sensitivity of presynaptic DA receptors is responsible for the decreasing effect of HA-966 after its repeated administration. Haloperidol and HA-966 clearly have different effects on postsynaptic DA receptors, as is shown by their differential effects on striatal [3H]spiperone binding.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Methodology of 3H-spiperone binding to lymphocytes.

Alterations in lymphocyte binding capacity for the dopamine antagonist 3H-spiperone may be of great interest in psychiatric and neurological disorders: an increase in capacity noted in lymphocytes of schizophrenic patients and their families may well turn out to be a phenotypic vulnerability marker. Since the 3H-spiperone binding assay with lymphocytes does not fulfill common receptor-binding assay criteria and depends more on crucial analytical conditions, shortcomings in binding assay might possibly lead to irreproducible results. A detailed methodological description of the binding assay and subsequent calculations has therefore been given in this paper.

Binding, Competitive↗
PubMed1982

Some calcium and lysosome antagonists inhibit 3H-spiperone binding to the porcine anterior pituitary.

The dopamine antagonist 3H-spiperone binds to dopamine receptors in crude membrane preparations of the porcine anterior pituitary. In competition studies, several calcium channel antagonists (bepridil, D600 and verapamil) and a lysosomal enzyme inhibitor (chloroquine) displaced spiperone binding in a dose related manner. Because dopamine receptor activity modulates prolactin release from the anterior pituitary, it is suggested that the previously observed effects of some of these agents on prolactin release or storage may have been initiated at the level of the dopamine receptor or through physical modifications of the plasma membrane rather than the calcium channel or lysosome.

Animals↗
PubMed1986

Tracer and maximal specific binding of tritiated spiperone or N-n-propylnorapomorphine to quantify dopamine receptors in rat brain regions in vivo.

Specific tracer and maximal specific binding (Bmax) were determined in rat brain regions from radioactivity accumulation after intravenous administration of 3H N-n-propylnorapomorphine (NPA) or 3H spiperone at various specific activities. With NPA the highest Bmax-values (expressed in pmol.g-1 tissue) were found in the striatum (26 pmol.g-1) nucleus accumbens (about 27 pmol.g-1) and the olfactory tubercle (11 pmol.g-1). Saturable NPA binding was also found in the amygdaloid complex, medulla oblongata and inferior colliculi, but not in the frontal cortex. Bmax values for spiperone were high in the striatum (73 pmol.g-1), the nucleus accumbens (48 pmol.g-1), the olfactory tubercle (34 pmol.g-1) and the frontal cortex (18 pmol.g-1). A similar order was found for the tracer contents in these regions. There was no linear relationship between these contents and Bmax values. The possible implications of these findings and usefulness of NPA for brain imaging are discussed.

Animals↗
PubMed1982

Suppression of drinking and induction of sedation by a dopamine agonist is blocked by small doses of spiperone.

ET 495 (piribedil) produced significant hypodipsia in thirsty rats at 5 and 20 mg . kg-1, the effect being greater at the lower dose. At 5 mg . kg-1 ET 495 also induced a significant sedating effect, a characteristic of small doses of dopamine agonists. Both the hypodipsic and sedating effects of ET 495 were completely reversed by pretreatment with spiperone. The slight hypodipsia produced at 20 mg . kg-1 was accompanied by signs of low intensity behavioural stereotypy. The stereotypy, unlike the other behavioural effects of ET 495 treatment, was not antagonized by spiperone pretreatment.

Animals↗
PubMed1991

Potentiation of spiperone-induced oral activity in rats after neonatal 6-hydroxydopamine.

The influence of central dopaminergic fibers on drug-induced oral activity in rats has not been well studied. Rats were treated 3 days after birth with bilateral intracerebroventricular 6-hydroxydopamine (6-OHDA; 134 micrograms total, base form) to destroy dopaminergic fibers in the brain. Control rats received vehicle by the same route. At about 10 weeks of age, a challenge dose of the dopamine D2 receptor antagonist, spiperone (40 micrograms/kg, IP), produced an 8-fold increase in the number of oral movements during a 60-minute observation period, vs. the control group. SKF 38393 (3.0 mg/kg, IP), a D1 agonist, produced the same number of oral movements as spiperone in the 6-OHDA group, representing a 2.4-fold increase over the controls. The Bmax and Kd for both D1 and D2 receptors was not changed in rat striatum by neonatal 6-OHDA treatment, even though dopamine content was reduced by 96%. These findings demonstrate that oral activity in rats can be greatly altered, even when there is no change in absolute numbers of D1 and D2 receptors and no change in the ratio of D1:D2 receptors.

Animals↗
PubMed1985

Binding of 3H-spiperone to human lymphocytes: a biological marker in schizophrenia?

The specific binding of the dopamine antagonist 3H-spiperone to lymphocytes from a healthy control group (n = 40), a group of acute, unmedicated schizophrenic patients (n = 27), and a psychiatric control group (n = 16) was investigated. There were no differences in binding parameters between the healthy controls (Bmax 2.6 +/- 0.7 fmoles/10(6) cells; Kd 0.17 +/- 0.07 nM) and the psychiatric control group. Binding capacity of 3H-spiperone was significantly increased in lymphocytes from the schizophrenic patients (Bmax 14.4 +/- 9.3 fmoles/10(6) cells). Moreover, a slight decrease in affinity was observed (Kd 0.44 +/- 0.21 nM). Because the increase in binding appeared only in schizophrenic patients, this peripheral model could prove valuable as a diagnostic criterion.

