Distribution of cholecystokinin-like immunoreactivity in the nervous system. Co-existence with classical neurotransmitters and other neuropeptides.
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Animals↗
Biomedical subjects
M Goldstein
Publications and source records attributed to M Goldstein.
Appearance of the noradrenergic markers tyrosine hydroxylase and neuropeptide Y in cholinergic nerves of the iris following sympathectomy.
Selective autonomic denervations of the iris have been used to study the possible redistribution of adrenergic markers within adult nerve fiber systems and to reveal the cellular origin of a nonsympathetic fiber plexus induced to express such markers. The presence and distribution of fibers showing neuropeptide Y (NPY)- and tyrosine hydroxylase (TH)-like immunoreactivity was studied in the rat iris using stretch-prepared whole mounts. Normal irides contained a dense regular network of NPY-positive varicose fibers. Such fibers were regularly seen innervating blood vessels. The choroid membrane had a high number of fluorescent fibers. A similar, although slightly denser TH-positive fiber system was visualized in the iris. One or 2 days after surgical removal of the superior cervical ganglion, almost all NPY- and TH-positive fibers had disappeared, suggesting that most, if not all, NPY-positive fibers in the iris originate in the superior cervical ganglion. In irides from long-term sympathectomized animals, a high number of TH- and NPY-immunoreactive fibers had reappeared, while such irides were devoid of catecholamine-containing fibers, as evidenced by Falck-Hillarp histochemistry. The appearance of TH- and NPY-positive fibers in sympathetically denervated irides was clearly time dependent. The distribution of fluorescent fibers in irides from intact and sympathectomized animals showed obvious dissimilarities such as a lower fluorescence intensity and fewer varicose fibers in denervated irides. Furthermore, in irides from sympathectomized rats, TH- and NPY-positive fibers were not associated with blood vessels. Unilateral removal of the parasympathetic ciliary ganglion, which supplies the iris with cholinergic fibers, 3 days prior to sacrifice in animals bilaterally sympathectomized 1 month earlier, led to a drastic reduction in numbers of TH- and NPY-positive iris fibers on the ciliarectomized/sympathectomized side as compared to the sympathectomized-alone side. The present experiments thus suggest that adult cholinergic neurons in vivo are capable of expressing adrenergic characteristics under experimental conditions.
Adrenergic Fibers↗
Inactivation of D1 and D2 dopamine receptors by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in vivo: selective protection by neuroleptics.
Treatment of rats with the peptide coupling agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (6 mg/kg i.p.) irreversibly reduced the binding of [3H]spiperone ([3H]SPIP) and cis-[3H] piflutixol to striatal D2 and D1 receptors, respectively, by 70 to 75%. In each instance only the receptor density was affected, without a change in the dissociation constant (Kd) of either radioligand. Pretreatment with sulpiride (200 mg/kg i.p.), a selective D2 antagonist, preferentially protected [3H]SPIP sites against N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline-induced inactivation, whereas pretreatment with SCH 23390 (3 mg/kg i.p.), a putative selective D1 antagonist, preferentially blocked the inactivation of cis-[3H]piflutixol binding sites. N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline markedly reduced radioligand binding to cortical alpha-1 ([3H]prazosin) and alpha-2 [( 3H]yohimbine) receptors (10-20% of control) but had a lesser effect on serotonin-2 ([3H]SPIP) and serotonin-1 ([3H]5-HT) receptors (30-40% of control). Muscarinic cholinergic ([3H] quinuclidinyl benzilate) and beta adrenergic ([3H]dihydroalprenolol) receptors were only slightly affected. None of these nondopaminergic sites were protected by sulpiride or SCH 23390, with the exception of serotonin-2 and serotonin-1 which were partially protected by the latter. SPIP (0.2 mg/kg i.p.), haloperidol (1 mg/kg i.p.) and pimozide (2 mg/kg i.p.) all selectively protected the D2 receptor, whereas cis-flupenthixol (2 mg/kg i.p.) protected both dopamine receptors; its inactive isomer trans-flupenthixol (20 mg/kg i.p.) protected neither. Bulbocapnine (25 mg/kg s.c.) selectively, but partially, protected the D1 site.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Antagonists↗
Regulation of tyrosine hydroxylase phosphorylation in PC12 pheochromocytoma cells by elevated K+ and nerve growth factor. Evidence for different mechanisms of action.
