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At least 199 records · Page 11Linked to original sources
PubMed1984

(3-N-[11C]methyl)spiperone, a ligand binding to dopamine receptors: radiochemical synthesis and biodistribution studies in mice.

Carbon-11-labeled 3-N-methylspiperone, a positron-emitting dopamine-receptor antagonist with potential for use in positron emission tomography studies of human neurotransmitter receptors, was synthesized from 11CO2 in 40 min, with a radiochemical yield of approximately 20-40%. The specific activity of the (3-N-[11C]methyl)-spiperone was determined by ultraviolet spectroscopy to be approximately 270 mCi/mumol at the end of synthesis. In in vitro binding experiments, the Ki for 3-N-methylspiperone was found to be approximately 250 pM (against H-3 spiperone). The brain-to-blood ratios in normal ICR mice were 2.8 or greater at the times studied, and the striatum-to-cerebellum ratio at 60 min after injection was 20:1.

Animals↗
PubMed1982

Lasting changes in high affinity 3H-spiperone binding to the rat striatum and mesolimbic area after chronic methamphetamine administration: evaluation of dopaminergic and serotonergic receptor components.

The presence of high and low affinity 3H-spiperone binding sites was demonstrated in both the rat striatum and mesolimbic area. Dopaminergic receptor component was displaced by 10 microM 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), and serotonergic receptor component by 0.2 microM mianserin. Dopaminergic receptor component was saturated at less than the range of ligand concentrations labeling the high-affinity binding sites. Treatment with 4 mg/kg of methamphetamine (MAP) for 14 days, followed by a 7-day drug-free period, resulted in significant changes in the maximal number of binding sites (Bmax) at the high-affinity sites (an increase in the mesolimbic area and a decrease in the striatum), but no significant changes in Bmax at the low affinity sites. The long-lasting increase in mesolimbic Bmax at the high-affinity 3H-spiperone binding site may be an underlying basis for MAP-induced behavioral hypersensitivity (reverse tolerance).

Animals↗
PubMed1994

Inhibitory action of haloperidol, spiperone and SCH23390 on calcium currents in rat retinal ganglion cells.

Patch-Clamp measurements in the whole-cell configuration were performed on isolated rat retinal ganglion cells to record voltage-activated calcium currents in the presence of dopamine antagonists. We report here that, in the absence of dopamine, application of the receptor antagonists haloperidol, spiperone and SCH23390 reduced calcium influx between 8% and 77%. The effect was fully reversible. After application of haloperidol and SCH23390, Ca2+ currents (ICa) recovered rapidly and completely within 30 s of washing. Current recovery after application of spiperone was completed only after 2 min of washing. I-V plots showed no change in the voltage-dependence of ICa during drug application. Also current kinetics remained unaffected by the dopamine antagonists.

Action Potentials↗
PubMed1995

Differential effects of dopamine depletion on the distribution of [3H]SCH 23390 and [3H]spiperone binding sites in the goldfish retina.

The distributions of dopamine D1 and D2 receptors were studied in intact goldfish retina with in vitro autoradiography. Specific [3H]SCH 23390 binding (D1 receptors) was greatest over the outer plexiform layer (OPL)/horizontal cell bodies and less so over the inner nuclear and inner plexiform layers (IPL). Specific [3H]spiperone binding (D2 receptors) appeared in two bands, over the OPL/horizontal cell bodies and the IPL. Depletion of retinal dopamine, by intraocular injections of 6-hydroxydopamine, had no effect on the pattern and density of [3H]SCH 23390 binding; however, specific [3H]spiperone binding over the OPL and IPL was virtually eliminated, suggestive of D2 autoreceptors on dopamine interplexiform cells. These data are consistent with electrophysiological studies indicating the presence of D1 and D2 receptors in both plexiform layers of the goldfish retina.

Adrenergic Agents↗
PubMed1986

Alzheimer's disease: monoamines and spiperone binding reduced in nucleus basalis.

Levels of dopamine and serotonin, and of their precursors and metabolites, were measured in the nucleus basalis of Meynert (nbM) of patients with Alzheimer's disease and control patients. [3H]Spiperone binding to membrane homogenates of the nbM, indicative of both dopaminergic and serotonergic receptors, was also measured. The nbM from patients with Alzheimer's disease showed significant decreases in both spiperone binding and in the levels of dopamine and serotonin but no decrease in either tyrosine or tryptophan levels. These data indicate a loss of both dopaminergic and serotonergic synapses in the nbM of patients with Alzheimer's disease.

Aged↗
PubMed1986

Dopamine denervation does not alter in vivo 3H-spiperone binding in rat striatum: implications for external imaging of dopamine receptors in Parkinson's disease.