Acute Disease↗
PubMed1993

3H-spiperone binding capacity in mononuclear cells: a family study.

1. A family study was carried out using a putative biological vulnerability trait in families of schizophrenics and schizoaffective indexprobands to investigate, if the clinical phenotype and a biological marker for schizophrenia are cosegregating within families. 2. The binding capacity of the dopamine antagonist spiperone to mononuclear cells was investigated in 21 indexprobands and a total of 147 first and second degree relatives. 3. Increased binding capacity could be found in 17 indexprobands and in their affected relatives, independently from clinical diagnosis and in 22% of their normal relatives. 4. No increased binding capacity was found in 4 indexprobands and in their affected relatives and not n any of the unaffected relatives. These results indicate, that increased spiperone binding may cosegregate with the risk for functional psychoses and that families, loaded with psychiatric disturbances may be distinguished on a biological basis.

Adult↗
PubMed1986

Analysis of [3H]spiperone binding sites in the rat striatum and frontoparietal cortex by means of quantitative receptor autoradiography after inactivation of dopamine receptors by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in vivo: selective protection by sulpiride in the striatum.

By means of quantitative receptor autoradiography in combination with inactivation of dopamine (DA) receptors by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), it was demonstrated in the male rat that [3H]spiperone predominantly labels D2 receptors in the striatum, nucleus accumbens and tuberculum olfactorium, and predominantly non-DA receptors in the frontoparietal cortex, probably mainly serotonin type 2 (5-HT2) receptors in layer IV. Furthermore, the [3H]spiperone-labelled D2 receptors found all over the dorsal and ventral striatum appear to be similarly inactivated by EEDQ and protected by the D2 antagonist (+/-) sulpiride but not the D1 antagonist SCH 23390, indicating a homogeneity of the striatal D2 receptors.

Animals↗
PubMed1994

Pharmacologic characterization of [3H]dopamine and [3H]spiperone binding in mouse cerebellum.

1. [3H]Dopamine and [3H]spiperone binding to cerebellar homogenates was characterized utilizing dopaminergic agonists, antagonists and non-dopaminergic drugs. 2. The [3H]DA binding to low affinity binding sites reveals a heterogeneous population consisting of dopaminergic as well as serotonergic and noradrenergic sites. However, the high affinity binding of [3H]DA reflects dopaminergic sites, although a small contribution of serotonergic and noradrenergic binding sites cannot be excluded. 3. [3H]Spiperone also labels a heterogeneous population of binding sites which, however, are mainly dopaminergic.

Animals↗
PubMed1986

Taurine interferes with spiperone binding in the striatum.

The effects of taurine and its structural analogues and two new anticonvulsant derivatives, taltrimide and MY-103, on the function of brain dopaminergic systems were studied by assessing their interference with the binding of [3H]spiperone to synaptic membranes isolated from rat striata. Two populations of binding sites were detected. The binding was effectively displaced by (+)butaclamol and dopamine, serotonin being less potent by one order of magnitude. Taurine, taltrimide and MY-103 inhibited spiperone binding moderately. The binding constants of both high- and low-affinity components and the maximal binding capacity of the low-affinity component decreased in the presence of taurine. The results show that taurine and its novel anticonvulsant derivates could modulate the function of striatal dopaminergic systems.

Animals↗
PubMed1986

Cardiovascular and drinking responses elicited by central administration of angiotensin II: differential effects of GABA injected into the ventral tegmental area and spiperone injected into the nucleus accumbens.

The ventral tegmental area and its dopamine projections to the nucleus accumbens have been shown to be involved in goal-directed behavior. This study investigated the contribution of GABAergic input to the ventral tegmental area and dopaminergic input to the nucleus accumbens to the drinking and cardiovascular responses elicited by central administration of angiotensin II. Injections of 25 ng of angiotensin II into a lateral cerebral ventricle of the conscious rat elicited water intakes averaging 8 ml in 15 min with latencies usually less than 3 min. Pretreatment of the nucleus accumbens with spiperone, a dopamine antagonist, or the ventral tegmental area with gamma-amino butyric acid (GABA) produced dose-dependent reductions in water intake and number of laps taken while increasing the latency to drink. Injections of spiperone into the nucleus accumbens in anesthetized animals failed to alter the cardiovascular response elicited following the central administration of angiotensin II. However, administration of GABA into the ventral tegmental of urethane anaesthetized animals attenuated the pressor response normally elicited by central administration of angiotensin II. These findings suggest that GABA input to the ventral tegmental area is involved in both the cardiovascular and drinking responses elicited following central administration of angiotensin II. The dopamine projections to the nucleus accumbens appear only to be involved in the drinking response elicited by central injections of angiotensin II. Divergence of the signals separately accessing the skeletal motor behavioral component and the cardiovascular component elicited by central administration of angiotensin II must occur before the involvement of these dopamine pathways.

