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A Beaudet

Publications and source records attributed to A Beaudet.

At least 73 records · Page 4Linked to original sources
PubMed1995

Expression of sstr1 and sstr2 in rat hypothalamus: correlation with receptor binding and distribution of growth hormone regulatory peptides.

With the aim of elucidating the role of individual somatostatin receptors in the central control of growth hormone secretion, we have examined the distribution of sstr1 and sstr2 mRNAs in the hypothalamus of the adult rat by in situ hybridization using 35S-labelled antisense riboprobes. Both receptors were expressed strongly in the preoptic area, suprachiasmatic nucleus and arcuate nucleus. High sstr1, but low sstr2, expression was evident in the paraventricular and periventricular nuclei as well as in the ventral premammillary nucleus. Conversely, moderate to high sstr2, but low sstr1, mRNA levels were detected in the anterior hypothalamic nucleus, ventromedial and dorsomedial nuclei and medial tuberal nucleus. Within the arcuate nucleus, the distribution of cells expressing sstr1 and sstr2 was comparable to that of neurons which bind somatostatin-14 selectively, one third of which have been documented to contain growth hormone-releasing hormone. Within the periventricular nucleus, the distribution of cells expressing sstr1 and, to a lesser extent, sstr2 was reminiscent of that of both [125I]somatostatin-labelled and somatostatin-immunoreactive cells. Taken together, these results imply a role for both sstr1 and sstr2 receptors in the central regulation of growth hormone-releasing hormone and somatostatin secretion, and hence of growth hormone release, by somatostatin.

Animals↗
PubMed1995

Binding and internalization of neurotensin in hybrid cells derived from septal cholinergic neurons.

Autoradiographic studies from our laboratory have previously demonstrated a selective association of high affinity neurotensin (NT) binding sites with basal forebrain cholinergic neurons. In search of an in vitro model for further characterization of the role and regulation of these sites, we have examined the binding and internalization of 125I-Tyr3-NT (125I-NT) and fluorescein isothiocyanate (FITC)-conjugated NT (fluo-NT) on SN17 hybrid cells, produced by fusion of embryonic murine septal cells with neuroblastoma. 125I-NT binding to SN17 membrane preparations was specific and saturable. Scatchard analysis of the data was suggestive of an interaction with a single population of sites, the affinity (Kd = 1.7 nM) and pharmacological profile of which were comparable to those of neural NT receptors. No specific binding was observed on the parent neuroblastoma cell line, confirming that the expression of those sites is a neuronal trait. Incubation of whole SN17 cells with 125I-NT resulted in a time- and temperature-dependent internalization of the specifically bound peptide. The t1/2 of this internalization was estimated at 13 min, a value nearly identical to that reported for neurons in culture. Confocal microscopic analyses using fluo-NT indicated that the internalization process was endocytic in nature in that: 1) it was entirely blocked by the endocytosis inhibitor phenylarsine oxide; and 2) it was mediated through small intracytoplasmic particles the size and maturation of which corresponded to that of endosomes. It is proposed that the expression and internalization of NT receptors by SN17 hybrid cells represent a new facet of these cells' cholinergic phenotype that makes them amenable to the study of NT interactions with cholinergic cells.

Acetylcholinesterase↗
PubMed1995

In vivo-synthesized radioactively labelled alpha-methyl serotonin as a selective tracer for visualization of brain serotonin neurons.

To investigate the use of alpha-[3H]methyl tryptophan (alpha-[3H]MTrp) as a tracer for the in vivo study of brain serotonergic neurons, we examined whether alpha-[3H]MTrp and its metabolite alpha-[3H]methyl serotonin (alpha-[3H]M5-HT) selectively label serotonergic neurons and whether once accumulated in these neurons, the radioactive metabolite behaves like endogenous serotonin. Rats received a systemic injection of 1-5 mCi of alpha-[3H]MTrp and 24 h later their brains were immediately removed or fixed by perfusion before removal. Tissue sections in which serotonergic neurons had been immunostained for 5-HT or its synthesizing enzyme, tryptophan hydroxylase, were processed for radioautography at the light and electron microscopic level. In another group of rats, the release of radioactivity from different brain areas was studied both under basal and depolarizing conditions. In the dorsal raphe nucleus, the light microscopic examination revealed almost complete colocalization between serotonergic neurons and those that accumulated radioactivity, with a heterogeneity in the content of alpha-[3H]M5-HT among the various cells. At the ultrastructural level, immunoidentified serotonergic perikarya and dendritic processes in the dorsal raphe nucleus, as well as nerve terminals in the cerebral cortex were also found to contain alpha-[3H]M5-HT. Under basal conditions, radioactivity was released from the brainstem raphe region and from projection areas such as the striatum and hippocampus. The basal output of alpha-[3H]M5-HT increased approximately twofold after a depolarizing 50 mM KCl solution was added to the perfusion fluid. These findings suggest that newly synthesized alpha-[3H]M5-HT can be released both at somatodendritic and terminal sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Patterns of expression of SSTR1 and SSTR2 somatostatin receptor subtypes in the hypothalamus of the adult rat: relationship to neuroendocrine function.