Striatal particulate preparations, both from rats with lesion-induced striatal dopamine (DA) loss and from some striatal dopamine (DA) loss and from some patients with Parkinson's disease, exhibit increased 3H-neuroleptic binding, which is interpreted to be the mechanism of denervation-induced behavioral supersensitivity to dopaminergic compounds. After intravenous 3H-spiperone (3H-SP) administration to rats with unilateral nigral lesions, we found no differences in accumulation of total or particulate-bound 3H-SP in dopamine-denervated compared with intact striata. 3H-SP in vivo binds to less than 10% of striatal sites labeled by 3H-SP incubated with striatal particulate preparations in vitro. Quantitative autoradiography of 3H-SP binding to striatal sections in vitro also failed to reveal any effects of dopamine denervation. 3H-SP bound to striatal sites in vivo dissociates more slowly than that bound to striatal particulate preparations labeled in vitro. Striatal binding properties of 3H-SP administered in vivo are quite different from the same kinetic binding parameters estimated in vitro using crude membrane preparations of striatum. In addition, striatal binding of in vivo-administered 3H-SP is not affected by prior lesion of the substantia nigra, which results in profound ipsilateral striatal dopamine depletion. Thus, behavioral supersensitivity to dopaminergic compounds may not be associated with altered striatal binding properties for dopamine receptor ligands in vivo.

Animals↗
PubMed1983

Dietary lithium during development: changes in amino acid levels, ionic content, and [3H]spiperone binding in the brain of rats.

We found that chronic lithium diet affects the sensitivity of neuroleptic receptors and the content of amino acids in the brain, and that the changes in adult animals differ from those in young rats. Pregnant rats were kept on lithium diet (pellets with 0.21% Li2CO3 and 0.21% NaCl) during the gestation period and the offspring were kept on lithium for six weeks after delivery. Control rats were kept on normal diet under identical conditions. In corpus striatum and cerebral cortex of lithium-treated young rats a reduction in apparent dissociation constant and no change in (3H)spiperone total binding sites were found, suggesting a sensitization of the neuroleptic receptor; this result was unlike that obtained with adult lithium-treated rats, where the total number of binding sites was decreased. The lithium content of brain was very high (2.32 meq/kg of wet weight), whereas in the serum only 0.75 meq/l was recorded. K+ and Na+ levels increased by 20% and 9% respectively in the brain and remained at normal levels in the serum. Analysis of free amino acids in the cerebral cortex, midbrain, and cerebellum showed increases in GABA and glycine levels in all three regions, a significant increase in taurine in midbrain, and an increase in lysine in cerebral cortex and cerebellum. The results indicate that the effect of chronic dietary lithium given during pregnancy on the neuroleptic receptor in young rats is different from that in adult animals. It produces an increase in the number of the neuroleptic receptor sites instead of the decline in the number of binding sites found in adult rats. It remains to be established whether this effect is related more to the age of the animal tested or to the stage of development of the CNS at which the lithium was administered.

Amino Acids↗
PubMed1982

Lithium: effect on [3H]spiperone binding, ionic content, and amino acid levels in the brain of rats.

After prolonged treatment of rats with lithium (pellets, 0.21% lithium carbonate, or 0.5 mg/ml lithium chloride in drinking water) for three months, the level of lithium in plasma was 0.87 meq/liter; in several brain regions, between 1.06-1.39 mueq/g wet weight. The content of sodium and potassium inthe plasma was normal. The level of potassium in the brain regions tested increased by 13-30% and that of sodium by about 10%. Glycine levels increased significantly in all the regions (cerebral cortex, midbrain, cerebellum, and spinal cord). In the cerebellum GABA was also increased, while glutamine was decreased. In midbrain, apart from increases in glycine levels, alanine, valine, GABA and lysine were also increased. In the spinal cord, glutamic acid was also increased. Changes were largely in the putative neurotransmitters. Long-term treatment with lithium also influenced the high-affinity binding of [3H] spiperone in the cerebral cortex and corpus striatum. Two specific binding sites were found in both brain regions; the main change was the reduction in the lower affinity binding site (B max 2).

Amino Acids↗
PubMed1997

Differentiation of clinically non-functioning pituitary adenomas from meningiomas and craniopharyngiomas by positron emission tomography with [18F]fluoro-ethyl-spiperone.