A specific antiserum was used to compare phosphorylation of tyrosine hydroxylase (TH) (EC 1.14.16.2, tyrosine 3-monooxygenase) as regulated by elevated K+ and nerve growth factor (NGF) in cultured PC12 pheochromocytoma cells. Exposure of cultures to either elevated K+ or to NGF significantly enhanced the incorporation of [32P]orthophosphate into TH. The effect of elevated K+ was evident at 10 mM and was maximal by 40-80 mM. Increased phosphorylation of TH was detected at 0.1 nM (3 ng/ml) NGF and reached a maximal level by 0.3-1 nM (10-30 ng/ml) NGF. Elevated K+ showed a biphasic time course of action with one maximum of phosphorylation at about 30 sec of exposure and a second after about 10 min of exposure. In contrast, the NGF effect showed an initial lag of several minutes followed by a monophasic increase in phosphorylation to reach a plateau. Both treatments enhanced TH activity, but in each case the time courses of this did not strictly correlate with that of phosphorylation. The effect of elevated K+ on TH phosphorylation required the presence of extracellular Ca2+ and was suppressed by trifluoperazine (100 microM). N-(6-Aminohexyl)-5-(chloronaphthalene)-1-sulfonamide (W-7) (100 microM), a potent inhibitor of calmodulin activity, also blocked the enhancement of phosphorylation by elevated K+, whereas N-(6-aminohexyl)-1-(naphthalene)sulfonamide (W-5) (100 microM), a less potent analogue of W-7, did not. In contrast to these findings, the increase in TH phosphorylation brought about by NGF did not require extracellular Ca2+, and was only slightly affected by trifluoperazine or W-7. When TH phosphorylated under various conditions (control medium, elevated K+, NGF) was subjected to peptide mapping after exposure to Staphylococcus aureus protease V8, multiple phosphorylated peptides were observed. Elevated K+ and NGF each produced increases in labeling of each of the peptides. However, the relative degree of labeling of different peptides was distinct for each condition. These data suggest that elevated K+ and NGF bring about rapid enhancement of the phosphorylation of TH by means of different mechanisms.
Animals↗
Ergot alkaloids and central monoaminergic receptors.
The interactions of ergolines and of ergopeptines with dopamine (DA), alpha 1 and alpha 2 central adrenoreceptors were studied. Ergolines and ergopeptines exert agonist activities at central DA receptors and exhibit antiparkinsonian activities in monkeys with unilateral ventromedial tegmental lesions of the brain stem. Both ergolines and ergopeptines are used in treatment of Parkinson's disease and their therapeutic efficacy, as well as their propensity to develop undesirable side effects is under investigation. The interactions of ergolines and of ergopeptines differ with DA receptor subtypes and states. The former are regulated by guanine nucleotides, but not the latter. Hydergine is used in treatment of disorders associated with senile dementia, and its interaction with DA, alpha 1 and alpha 2 adrenoreceptors may affect the monoaminergic imbalance in the aging brain.
Animals↗
Evidence for differential localization of noradrenaline and neuropeptide Y in neuronal storage vesicles isolated from rat vas deferens.
Using the technique of homogenization and subsequent density gradient centrifugation combined with ultrastructural analysis, the subcellular localization of noradrenaline and neuropeptide Y (NPY) was studied in vas deferens of castrated male rats. Noradrenaline showed two peaks in the gradient: one major peak at low density and another at high density. Only one NPY peak was seen, which coincided with the high density peak of noradrenaline. Electron microscopic analysis revealed high proportions of small and large vesicles in the light and heavy fractions, respectively. The present results indicate a differential subcellular localization of noradrenaline and NPY in the noradrenergic nerve endings of vas deferens. Thus, small vesicles seem to contain only noradrenaline, whereas the large vesicles may contain both noradrenaline and NPY.
Animals↗
[Symposium on aneurysms of the abdominal aorta. Introduction].
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Aorta, Abdominal↗
Phenotypic and functional analysis of B cell lines from patients with multiple myeloma.
