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Biomedical subjects

M Goldstein

Publications and source records attributed to M Goldstein.

At least 433 records · Page 24Linked to original sources
PubMed1986

Management of levodopa failures: the use of dopamine agonists.

In the past decade, dopamine agonists have emerged as important treatment options for patients with Parkinson's disease. Originally, dopamine agonists were used only in patients with advanced disease in whom the response to levodopa had decreased (levodopa failures). The decreased response to levodopa, usually associated with diurnal oscillations in performance and the 'wearing-off' and 'on-off' phenomena, is secondary to disease progression with continued degeneration of the nigrostriatal neurons. In addition, chronic levodopa treatment itself may contribute to the decreased drug response and the diurnal oscillations in performance. Dopamine receptor agonists bypass the degenerating nigrostriatal neurons and directly stimulate the striatal dopamine receptors. Dopamine receptor agonists also permit a reduction in the dose of levodopa. Five ergoline dopamine agonists--bromocriptine, lergotrile, pergolide, lisuride, mesulergine, and the nonergoline agonist, ciladopa--have undergone clinical trials in Parkinson's disease. In 10 years, we treated a total of 278 patients with advanced Parkinson's disease, a declining response to levodopa, and diurnal oscillations in performance with five ergoline dopamine agonists (in addition to levodopa). The mean duration of treatment was one year (with a range of 1-60 months). Improvement was noted in 140 (50%) of our patients. Adverse effects necessitating discontinuation of the agonist occurred in 131 patients (46%). We compared our results with those of others who, unlike us, began treatment with a dopamine agonist earlier, using the agonist alone or adding it to levodopa before the response to levodopa had decreased. Many of the patients so treated had mild or moderate Parkinson's disease. A total of 1,599 patients were treated with ergoline dopamine agonists. Of these patients, 976 (61%) improved, while 407 (25%) experienced adverse effects. We believe that a greater number of these patients improved and fewer experienced adverse effects, in comparison to our patients, because the patients had less advanced disease.

Animals↗
PubMed1985

Tyrosine hydroxylase and 28K-vitamin D-dependent calcium binding protein are localized in different subpopulations of periglomerular cells of the rat olfactory bulb.

Successive incubations of rat olfactory bulb cryostat sections with antibodies against the chick 28K-vitamin D-dependent calcium (Ca) binding protein and tyrosine hydroxylase were performed, and the distribution of the label was examined in the fluorescence microscope. Both antibodies labeled cells and processes in highest number in the glomerular layer. The two immunopositivities were not co-localized in the same neurons. This suggests that the presence of this Ca-binding protein is not a necessary prerequisite for dopaminergic neurotransmission in periglomerular neurons.

Animals↗
PubMed1985

Recovery of alpha 2-adrenoceptor binding and function after irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).

Treatment of rats with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) resulted in a pronounced loss of alpha 2-adrenoceptor binding ( [3H]RX-781094) and a marked reduction in the ability of the alpha 2-agonist UK-14,304 to inhibit K+-stimulated release of both [3H]NA and [3H]5-HT in cerebral cortex. Repopulation of alpha 2-adrenoceptors was monoexponential with a t1/2 of 4.1 days; functional recovery was also monoexponential, with t1/2 values of 2.4 and 4.6 days for restoration of alpha 2-mediated inhibition of [3H]NA and [3H]5-HT release, respectively. Other studies suggest the difference in functional recovery rate may reflect the presence of a large receptor reserve for autoreceptors relative to heteroreceptors.

Adrenergic alpha-Antagonists↗
PubMed1985

Adrenergic control of serotonin release from a midgut carcinoid tumour.

A case of recurrent midgut carcinoid tumour with disseminated spread is described, in which the clinical diagnosis was supported by measurements of elevated basal serotonin (5-HT) levels in peripheral blood and increased 5-HT responses to pentagastrin provocation, despite normal urinary levels of 5-hydroxyindoleacetic acid. Preoperative diagnosis was obtained by concomitant determinations of 5-HT in mesenteric and hepatic veins. The carcinoid tumour was studied immunocytochemically using antisera to tyrosine hydroxylase and 5-HT. Neuroendocrine complexes between adrenergic nerve terminals and 5-HT-containing tumour cells could be demonstrated. 5-HT release from tumour cells in suspension was studied in vitro after incubation with adrenoceptor agonists or pentagastrin. Tissue pieces from the tumour were also transplanted into the anterior eye chamber of Sprague-Dawley rats, some of which were subjected to immunosuppression (Cyclosporin A 20 mg/kg s.c.). After 10 days in oculo the tumour transplants (with preserved immunocytochemical characteristics) were stimulated with adrenoceptor agonists. Tumour cells in suspension as well as tumour transplants released 5-HT upon adrenoceptor stimulation but no release was induced by pentagastrin. The pentagastrin test is suggested to cause release of 5-HT in carcinoid tumour patients via release of endogenous catecholamines, in turn activating adrenoreceptors on carcinoid tumour cells.

