Different behavioral profiles of the non-peptide substance P (NK-1) antagonists CP-96,345 and RP 67580.
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Animals↗
Biomedical subjects
A Saria
Publications and source records attributed to A Saria.
Increased synthesis of neurokinin B and enkephalin after chronic haloperidol treatment.
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Animals↗
Indomethacin reduces substance P levels in human ocular aqueous humor.
Substance P immunoreactivity was measured by radioimmunoassay in aqueous humor samples of patients treated 13 h earlier with gentamicin, indomethacin or timolol. The indomethacin-treated group showed significantly decreased levels of substance P. The indomethacin effect is due to inhibition of the synthesis of arachidonic acid metabolites or involves non-specific mechanisms. It is suggested that suppression of substance P release may contribute to therapeutic effects of indomethacin in the human eye in conditions such as surgical miosis.
Adult↗
Different behavioral profiles of the non-peptide substance P (NK1) antagonists CP-96,345 and RP 67580 in Swiss albino mice in the black-and-white box.
The non-peptide NK1 antagonists, RP 67580, and (2S,3S)-CP-96,345, the NK1 receptor-selective enantiomer of the racemic compound, were tested in Swiss albino mice in the black-and-white box behavioral paradigm. Both qualitatively and quantitatively, (2S,3S)-CP-96,345 produced the same behavioral effects as the racemic compound. In contrast, RP 67580 decreased exploratory behavior only in the white section, whereas crossings and rearings in the black section were not changed. In addition, RP 67580 decreased transitions. While the observed changes induced by CP-96,345 are caused by sedation and motor impairment, the effects of RP 67580 might be due to sedation plus an additional anxiogenic effect.
Animals↗
Characterization of neurokinin binding sites in rat brain membranes using highly selective ligands.
Neurokinin binding sites are distributed throughout the central and peripheral nervous system and three neurokinin binding sites have been described until now. The endogenous tachykinins substance P, neurokinin A and eledoisin as well as the highly selective neurokinin ligands [Arg6, Sar9, Met(O2)11]SP6-11 and [Sar9, Met(O2)11]SP (for neurokinin-1), MEN 10,376 and [beta Ala8]NKA(4-10) (for neurokinin-2) and senktide and [MePhe7]NKB (for neurokinin-3) were used for displacement experiments. Neurokinin-1 and -3 binding sites were demonstrated in membrane preparations of rat striatum, frontal cortex, hypothalamus, hippocampus and amygdala by displacing [125I]-BH-substance P and [125I]-BH-eledoisin, respectively. The highly selective neurokinin-2 ligand MEN 10,376 was iodinated to measure neurokinin-2 binding sites, but no specific binding was found in membranes of all brain regions, the spinal cord, the stomach, the urinary bladder or the guinea-pig lung, probably due to loss of binding properties. We conclude that neurokinin-1 and neurokinin-3 binding sites are distributed in several brain regions of the rat brain and selective neurokinin ligands are important tools to characterize neurokinin binding sites.
Amino Acid Sequence↗
Secretoneurin releases dopamine from rat striatal slices: a biological effect of a peptide derived from secretogranin II (chromogranin C).
Proteolytic processing of secretogranin II (chromogranin C) in brain leads to the formation of a 33-amino acid peptide which we have named secretoneurin. All the properties of secretoneurin are consistent with the concept that this peptide represents a neuropeptide. However, a biological function has not yet been demonstrated. Therefore, we have now investigated whether secretoneurin could alter transmitter release in brain. Slices of rat caudate-putamen were superfused in an in vitro system and dopamine was measured in the superfusate. Secretoneurin dose-dependently increased the outflow of dopamine. This response was abolished in Ca(2+)-free medium. The secretoneurin-response could also be blocked by preincubation of the peptide with a specific antiserum and was subject to rapid specific and reversible desensitization. This effect on dopamine release constitutes the first discovered biological effect found for a peptide derived from secretogranin II. Thus, secretoneurin can be added to the ever-growing number of neuropeptides.
Animals↗
Distribution of secretoneurin, a peptide derived from secretogranin II, in rat brain: an immunocytochemical and radioimmunological study.