We characterized phenotypic and functional properties of B cell lines obtained from patients with multiple myeloma to determine how well they conform to particular stages of B cell differentiation. This information is a prerequisite for using such lines as tools for studying B cell growth and the regulation thereof. Two lines, GM1312 and GM1500, expressed B1 and Ia, determinants on early B cells, but expressed little, if any, T10, a determinant expressed on plasma cells. By contrast, B1 and Ia were poorly expressed on two other lines, GM2132 and U266. T10 was expressed on GM2132 but not on U266. Using a reverse hemolytic plaque assay, we also assessed the numbers of cells actively secreting immunoglobulin (IgSCs) in such cultures to provide a functional marker of B cell differentiation. We observed consistently higher numbers of IgSCs in cultures of GM2132 than in GM1500 and GM1312. These phenotypic and functional markers were stable over several months. The data suggest that such cell lines represent early (GM1312, GM1500) and later stages (GM2132, U266) of B cell differentiation, although all lines were derived from patients with multiple myeloma.
Antibodies, Monoclonal↗
Bromocriptine in Parkinson disease.
Bromocriptine is an ergopeptine derivative and dopamine agonist that predominantly stimulates the striatal D2 non-adenyl cyclase-linked dopamine receptors. Bromocriptine, unlike other dopamine agonists, has mixed "agonist-antagonist" properties at these receptors. The striatal dopamine receptors exist in two different affinity states: a low and a high affinity state. Bromocriptine, unlike other dopamine agonists, does not differentiate between the low and the high affinity state of the D2 receptors, and bromocriptine does not induce a conformational change in these receptors. Bromocriptine, in low doses, is effective in patients with mild to moderate Parkinson's disease, while bromocriptine in higher doses is needed in patients with advanced disease. Both in low doses and in high doses, bromocriptine combined with levodopa is usually more effective than bromocriptine alone. The efficacy of low dose (5-30 mg/day) and high dose (31-100 mg/day) bromocriptine alone and with levodopa was examined in 27 studies encompassing 790 patients. Forty-six % of the studies were done in a double blind manner. In four studies of 79 patients, low dose bromocriptine (16 mg/day) without levodopa resulted in improvement in 58% of the patients. Only 9% of the patients experienced adverse effects. Most of the patients (63%) and mild or moderate Parkinson disease. In seven studies of 143 patients, high dose bromocriptine (56 mg/day) without levodopa resulted in improvement in 62% of patients, but with 27% having adverse effects. Most of these patients (77%) had mild or moderate disease. Diurnal oscillations in performance, the "wearing off" or "on-off" effect, were not seen during treatment with bromocriptine alone. In nine studies of 201 patients, low dose bromocriptine (23 mg/day) and levodopa resulted in improvement in 71% of patients with 26% having adverse effects. Most of these patients (66%) had advanced disease, and many had diurnal oscillations in performance. In seven studies of 367 patients, high dose bromocriptine (48 mg/day) and levodopa resulted in improvement in 58% with 37% having adverse effects. Most of these patients (85%) had advanced disease. The increased effectiveness of bromocriptine in combination with levodopa may be explained as follows. Bromocriptine by itself does not discriminate between the low and the high affinity states of the dopamine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
Aged↗
Medical treatment of male infertility.
None of the previously described treatments for idiopathic infertility have been shown to be effective (Table). Controlled clinical trials may indicate that certain treatments are effective in carefully selected subsets of infertile men. The key to rational therapy will be basic research leading to the elucidation of the pathophysiology of what is presently "idiopathic infertility." Our policy is to present the facts honestly and invite our patients to participate in controlled clinical trials with therapies of uncertain value.
Endocrine System Diseases↗
[Mercury strain gauge plethysmography. A noninvasive exploration method for monitoring the efficacy of treatment of deep venous thrombosis].
The plethysmographic tracings of a patient presenting a deep venous thrombosis, give information about the functional evolution of the affected limb. The plethysmographic parameters which are used to estimate the efficacy of the treatment of the deep venous thrombosis are: the venous capacitance, the venous outflow and the venous pressure. These values are always compared with the contralateral limb. The decision to stop an anticoagulant treatment is made after observing an increase of the venous capacitance and outflow and, simultaneously, a decrease of the venous pressure. During the last three years, we have followed up 200 patients with this method. It allows a rational therapeutic management which is based on the objective monitoring of the functional potentialities of the venous system.
Adolescent↗
Chemical anatomy of the brain.
The development of sensitive histochemical-neuroanatomical techniques has made it possible to analyze the content of specific compounds in single nerve cells and their processes. In consequence, it has been possible to construct detailed maps of the distribution of various types of neurons on the basis of their transmitter substance. There are now many examples of neurons containing both a classical transmitter and a peptide. In some instances the peptides seem to support the action of the classical transmitters. This interaction may have applications in the prevention and treatment of nervous disease states.