Adrenergic alpha-Agonists↗
PubMed1985

Evidence for crossed catecholaminergic nigrostriatal projections by combining wheat germ agglutinin-horseradish peroxidase retrograde transport and tyrosine hydroxylase immunocytochemistry.

After unilateral injections of wheat germ agglutinin-horseradish peroxidase into the rat caudate-putamen, a few retrogradely labeled neurons were found in the contralateral pars compacta of the substantia nigra. These contralaterally projecting nigral cell bodies also immunoreacted positively to a specific tyrosine hydroxylase antiserum. We conclude that crossed catecholaminergic nigrostriatal projections may contribute to the reciprocal regulation exerted by the two nigrostriatal dopaminergic systems.

Animals↗
PubMed1985

Ontogeny of phenylethanolamine N-methyltransferase- and tyrosine hydroxylase-like immunoreactivity in presumptive adrenaline neurones of the foetal rat central nervous system.

The appearance of phenylethanolamine N-methyltransferase (PNMT)- and tyrosine hydroxylase (TH)-like immunoreactivity (LI) in the foetal rat central nervous system has been investigated. Antibodies raised against PNMT and TH were used in an indirect immunofluorescence method. Attention was focussed on areas containing putative adrenaline-containing nerve cell bodies or fibres and, using an elution-restaining technique, it was possible to analyze whether neurones contained PNMT-LI, TH-LI, or both. PNMT-immunoreactive neurones could first be visualized on day 13 of gestation, in the ventrolateral and dorsal medulla oblongata, and probably corresponding to those of the C1 and C2 groups. The number of positive cell bodies and the intensity of their fluorescent staining in these areas were not dissimilar at this stage to the number and intensity observed at 1 day postnatal, the final age studied. At day 16, PNMT-positive cells were observed for the first time in midline areas of the rostral dorsal medulla oblongata-caudal pons, associated with the medial longitudinal fasciculus. These cells probably composed the C3 cell group. Many PNMT-immunoreactive fibres could be seen at day 13 of gestation, in the medulla, and coursing both in an ascending bundle around the mesencephalic flexure and in a descending bundle toward the spinal cord. The extent of the bundles increased with gestational age, such that dense meshworks of PNMT-immunoreactive varicose fibres were visible ventral to the aqueductus Sylvii, and the periventricular and lateral regions of the hypothalamus by days 18 to 19, and in the paraventricular nucleus, the septum, and the thoracic spinal cord by day 1 after birth. A sparser fibre plexus was observed in the amygdala at day 1 postnatal. In contrast to the explosive appearance of PNMT-immunoreactive cells at day 13 of gestation, the development of TH-LI within these same neurones was much more protracted. Only rarely were TH-LI and PNMT-LI colocalized at day 13, and even at birth TH-LI could not be visualized in 5% of PNMT-immunoreactive cells in the ventrolateral medulla oblongata, and in 50% of those in the dorsal vagal complex. A similar tardy appearance of TH-LI in PNMT-immunoreactive fibres was observed also. It should be emphasized that strongly TH-immunoreactive neurones were found already at gestational day 10.5 in the medulla oblongata, caudal to the PNMT-immunoreactive cells. It is concluded that the expression of enzymes involved in the synthesis of adrenaline is not unitarily controlled, and may be partly dependent on other than epigenetic factors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Selective D2 dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D1 antagonist.

SCH 23390, an apparently selective antagonist of central D1 dopamine receptors, produced profound catalepsy at low doses (0.1 mg/kg, s.c.). Pretreatment with the selective D2 receptor agonists LY 141865, RU 24213 or LY 171555, the active (-) enantiomer of LY 141865, elicited a dose-dependent inhibition of the cataleptic response. Pergolide and apomorphine were also effective. This effect was not due to altered disposition or penetration of SCH 23390 into the brain since pretreatment with a dose of LY 171555 which completely blocked catalepsy had no effect on the ID50 of SCH 23390 to inhibit 3H-cis-piflutixol binding to D1 receptors measured ex vivo. Alternative mechanisms are considered to explain the results, which offer new insights into striatal dopaminergic regulation of motor activity.