The differential diagnosis among various types of non-functioning sellar and parasellar tumours is sometimes difficult using currently available methods of morphological imaging. The aim of this study was to define whether assessment of the uptake of [18F]fluoro-ethyl-spiperone (FESP) with positron emission tomography (PET) could be helpful for the differential diagnosis of pituitary adenomas and other parasellar lesions, and for establishing the appropriate therapeutic approach. The population examined comprised 16 patients with the diagnosis of primary tumour of the sellar/parasellar region who were waiting to undergo surgical treatment. The results demonstrated that PET with [18F]FESP is a very specific method for differentiating adenomas from craniopharyngiomas and meningiomas. The visual interpretation of images allows such differentiation at approximately 70 min after tracer injection. Semiquantitative analysis of the dynamic PET data confirmed the results of visual interpretation, demonstrating that the uptake of [18F]FESP was consistently (i.e. throughout the series) at least two- to threefold higher in non-functioning adenomas than in other parasellar tumours as early as 70 min after tracer injection, and that it increased still further thereafter. It is concluded that PET with [18F]FESP might be of clinical value in those cases in which the differential diagnosis among various histological types of sellar tumour is uncertain with conventional methods.

Adenoma↗
PubMed1990

Quantification of the whole-body distribution of PET radiopharmaceuticals, applied to 3-N-([18F]fluoroethyl)spiperone.

Using a multi slice whole body PET scanner PC4096-15WB, diagnostic measurements of the cerebral distribution of the D2 receptor ligand 3-N-([18F]fluoroethyl)spiperone were extended to quantify the biodistribution of this PET radiopharmaceutical. As a rotating line source was used for measured attenuation correction, transmission scans could be combined with emission scans even after injection of the tracer. Only 1% of the total administered dose (TAD) was found in the whole brain at 180 min, but the striatum and pituitary were still excellently delineated. Urinary bladder, gall bladder, and liver were the organs with the highest TAD ranging from 6% to 25%. The gall bladder is the critical organ with an absorbed dose of about 200 muGy/MBq followed by the urinary bladder and liver with 83 and 66 muGy/MBq, respectively. In the rest of the body radioactivity was evenly distributed. The total body dose was found to be 11.9 muGy/MBq.

Brain↗
PubMed1993

Striatal [11C]-N-methyl-spiperone binding in patients with focal dystonia (torticollis) using positron emission tomography.

Specific binding of [11C]-N-methyl-spiperone to striatal dopamine D2 receptors was assessed using positron emission tomography (PET) in 6 patients with adult-onset focal dystonia (predominantly spasmodic torticollis) and in 5 healthy subjects. No significant difference in average specific striatal tracer uptake between patients and healthy subjects was found. However, in the 5 patients showing lateralisation of clinical signs a trend to higher striatal tracer uptake in the contralateral hemisphere was observed.

Adolescent↗
PubMed2001

A consideration of the dopamine D2 receptor monomer-dimer equilibrium and the anomalous binding properties of the dopamine D2 receptor ligand, N-methyl spiperone.

Some discrepancies between experimental results with the two D2 antagonists N-methyl spiperone (NMSP) and raclopride (RAC) have been observed. Among these are the observation that MK-801 increases NMSP binding but not RAC binding: pretreatment with reserpine increases RAC binding but decreases NMSP binding; and that the two ligands yield different values for Bmax. It has been observed that the D2 receptor can exist in both a monomer and dimer form and that a NMSP photolabel ligand binds primarily to the monomer form while a RAC-like photolabel ligand binds both. Using a model of the dimerization in which the equilibrium dissociation constant increases with increasing dopamine (DA) concentration, the free monomer concentration can be shown to go through a maximum value with increasing DA. Using this model with data from a baboon PET study, it can be shown that under certain conditions an increase in binding could be observed. Further research may show that there are clusters of D2 receptors forming oligomers with more than two receptors in which NMSP binds to more sites on clusters with fewer receptors. If increasing DA favors cluster with fewer receptors, an increase in NMSP binding sites may also occur under some circumstances with an increase in DA.

Animals↗
PubMed1979

Neuroleptic and dopamine receptors: autoradiographic localization of [3H]spiperone in rat brain.

Rats were administered [3H]spiperone (SP: spiroperidol) by tail vein injection and 2 h later the brain was processed for light microscopic autoradiography. High densities of autoradiographic grains were found in all areas known to have a dopaminergic innervation, including the olfactory tubercles, nucleus accumbens, nucleus caudate-putamen, lateral septum, zona incerta, nucleus subthalamicus, arcuate nucleus, nucleus of the central amygdala, areas in the ventral tegmentum and the claustrum. There were also increased autoradiographic grain densities in other areas such as the midbrain and the frontal cortex indicating that binding occurred to other neurotransmitter receptors besides dopamine receptors. These studies delineate with a high resolution at an anatomical level the major binding sites for neuroleptic drugs in the forebrain. They suggest which areas of the brain are the most involved in neuroleptic drug action and they add further evidence that important regions are those receiving a dense dopaminergic innervation.

Animals↗
PubMed1979

Dopamine metabolism, spiperone binding and adenylate cyclase activity in the adult rat hippocampus after ingrowth of dopaminergic neurones from embryonic implants.