The distribution of secretoneurin, a peptide derived from its precursor secretogranin II by proteolytic processing, was studied in the central nervous system of the rat by immunocytochemistry and radioimmunoassay and compared to the distribution of secretogranin II messenger RNA by using in situ hybridization. With a specific antiserum a distinct staining of fibers and to a lesser extent also of perikarya was observed throughout the central nervous system. A high density of immunoreactive fibers and terminals was found in several brain areas, i.e. the lateral septum, the medial parts of the amygdala, some medial thalamic nuclei, the hypothalamus, habenula, nucleus interpeduncularis, locus coeruleus, nucleus tractus solitarii, the substantiae gelatinosae of the caudal trigeminal nucleus and of the spinal cord. The quantitative distribution as measured by a radioimmunoassay agreed well with the varying densities of immunoreactivity found by immunocytochemistry. The highest concentrations of this peptide were present in the hypothalamus, in particular, in the median eminence and are comparable to those of the most highly concentrated neuropeptides. The distribution of immunopositive perikarya corresponded well with that of secretogranin II messenger RNA obtained by in situ hybridization. The pattern of secretoneurin expression in rat brain was widespread and unique, partially overlapping with established chemical transmitters and neuropeptides. The functional significance of this new brain peptide remains to be established.
Animals↗
Autonomic and peptidergic innervation of human nasal mucosa.
The localization and distribution of vasoactive intestinal polypeptide (VIP), peptide histidine methionine (PHM), the novel peptide helospectin, neuropeptide tyrosine (NPY) and its C-flanking peptide (C-PON), substance P and calcitonin gene-related peptide (CGRP) were studied in the middle and inferior turbinate of the human nose using sensitive immunocytochemical and radioimmunological methods. For light microscopy, double immunofluorescence and immunogold-silver staining methods were applied. Ultrastructural immunoelectronmicroscopy was performed using a pre-embedding method. In addition, semithin Epon resin sections were immunostained. The concentrations of VIP, NPY, CGRP, substance P and neurokinin A were measured using radioimmunological methods. A dense network of autonomic and peptidergic nerve fibers in the normal human nasal mucosa was demonstrated. Colocalization studies showed the coexistence of peptides with components of the autonomic nervous system. Scattered chromogranin A-, CGRP and bombesin-flanking peptide (BFP)-immunoreactive endocrine-like cells were detected within the lamina propria and in groups within exocrine ducts. Highest radioimmunoassay (RIA) tissue concentrations were detected for VIP, followed by NPY, substance P, CGRP and neurokinin A.
Autonomic Nervous System↗
Regulatory peptides in the human larynx and recurrent nerves.
We studied the peptide-innervation of the human larynx (vocal cord, ventricular folds, epiglottis, subglottic region and the recurrent nerves) using immunocytochemical and radioimmunological methods. In the tissues of the larynx investigated, the following regulatory peptides were detected: vasoactive intestinal polypeptide (VIP), peptide histidine methionine (PHM), helospectin, neuropeptide Y (NPY), C-flanking peptide of NPY (C-PON), calcitonin gene-related peptide (CGRP), substance P and neurokinin. In the recurrent nerves only small numbers of peptide-immunoreactive nerve fibers were found. Most of them showed positive immunoreactivities with antibodies to PHM, NPY and C-PON, but only rare and scattered nerve fibers were positive for VIP-, CGRP- and substance P.
Fluorescent Antibody Technique↗
Differential increases of neurokinin B- and enkephalin-like immunoreactivities and their mRNAs after chronic haloperidol treatment in the rat.
Changes in neurokinin B-like immunoreactivity (NKB-IR) and neurokinin B mRNA were investigated after daily injection of haloperidol for 10 days on adjacent sections by means of immunocytochemistry and in situ hybridization in the caudate putamen of the rat. In the dorsal striatum the number of NKB immunoreactive perikarya and the staining intensity of striatal efferents increased. The number of NKB mRNA-expressing cells (45%) and the grain density over single positive cells (37%) were significantly higher after the neuroleptic treatment. The levels for enkephalin mRNA were uniformly increased throughout the rostrocaudal extent of the caudate putamen (85%). A main difference to the enkephalin system was that the dorsal pallidum was nearly devoid of NKB-IR in untreated as well as in haloperidol-treated animals. The present data for the first time provide evidence for the regulation of the biosynthesis of NKB after pharmacological intervention.
Animals↗
The substance P (NK1) receptor antagonist (+/-)-CP-96,345 causes sedation and motor impairment in Swiss albino mice in the black-and-white box behavioral paradigm.