Animals↗
PubMed1985

Immunohistochemical evidence for phenylethanolamine-N-methyltransferase-positive/tyrosine hydroxylase-negative neurones in the retina and the posterior hypothalamus of the rat.

Phenylethanolamine-N-methyltransferase (PNMT)-immunoreactive neurons were observed in the inner nuclear layer of the rat retina, apparently giving rise to fiber networks mainly in layer 3 of the inner plexiform layer. These neurons did not seem to contain tyrosine hydroxylase (TH)-like or dopamine-beta-hydroxylase (DBH)-like immunoreactivity and were much smaller and more numerous than the previously described TH-positive dopamine neurons. PNMT-positive, but TH- and DBH-negative neurons were also observed in small numbers in the basal posterior hypothalamus.

Animals↗
PubMed1985

Rat medulla oblongata. II. Dopaminergic, noradrenergic (A1 and A2) and adrenergic neurons, nerve fibers, and presumptive terminal processes.

The aim of this study was to determine the anatomical relationships between catecholaminergic neurons and cytoarchitectonically defined nuclei in the caudal medulla oblongata. Previous studies have demonstrated the existence of noradrenergic cell bodies (designated as the A1 and A2 cell groups) in the caudal medulla oblongata of the rat (Dahlström and Fuxe, '64), including the nTS. There is no information currently available with regard to details of the distribution of these noradrenergic neurons in the functionally distinct subnuclei of the medulla oblongata. In this study the location of catecholamine-synthesizing enzymes was examined in the serial sections of the caudal medulla oblongata of the rat: tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine N-methyl transferase (PNMT). The immunoperoxidase method of Sternberger ('79) was used to demonstrate the location of immunoreactive neurons, nerve fibers, and presumptive terminal processes. This was followed by Nissl staining of the same sections to localize accurately the immunoreactivity. Noradrenergic neurons (TH- and DBH-positive and PNMT-negative) were localized in a number of subnuclei of the nucleus of the tractus solitarius (nTS), the area postrema (ap), and in the dorsal motor nucleus of the vagus (dmnX). The distribution of these noradrenergic cells was different at different rostrocaudal levels. In addition, adrenergic neurons (TH-, DBH-, and PMNT-positive) were identified dorsal to the tractus solitarius (TS), in the dorsal strip region (ds), the periventricular region (PVR), the dorsal parasolitarius region (dPSR), and the dmnX (rostral to obex). In addition, dopaminergic neurons (TH-positive and DBH- and PNMT-negative) were found in the ap and dmnX. The A1 cell group in the ventrolateral medulla consisted almost exclusively of noradrenergic neurons (TH- and DBH-positive and PNMT-negative). These results indicate that in the rat the A2 cell group is a mixed population of catecholaminergic neurons that are localized in well-defined regions of the dorsal medulla oblongata. The distribution of these neurons is very specific both in terms of rostrocaudal levels and cytoarchitectonic subdivisions of regions of the medulla known to be involved in central autonomic control. This supports the hypothesis that monoaminergic neurons in the dorsal medulla play important roles in the central regulation of visceral function.

Adrenergic Fibers↗
PubMed1985

Rat medulla oblongata. III. Adrenergic (C1 and C2) neurons, nerve fibers and presumptive terminal processes.

The goal of this study was to define the cytoarchitectonic relationships between the catecholaminergic cell groups (the C1 and C2) in the rostral medulla oblongata of the rat. Immunocytochemistry was combined with Nissl staining to determine the nuclear boundaries in this region of the brain stem. In addition, the morphological characteristics of neurons in the C1 and C2 cell groups were determined and the relationship between these populations of neurons and their caudaul counterparts (A1 and A2 cell groups) was established (Kalia et al., '85a). The results indicate that the C1 and C2 cell groups are distributed over a wide region of the rostral medulla. The location of these adrenergic neurons is related to a number of nuclear groups in this region. This finding was remarkably consistent in all the animals studied in this series. In addition, adrenergic nerve fibers were found to be distributed over a large region of the medullary reticular formation. There was homogeneity in the morphology of the C1 and C2 cell groups. These rostrally located adrenergic neurons did not share morphological features in common with the recently described (Kalia et al., '85a) caudally located adrenergic neurons in the dorsal region of the nucleus of the tractus solitarius. These striking anatomical features of the adrenergic C1 and C2 cell groups support the proposal that adrenergic neurons in the rostral medulla oblongata play an important role in the integration of visceral functions (Fuxe et al., '80).