The growth of dopamine (DA) neurones of rat embryonic mesencephalic brain tissue implanted close to the anterior part of the hippocampus of adult rats was studied by measuring the levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the host hippocampus. The hippocampal levels of DA and DOPAC reached maximal values 6 months after transplantation. The neuroleptic drug haloperidol evoked an increase in the levels of DOPAC. No evidence was found for the induction of DA-sensitive adenylate cyclase activity or of binding sites of [3H]spiperone. These results indicate that there is a substantial ingrowth of transplanted DA neurones into the host hippocampus, but no evidence was found for the development of functional contacts between the embryonic DA neurons and the host tissue.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Chronic bombesin treatment increased the [3H]spiperone binding, glutamate decarboxylase and choline acetyltransferase activity in the rat brain.

The effects of chronic bombesin (BBS) on [3H]spiperone (SPD) binding activity, choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and glutamate decarboxylase (GAD) were investigated in the rat brain corpus striatum (CS). The chronic i.p. administration of BBS to rats increased: (1) the specific [3H]SPD binding to the striatal Pm (plasma membrane) (16%, P less than 0.03 and 34%, P less than 0.008 at 5 micrograms/kg respectively), (2) the specific GAD activity in the CS by 52% (5 micrograms/kg, n.s.) and 46% (10 micrograms/kg, P less than 0.05) respectively, (3) the specific ChAT activity in the CS by 54% (10 micrograms/kg, P less than 0.002), and (4) the specific AChE activity by 23% (10 micrograms/kg, P less than 0.02) after 14 days. It increased only: (1) the specific [3H]SPD binding by 29% (P less than 0.001, at 10 micrograms/kg) and (2) the specific GAD activity by 23% (P less than 0.015, 10 micrograms/kg), after 7 days. Neither ChAT nor AChE activity was affected after 7 days treatment of BBS at 10 micrograms/kg. In vitro study showed that BBS at 0.2 microM did not affect any of the neurochemical parameters examined in the CS. Thus, the changes in brain chemistry caused by chronic BBS were not due to direct effects of BBS but may be mediated through its metabolites or CCK release. Data indicate that the central effects of peripherally administered BBS are dependent on both the duration and the dosage of the drug treatment and that the dopaminergic and GABAergic systems seem to be more vulnerable to chronic BBS than the cholinergic system in the rat brain CS.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1987

[3H]spiperone binds selectively to rat striatal D2 dopamine receptors in vivo: a kinetic and pharmacological analysis.

We have determined the kinetic, equilibrium saturation, and pharmacological characteristics of [3H]spiperone ([3H]SPIP) binding to rat brain regional particulate fractions following i.v. injections of [3H]SPIP and compared these parameters to those determined in vitro with traditional ligand-homogenate binding assays. [3H]SPIP binding to rat striatum in vivo and in vitro occurs to a single class of non-interacting binding sites which possess the pharmacological properties of a D2 dopamine (DA) receptor. The potencies of neuroleptic drugs in inhibiting DA receptor-mediated behaviors correlate with their potencies at displacing striatal [3H]SPIP binding in vivo. While striatum possesses a similar density of [3H]SPIP binding sites in vivo (34 pmol/g) and in vitro (31 pmol/g), binding affinity in vivo is about 200 times lower than in vitro. This difference in binding affinities appears to arise from alterations of [3H]SPIP association and dissociation rate constants brought about by tissue homogenization. The implications of our findings for external imaging of DA receptors and studies of DA receptor function in human brain homogenates are discussed.

Animals↗
PubMed1990

Remote lateralized changes in cortical [3H]spiperone binding following focal frontal cortex lesions in the rat.

Positron emission tomography (PET) studies in stroke patients have shown that right hemisphere lesions lead to increases in ipsilateral (compared to contralateral) cortical S2-serotonin receptors, while left hemisphere lesions do not. To assess whether similar lateralized changes in cortical S2-receptors could be demonstrated in response to brain injury in the rat, [3H]spiperone (SP) autoradiography was performed 30 days after unilateral cortical suction lesions. Right lesions produced bilateral increases in total SP binding in frontal cortex (excluding the lesion site): 48% greater than after left lesions, and 23% greater than shams. Left lesions led to bilateral decreases in S2-receptors in the frontal and perirhinal cortex and these decreases were asymmetric. There was a greater decrease in the hemisphere contralateral to the lesion than in the side with the lesion. Frontal S2-receptor binding was positively correlated with running wheel activity in all animals with lesions, regardless of lesion side. These results suggest that there is a lateralized receptor and behavioral response to focal injury in rats, analogous to that previously observed in humans.

Animals↗