Angiotensin II↗
PubMed1986

An improved synthesis of (3-N-[11C]methyl)spiperone.

An improved radiochemical synthesis of (3-N-[11C]methyl) spiperone is reported. The radiotracer was prepared by N-alkylation of spiperone in dimethylformamide in the presence of equimolar aqueous tetrabutylammonium hydroxide and was purified by semi-preparative reversed phase high performance liquid chromatography (C-18 HPLC). The average radiochemical yield was approximately 21% end-of-synthesis (EOS) with an average specific activity of over 2750 mCi/mumol EOS. The total time for synthesis and specific activity determination was approximately 21 min.

Carbon Radioisotopes↗
PubMed1989

Technetium-99m spiperone dithiocarbamate: a potential radiopharmaceutical for dopamine receptor imaging with SPECT.

Spiperone dithiocarbamate (SPDC) was prepared by reacting spiperone with carbon disulfide followed by sodium hydroxide. SPDC was labelled with 99mTc by reduction of pertechnetate with formamidine sulfinic acid or sodium dithionite at alkaline pH, resulting in approximately 40% incorporation of 99mTc. The lipophilic complex was conveniently isolated at high specific activity and high radiochemical purity by extraction into dichloromethane, which was then evaporated and the residue was redissolved in a 1:3 mixture of ethanol and saline containing 0.1 mg/mL gentisic acid. Biodistribution studies following i.p. injection in rats showed low uptake of radioactivity in the brain, but striatum/cortex and striatum/cerebellum ratios were reduced by pretreatment with haloperidol. This agent may allow imaging of dopamine D-2 receptors using single-photon emission computed tomography (SPECT).

Animals↗
PubMed1993

Synthesis and in vivo evaluation of [18F]-N-(p-nitrobenzyl)spiperone ([18F]PNBS) in rats.

[18F]-N-(p-nitrobenzyl)spiperone, [18F]PNBS, was prepared and its in vivo uptake in rat brain was measured. A temporal increase in striatum:cerebellum ratio and frontal cortex:cerebellum (FC:Cb) ratio was observed. Blocking studies suggested the formation of a radiolabeled metabolite, presumably [18F]spiperone, that is capable of crossing the blood-brain barrier and labeling cortical 5-HT2 receptors. This was confirmed using the ISRP method of metabolite analysis indicating [18F]PNBS is not a suitable tracer for studying D2 receptors in vivo with PET.

Animals↗
PubMed1985

Effect of lipophilicity on the in vivo localization of radiolabelled spiperone analogues.

A series of N-alkylated and para-brominated analogues of spiperone were synthesized to ascertain the effect of lipophilicity on the in vivo localization of neuroleptics. While the IC50 for D2 receptor binding was within the same order of magnitude for these compounds, the calculated octanol-water partition coefficients varied 300-fold. When the in vivo distribution data for 77Br-labelled compounds were compared with previous data for 18F- and 11C-labelled analogues it was seen that the highest cerebral uptake was for bromospiperone, but the optimum striatum-to-cerebellum and brain-to-blood concentrations were achieved by N-methyl spiperone. The implications of these results for radiopharmaceutical design or medicinal chemistry are discussed.

Animals↗
PubMedDate not supplied

Long-term effects of pergolide and (-)-deprenyl on 3H-mazindol and 3H-spiperone binding in rat brain.

The effects of long-term administration of the putative neuroprotective agents pergolide and (-)-deprenyl was assessed by studying 3H-mazindol and 3H-spiperone binding at 12 and 20 months in the major dopamine brain regions. Male Wistar rats were treated from 3 to 20 months, together with their respective untreated and saline injected control groups. The main findings were: 1) there was a decrease in both 3H-mazindol and 3H-spiperone binding with age between 12 and 20 months; 2) there were no differences at 20 months between the pergolide or the (-)-deprenyl treated groups and their controls, thus providing no evidence for long-term neuroprotection; and 3) there was a marked decrease in 3H-mazindol binding in the injected controls compared with the untreated controls at both 12 and 20 months. This raises the possibility that mild chronic stress may accelerate the aging of the dopamine system.

Animals↗
PubMedDate not supplied

3H-spiperone binding to lymphocytes in neuroleptic-naive-schizophrenia and the effect of neuroleptic treatment.

The aim of this study was to determine whether spiperone binding to lymphocytes could serve as a biological marker of susceptibility to schizophrenia and schizophrenic spectrum disorders or as a measure of response to neuroleptic treatment. Lymphocyte spiperone binding parameters (Bmax, KD) were assessed in 13 patients with schizophrenia and 4 patients with schizotypal personality disorder, all neuroleptic naive, and in 19 age- and sex-matched control subjects. A repeated determination was carried out in 11 of the schizophrenic subjects after several months of neuroleptic treatment. In addition, the binding characteristics of 12 of the schizophrenic/schizotypal patients were compared with those of 13 healthy family members and normal unrelated controls. No significant differences were detected between the schizophrenic subjects and controls before or after neuroleptic treatment or between the patients and their non-affected family members and controls.

Adult↗