Animals↗
Evidence for the existence of putative dopamine-, adrenaline- and noradrenaline-containing vagal motor neurons in the brainstem of the rat.
A combined technique utilizing retrograde transport of horseradish peroxidase (HRP) combined with immunocytochemistry using antibodies raised against tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyl transferase (PNMT) has been used to characterize monoaminergic neurons located within the region of the brainstem vagal motor nucleus. TH-immunoreactive (IR) but not DBH-IR and PNMT-IR neurons were double labelled predominantly at the caudal-most pole of the dorsal motor nucleus of the vagus (dmnX), whereas double-labelled PMNT and DBH plus TH-IR neurons extended from levels just rostral to the obex to 1-2 mm rostrally in the medial and lateral poles of the dmnX, respectively. The presence of putative dopamine (DA), noradrenaline (NA) and adrenaline (A) neurons in topographically distinct regions of the dmnX implicates, DA, NA and A in the modulation of cholinergic transmission at the level of parasympathetic ganglia in discrete parts of the thoracic and abdominal viscera.
Animals↗
Distribution of tyrosine-hydroxylase-immunoreactive neurons in the hypothalamus of rats.
The distribution and morphology of cells containing tyrosine hydroxylase (TH) immunoreactivity in the hypothalamus of rats were studied by using a modified immunoperoxidase technique. The TH cell system is more complexly organized than was previously thought. On the basis of their clustering patterns, hypothalamic TH neurons could be subdivided into two groups: dorsal and ventral. The ventral group consists of a prominent aggregate of cells located in the caudal part of the arcuate nucleus. From here, cells extend around the caudal part of the ventromedial and dorsomedial nuclei and the base of the diencephalon. Tyrosine hydroxylase-positive cells are present throughout the arcuate nucleus, except in its ventromedial part. Anteriorly, immunoreactive cells appear in the suprachiasmatic and supraoptic nuclei, in the retrochiasmatic area, and in the ventral part of the anterior hypothalamic nucleus. The dorsal group has its main concentration of cells in the medial part of the zona incerta, from which two clusters of cells, one medial and one lateral, extend rostralward. The medial group comprises cells in the medial part of the dorsomedial, paraventricular, and anterior hypothalamic nuclei. These cells adjoin the periventricular cells. The lateral group of cells emanating from the zona incerta occupies the lateral part of the dorsomedial and anterior hypothalamic nuclei and the dorsal hypothalamic area. The dorsal and ventral TH cell groups are in continuity medially in the periventricular layer, and laterally through the cells that surround the ventromedial nucleus. Although the cells vary widely in size, shape, and dendritic arborization pattern, there are two main cell types. Small (21 X 11 microns), round to fusiform cells, with two or three dendrites arborizing simply, were frequently seen in the arcuate, suprachiasmatic, periventricular, supramammillary nuclei and at the borders of the ventromedial nucleus. The other cell type is larger (40 X 15 microns) and multipolar, with three to five frequently branching dendrites. The dendritic field is large and the cells are intensely TH-immunoreactive. Although the larger cells occur occasionally in every hypothalamic nucleus, their principal locations are in the dorsal parts of the dorsomedial, posterior hypothalamic nuclei and the dorsal and lateral parts of the zona incerta, and in the areas dorsal and medial to the mammillothalamic tract at caudal hypothalamic levels. In this paper we give a detailed description of TH-immunoreactive fibers and terminals in the hypothalamus and a comparison with previous studies of catecholamine cells in the hypothalamus.
Animals↗
Effect of intranigral injections of dynorphin, dynorphin fragments and alpha-neoendorphin on rotational behaviour in the rat.
Peptides deriving from the proenkephalin B precursor were studied in the Ungerstedt rotational model after their unilateral injection into the substantia nigra. Dynorphin (DYN)-(1-17), DYN-(1-13) and DYN-(1-8) in 0.1-10 micrograms doses induced marked contralateral rotation. This effect was enhanced by subsequent systemic administration of D-amphetamine and blocked by previous treatment with naloxone. alpha-Neoendorphin produced similar effects although there was no evidence for dose-dependency. DYN-(6-17) which lacks opioid activity also produced contralateral rotation, which, however, was not naloxone reversible and D-amphetamine given subsequently did not induce asymmetric activation. Methionine enkephalin and leucine enkephalin, deriving from the proenkephalin A precursor were tested for comparison. Only the former produced weak contralateral rotation. GABA injected at the same site as DYN-(1-17) also induced contralateral rotation which was mimicked by nanogram doses of the gabaergic agonist muscimol. These findings suggest an interaction between peptides from the proenkephalin B precursor and nigro-striatal dopamine neurons as well as gabaergic striato-nigral efferents and/or interneurons.