In order to test the suggested involvement of substance P (NK1) receptors in anxiety, the non-peptide NK1 antagonist (+/-)-CP-96,345 was tested in Swiss albino mice using the black-and-white box behavioral paradigm. Intraperitoneal (+/-)-CP-96,345 dose-dependently decreased the motor activity and the number of exploratory rearings in both the brightly lit and dark compartment as well as the transitions between the compartments, whereas it increased the latency of the initial movement into the dark compartment as well as the time spent in the light section. ED50 or ID50 values ranged from 1.9 to 3.6 mg/kg and Hill slopes from 1.4 to 5.0. (+/-)-CP-96,345 also produced rotatory behavior of no preferred lateralization as well as the Straub phenomenon in some animals. The effects of (+/-)-CP-96,345 (5 mg/kg) were not affected by 2 mg/kg naloxone (i.p.) which was also ineffective when given alone. Thus, (+/-)-CP-96,345 does not display any anxiogenic effect but causes dose-dependent sedation and motor impairment.
Animals↗
Calcitonin gene-related peptide in the brain. Neurochemical and behavioral investigations.
CGRP in the amygdala is concentrated in an area close to the central nucleus. High potassium releases CGRP, and this release, as well as the tissue concentration of CGRP in the amygdala, can be influenced by neuroleptic drugs. Both molecular forms, alpha- and beta-CGRP, are present in the amygdala in a ratio of approximately 3:1. CGRP influences social behavior in chicken. Therefore, CGRP may have a prominent role in psycho-behavioral function and may be a target for action and/or side effects of antipsychotic drugs.
Amygdala↗
Identification of alpha- and beta-species of calcitonin gene-related peptide in the rat amygdala after separation with capillary zone electrophoresis.
Calcitonin gene-related peptide (CGRP) may be present in two forms in nervous tissue. Reversed-phase high-performance liquid chromatography has previously been found to be insufficient to clearly separate alpha-CGRP and beta-CGRP. A method for the separation of CGRPs by capillary zone electrophoresis has been developed. Separation of human or rat alpha-CGRP and beta-CGRP was achieved at pH values between 3.5 and 4.5 and a potential of 20 kV in a fused-silica capillary. Electrophoresis of an extract of rat amygdala in a micropreparative way, with subsequent radioimmunoassay, revealed for the first time the presence of alpha-CGRP and beta-CGRP in this brain area. The method may thus be used for separation of CGRPs, to reveal the distribution of alpha-CGRP and beta-CGRP, and for purity control.
Amino Acid Sequence↗
Effects of bright artificial light on monoamines and neuropeptides in eight different brain regions compared in a pigmented and nonpigmented rat strain.
Seasonal affective disorder is a form of depression which recurs at the same time of the year. Exposure to bright artificial light at a dose of 2,500 lux is used to treat seasonal affective disorders. We exposed a pigmented (Brown Norway) and a nonpigmented (Sprague-Dawley) rat strain with bright artificial light for 21 days at two doses (2,500 and 6,100 lux) and analyzed dopamine, dihydroxyphenyl-acetic acid, 5-hydroxytryptamine (5-HT), and 5-hydroxyindole-acetic acid (5-HIAA) by high performance liquid chromatography (HPLC) and electrochemical detection in eight different brain regions. Furthermore, we measured tissue levels of substance P (SP), neurokinins (NK), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) with radioimmunoassay. Our data obtained with light microscopy show that bright artificial light at both doses induced a massive destruction of photoreceptors in the retina of albino rats but not of the pigmented rat strain. Retinal lesion of photoreceptors resulted in increased tissue levels of all measured neuropeptides except SP in the hypothalamus and increased VIP in the ventral tegmental area/substantia nigra. Furthermore, increased 5-HT and 5-HIAA tissue levels were found in the ventral tegmental area/substantia nigra. In contrast, in the frontal cortex there was a significant reduction in 5-HIAA tissue levels and a decreased 5-HIAA/5-HT ratio, indicating decreased 5-HT metabolism. Light exposure of the pigmented rat strain revealed no changes in the measured biogenic amines and neuropeptides in any investigated brain region. Our data suggest that retinal lesion but not direct visual neurotransmission induced changes in neurotransmitters in some brain regions. We conclude that Brown Norway rats but not Sprague-Dawley rats are useful to study neurochemical effects of bright artificial light. However, Sprague-Dawley rats may be a useful tool to study biochemical mechanisms of photoreceptor damage by bright light.
Animals↗
Calcitonin gene-related peptide in patients with and without early reperfusion after acute myocardial infarction.