Adrenergic Fibers↗
PubMed1985

Morphometrical analysis of the distribution of corticotrophin releasing factor, glucocorticoid receptor and phenylethanolamine-N-methyltransferase immunoreactive structures in the paraventricular hypothalamic nucleus of the rat.

By means of the indirect immunoperoxidase technique the corticotrophin releasing factor (CRF) and glucocorticoid receptor (GR) immunoreactive nerve cell bodies and the phenylethanolamine-N-methyltransferase (PNMT) immunoreactive nerve terminals in the paraventricular hypothalamic nucleus of the rat have been mapped out in adjacent vibratome sections (30 micron thick). By means of morphometrical analysis using a semiautomatic image analyser, it was possible to obtain density maps of CRF, GR and PNMT immunoreactive structures within the paraventricular hypothalamic nucleus. The statistical analysis by the use of correlation coefficients gives evidence that the PNMT immunoreactive nerve terminals innervate the majority of the CRF immunoreactive nerve cell bodies and that GR are located in the majority of the CRF immunoreactive neurons.

Animals↗
PubMed1985

Chronic haloperidol does not alter agonist affinity for dopamine receptors in vitro.

Agonist competition for [3H]spiperone binding to striatal dopamine D2 receptors was studied in rats rendered supersensitive by chronic treatment with haloperidol. The classical dopamine agonist (-)-N-n-propylnorapomorphine displaced [3H]spiperone biphasically, with IC50 values of 0.5 and 140 nM for the high and low affinity components, respectively. Neither the relative density nor the affinity of either site for (-)-N-propylnorapomorphine was affected by chronic haloperidol treatment. On the other hand, the novel agonist EMD 23 448 displaced [3H]spiperone monophasically. Although this agent only displays potent dopaminergic agonism in supersensitive animals, chronic treatment with haloperidol likewise did not alter the affinity of this drug for [3H]spiperone binding sites. The results suggest that the enhanced in vivo potency of certain agonists in supersensitive animals is probably not mediated by changes in D2 receptor affinity.

Animals↗
PubMed1985

Central dopamine agonist activity on the 8-alpha-amino-ergoline CU 32-085.

The effects of the 8-alpha-amino-ergoline CU 32-085 on central dopamine neuronal systems was investigated. Two h after administration of CU 32-085 a slight increase of dopamine levels was observed in the nucleus caudatus-putamen. Radioligand binding studies in vitro have shown that CU 32-085 has a low affinity for striatal dopamine receptors labeled by [3H]n-propylapomorphine or [3H]spiroperidol. However, CU 32-085 effectively displaces in vivo [3H]n-propylapomorphine and [3H]spiroperidol from their respective binding sites in the mouse striatum. Functional studies have shown that CU 32-085 elicits contralateral rotation in rats with unilateral 6-OH-dopamine induced lesions of the meso-striatal dopamine neurons, and ipsilateral rotation in rats with unilateral intrastriatal ibotenic acid lesions. CU 32-085 relieves tremor in monkeys with ventromedial tegmental lesions and produces only slight abnormal involuntary movements. The biochemical and functional studies suggest that CU 32-085 and/or its metabolite exerts central dopamine agonist activity in vivo. Studies in monkeys with ventromedial tegmental lesions suggest that CU 32-085 might be an effective antiparkinsonian agent which produces less dyskinesias than the other tested dopamine agonists.

Animals↗
PubMed1985

Distribution of catecholamine-containing neurons in the normal human hypothalamus.

We have studied the distribution of catecholamine-containing neurons in the hypothalamus of 8 normal adult human brains, using Schmorl's stain for melanin and immunohistochemical staining for tyrosine hydroxylase (TH). TH immunoreactive perikarya were found in the wall of the third ventricle, in the areas in which dopaminergic neuroendocrine neurons are found in other primate species. Many of these neurons contained melanin pigment, and the percentage increased with age. Other melanin-pigmented neurons in the same distribution did not stain for TH, suggesting that postmortem TH immunostaining may not be sufficiently sensitive to visualize all catecholaminergic neurons. A separate group of larger TH-positive perikarya was seen in the lateral hypothalamic area. These may correspond to the incerto-hypothalamic dopamine neurons in other primate species. Only rare melanin-pigmented neurons were seen in this cell group, even at 66 years of age. Our data indicate that the hypothalamic neuroendocrine dopamine neurons in the human brain are distributed in a pattern similar to that in other primate species, and that both postmortem tyrosine hydroxylase and melanin staining provide an incomplete but representative sampling of the periventricular-arcuate cell group.

Adolescent↗