Animals↗
Simultaneous expression of the SP-peptidergic and noradrenergic phenotypes in rat sympathetic neurons.
We previously observed that substance P (SP) levels in the rat superior cervical ganglion (SCG) rise sharply when the ganglion is maintained in vitro. To define the cellular localization of SP, sections of cultured SCG were stained for the possible dual presence of SP and tyrosine hydroxylase (TOH). Immunoreactivity to both SP and TOH was present in the majority of principal neurons. This observation suggests that principal sympathetic neurons can express simultaneously both the noradrenergic and SP-peptidergic phenotypes.
Animals↗
Golgi-like immunoperoxidase staining of dopamine neurons in the reticular formation of the rat brainstem using antibody to tyrosine-hydroxylase.
The distribution and morphology of presumed dopaminergic neurons within the reticular formation (RF) and the ventrolateral tegmental area (VLT) were studied by using a specific antibody to the enzyme that converts tyrosine to dihydroxyphenylalanine, tyrosine-hydroxylase (TH), in combination with a sensitive immunoperoxidase method (Hsu et al., '81). Incubation of thick (70-120 micron) sections for 3-5 days in high dilutions of antibody resulted in staining of TH-immunoreactive neurons in a Golgi-like fashion. Analysis of serial sections cut in the coronal, horizontal, and parasagittal planes revealed an extensive system of TH-positive neurons in the RF and VLT extending from the Edinger-Westphal nucleus caudally to the level of the decussations of the superior cerebellar peduncle. Within this region, the TH-positive cells belong to two subgroups: (1) a relatively well-defined population of cells aggregated in the reticular formation (corresponding to cell group A8 of Dahlström and Fuxe, '64), and (2) a more loosely defined group of cells that appears to be continuous with the cells of the nucleus raphe linearis. This latter cell group extends laterally from the midline to the nucleus parapeduncularis. An analysis of the individual TH-immunoreactive cells revealed large differences in their morphology. Thus, the somata of TH-positive cells in the RF and the VLT are fusiform, ovoid, or triangular. A majority of the TH neurons are of medium (long axis: 15-35 micron) to large (long axis: 35-40 micron size. While the cells in the A8 area appeared relatively homogeneous, the TH-positive cells of the VLT showed great variations in dendritic branching pattern and orientation. Taken together, the present study has shown that within the RF and the VLT, the TH-immunoreactive neurons are more numerous than hitherto recognized, and that this cell group consists of a morphologically heterogeneous population of dopamine-synthesizing neurons.
Animals↗
Occurrence of neurotensinlike immunoreactivity in subpopulations of hypothalamic, mesencephalic, and medullary catecholamine neurons.
By using indirect immunofluorescence histochemistry combined with the elution-restaining technique, the presence of a neurotensinlike peptide in some catecholamine neurons in the rat brain has been demonstrated. At the level of the medulla oblongata neurotensinlike immunoreactivity was observed in most of the small-sized catecholamine (adrenaline) cell bodies in the dorsolateral part of the nucleus of the solitary tract and in some catecholamine (noradrenaline) cells in the medial part. Neurotensin-positive fibers were found throughout the solitary tract nucleus with increasing concentrations in the rostral direction. Very few neurotensin fibers were seen in the vagal dorsal motor nucleus, which contained a dense network of adrenaline fibers. In the ventral mesencephalon, neurotensinlike immunoreactivity was seen mainly in dopamine cell bodies in the ventral tegmental area, including midline structures, with only single examples of coexistence in the substantia nigra. The dopamine cell bodies of both the A9 and A10 cell groups were surrounded by dense to medium-dense networks of neurotensin fibers. In the hypothalamus numerous dopamine neurons in the arcuate nucleus exhibited neurotensinlike immunoreactivity. Neurotensin-positive nerve terminals, partially overlapping catecholamine (mainly dopamine) fibers, were seen in the external layer of the median eminence. The present results demonstrate coexistence of neurotensinlike immunoreactivity and catecholamines in populations of neurons in some of the central catecholamine cell groups and provide a morphological basis for interactions between the peptide and amines.
Animals↗