Plasma concentrations of calcitonin gene-related peptide (CGRP), a potent regulator of vascular tone, creatine kinase, myoglobin, and cardiac troponin T were assessed in 31 patients with acute myocardial infarction. In patients who had sustained acute myocardial infarctions, maximum CGRP concentrations (median, 3.2 pmol/L; interquartile range, 1.5 to 4.8 pmol/L) were markedly elevated as compared with healthy control subjects (n = 23; median, 1.02 pmol/L; p = 0.02). However, no marked differences in CGRP levels were observed between patients with early reperfusion (n = 19; median, 3.5 pmol/L) and patients without early reperfusion (n = 12; median, 2.6 pmol/L; p = 0.96), as well as between those with congestive heart failure (n = 8; median, 3.9 pmol/L) and those without congestive heart failure (n = 23; median, 3.2 pmol/L; p = 0.62). CGRP did not correlate closely with myocardial protein release or hemodynamic parameters (heart rate and blood pressure) or the occurrence of arrhythmias. Therefore we conclude that elevated peripheral venous CGRP concentrations in patients who have sustained an acute myocardial infarction are independent of successful reperfusion and hemodynamic state. Although the cause of CGRP increase is not yet identified, CGRP may play a role in the regulation of coronary vascular tone in patients after acute myocardial infarction.
Adolescent↗
Effect of noradrenergic denervation by neonatal DSP-4 on peptide neurotransmitter systems in the rat brain.
The specific effects of a neonatal treatment of rats with the noradrenergic neurotoxin DSP-4 were investigated in the adult rat by measuring monoamine and peptide transmitter levels in eight brain regions. When applied concomitantly with a 5-hydroxytryptamine uptake blocker, neonatal DSP-4 induced a selective depletion of noradrenaline (NA) in cortex, hippocampus and amygdala. An increase of NA was observed in the medulla and substantia nigra/ventral tegmental area and a decrease in dopamine was observed in the thalamus. The vasoactive intestinal polypeptide levels were markedly elevated in the DSP-4 treated rats in almost all CNS regions whereas those of three other neuropeptides remained unchanged. It is concluded that certain adaptational changes can be observed in the peptide systems of the CNS upon disruption of the development of the noradrenergic innervation.
3,4-Dihydroxyphenylacetic Acid↗
Comparative distribution of neurokinin B-, substance P- and enkephalin-like immunoreactivities and neurokinin B messenger RNA in the basal forebrain of the rat: evidence for neurochemical compartmentation.
The distribution of neurokinin B was investigated in the basal forebrain of the rat by immunocytochemistry with an antibody directed against neurokinin B, and with a second antiserum directed to a peptide sequence contained within its precursor, and by means of in situ hybridization. The staining pattern was compared in closely adjacent sections to that of substance P- and enkephalin-like immunoreactivities. Cholecystokinin immunoreactivity was used to delineate the apparent dorsolateral border of the ventral pallidum with the nucleus accumbens. Remarkable similarities are found in the distribution of these peptides in the basal forebrain, especially in its ventral part. The coarse band-like terminal staining pattern (woolly fibers) that has been shown by others for substance P- and enkephalin-like immunoreactivity, is also observed for neurokinin B-like immunoreactivity, mainly in the ventral pallidum. Medium-sized cells are found arranged in clusters or singularly within the caudate-putamen even without colchicine. A band of strong neurokinin B immunoreactivity extends just underneath the dorsal pallidum to the amygdala. In comparison to enkephalin the most distinct observation is that neurokinin B immunoreactivity is not present in the dorsal pallidum (global pallidus). Neurokinin B immunoreactivity was not found in the pars reticulata of the substantia nigra which is strongly immunopositive for substance P. The number of cells detected by in situ hybridization was higher compared to the immunopositive perikarya throughout the basal ganglia. The staining pattern observed reflects a partial overlap with the substance P and enkephalin system although a differential distribution for each of these peptides was observed for cell bodies and axons terminals.
Animals↗
Neuropeptides in human salivary (submandibular and parotid) glands.
The existence, distribution and density of various neuropeptides in human submandibular and parotid glands were investigated using immunocytochemistry and radioimmunoassay. Numerous nerve fibers containing vasoactive intestinal polypeptide (VIP) and peptide histidine methionine (PHM), or neuropeptide Y (NPY) and C-flanking peptide of NPY (CPON) immunoreactivities (ir) were found in close association to acini, ducts and blood vessels. Only few calcitonin gene-related peptide (CGRP)- and substance P (SP)-ir nerve fibers could be demonstrated, mainly localized around blood vessels and ducts. Galanin and the newly discovered peptides helospectin and pituitary adenylate cyclase activating peptide (PACAP) could not be detected in human salivary glands.
Fluorescent Antibody Technique↗