The neuropeptide somatostatin is the major physiological inhibitor of growth hormone secretion. With the aim of identifying the receptor subtypes through which this neuropeptide may be exerting its neuroendocrine actions in the brain, we have examined by in situ hybridization the distribution of the messenger RNA for SSTR1 and SSTR2 isoforms in the hypothalamus of adult male and female rats. Both receptor subtypes were highly expressed in the medial preoptic area, suprachiasmatic nucleus and arcuate nucleus. High SSTR1, but low SSTR2, expression was evident in the para- and periventricular nuclei as well as in the ventral premammillary nucleus. Conversely, moderate to high SSTR2, but low SSTR1, messenger RNA levels were detected in the anterior hypothalamic nucleus, ventromedial and dorsomedial nuclei and medial tuberal nucleus. Taken together, these distributional patterns conform to those of somatostatin binding sites as visualized by in vitro autoradiography, suggesting that an important proportion of SSTR1 and SSTR2 receptors in the hypothalamus are associated with the perikarya and dendrites of intrinsic neurons. The distribution of SSTR1-expressing cells within the periventricular, paraventricular and suprachiasmatic nuclei was similar to that of neurons previously reported to contain and/or express somatostatin in the brain suggesting that some of the SSTR1 receptors may correspond to autoreceptors. Within the arcuate nucleus, the distribution of SSTR1 and SSTR2 messenger RNA-expressing cells was comparable to that of neurons previously found to selectively bind somatostatin-14 within this area. Given that over one third of these cells also contain and express growth hormone-releasing factor, the present findings suggest that both of these receptor subtypes are involved in the central regulation of growth hormone-releasing factor secretion by somatostatin. Taken together, the present results suggest that SSTR1 and SSTR2 somatostatin receptor messenger RNAs are heavily expressed in those neurons containing somatostatin and/or growth hormone-releasing factor and thereby imply a role for both SSTR1 and SSTR2 somatostatin receptor subtypes in neuroendocrine regulation of growth hormone secretion in both sexes of this species.

Animals↗
PubMed1995

Axonal and dendritic transport of internalized neurotensin in rat mesostriatal dopaminergic neurons.

Previous studies have demonstrated that neurotensin is internalized and retrogradely transported in neurons of the substantia nigra following its intracerebral injection in the neostriatum. The aim of the present study was to compare the intracellular distribution of retrogradely transported material with that observed following internalization of the peptide at the somatodendritic level and to confirm that the internalization was confined to dopamine neurons. To document somatodendritic internalization, slices (350 microns) from the rat ventral midbrain were incubated in vitro with 20 mM fluoresceinylated neurotensin, a fluorescent derivative of neurotensin, and immunostained 5-60 min later for tyrosine hydroxylase. To document retrograde transport, rats were injected with the same compound into the neostriatum and the brains processed for tyrosine hydroxylase immunohistochemistry 4.5 and 8 h later. Confocal laser microscopic examination of superfused slices revealed that fluoresceinylated neurotensin was internalized at the level of the perikarya and processes of neurons in the substantia nigra, ventral tegmental area and interfascicular nucleus. At short time intervals, the label was detected in the form of small, intensely fluorescent particles distributed within the cytoplasm of both perikarya and dendrites. At longer time intervals, these fluorescent particles were larger, less numerous and confined to the perikarya where they eventually clustered against the nucleus. Following intrastriatal injection of fluoresceinylated neurotensin, retrogradely labeled cells were apparent throughout the substantia nigra, pars compacta, as well as in the lateral part of the ventral tegmental area. Here again, the label took the form of small fluorescent particles, comparable in size, shape and distribution to those detected following superfusion of midbrain slices. In both labeling conditions, fluoresceinylated neurotensin was almost exclusively confined to tyrosine hydroxylase-immunoreactive cells. These results indicate that neurotensin is internalized throughout the terminal and dendritic arborization of mesostriatal dopamine cells and that the internalized peptide is transported centripetally from both locations to the soma of the cells. The clustering of fluorescent particles in the perinuclear region of the cells further suggests that the internalized process may play a role in the long term transcellular signalling.

Animals↗
PubMed1995

Somatodendritic internalization and perinuclear targeting of neurotensin in the mammalian brain.

Polypeptide hormones and growth factors have long been known to internalize into peripheral target cells as a result of their interaction with cell surface receptors. Studies in culture have suggested that certain neuropeptides might undergo a similar type of translocation in neurons. To investigate this possibility in adult mammalian brain, we have examined by confocal laser microscopy the events that follow the binding of fluorescein-tagged derivatives of the tridecapeptide neurotensin to basal forebrain cholinergic cells. Our results demonstrate a selective time- and temperature-dependent internalization of fluo-neurotensin in these cells. This internalization is receptor mediated, proceeds from the entire somatodendritic membrane of the cells, and utilizes endosome-like organelles which are mobilized from dendrites to perikarya and from the periphery of the cell to its perinuclear region. Parallel studies carried out on Sf9 insect cells expressing the rat neurotensin receptor from a recombinant baculovirus indicated that the internalization process involves receptor-ligand complexes and not merely the fluorescent peptide itself. These data suggest that receptor internalization plays a role in neuropeptide signaling in the brain and that it can be harnessed for selective identification of neuropeptide target cells.

Animals↗
PubMed1994

The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic beta-endorphin in adult female rats.

A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats. We have hypothesized that peroxidase-positive astrocytes in this brain region oxidize estrogens and catecholestrogens to semiquinone radicals which mediate oxidative neuronal injury. In the present study, dietary administration of the potent antioxidant 21-aminosteroid, U-74389F, completely blocked EV-induced beta-endorphin depletion in the hypothalami of adult female rats. Neither EV nor 21-aminosteroid treatment had any effect on hypothalamic concentrations of neuropeptide Y and Met-enkephalin, confirming that the estradiol lesion is fairly selective for the beta-endorphin cell population. The present findings support the hypothesis that the toxic effect of estradiol on hypothalamic beta-endorphin neurons is mediated by free radicals.

Animals↗
PubMed1994

Retrograde axonal transport of neurotensin in rat nigrostriatal dopaminergic neurons. Modulation during ageing and possible physiological role.

Biochemical and anatomical data are reported which demonstrate for the first time the existence of a retrograde axonal transport process for a neuropeptide, neurotensin, in rat brain. Neurotensin receptors are mainly located in the striatum on nerve terminals of the nigrostriatal dopaminergic pathway. Thus, the association of specific neurotensin receptors on a well defined pathway provides an excellent model to investigate the existence of such a process. Two hours after the intrastriatal injection of iodinated neurotensin, radioactivity started to accumulate in the ipsilateral substantia nigra. The levels were maximal during the fourth hour. The appearance of this labelling was prevented by injection of a large excess of unlabelled neurotensin or of neurotensin 8-13, an active neurotensin fragment, but not by neurotensin 1-8 which had no affinity for neurotensin receptors. These results suggest that the appearance of radioactivity in the ipsilateral substantia nigra was dependent on the initial binding of this peptide to its receptors in the striatum. HPLC studies demonstrated that the radioactivity found in the substantia nigra corresponded to intact neurotensin and to degradation products of this peptide. Moreover, it has been shown that this retrograde transport was microtubule-dependent and occurred in dopaminergic nigrostriatal neurons. Light and electron microscopic data confirmed and extended the present results. Four and a half hours after intrastriatal injection of iodinated neurotensin, silver grains were mainly detected in dopaminergic perikarya of the substantia nigra pars compacta. The vast majority were associated with neuronal elements and their localization within cell bodies suggests that retrogradely transported neurotensin may be processed along a variety of intracellular pathways including those mediating recycling in the rough endoplasmic reticulum and degradation in lysosomes. However, the presence of silver grains over the nucleus, as well as the increase in tyrosine-hydroxylase mRNA expression in the ipsilateral substantia nigra 4 hr after intrastriatal injection of neurotensin support the concept that neurotensin alone, or associated with its receptor, might be involved in the regulation of gene expression. Finally, we have demonstrated that in old rats the quantity of retrogradely transported neurotensin was significantly decreased as compared to that observed in young adult rats. This retrograde axonal transport of a neuropeptide may represent, as already suggested for growth factors, an important dynamic process conveying information from nerve terminals to the cell body.

Aging↗
PubMed1994

Post-translational processing of the neurotensin/neuromedin N precursor in the central nervous system of the rat--I. Biochemical characterization of maturation products.

Neurotensin and neuromedin N are two biologically active related peptides which are encoded in the same precursor molecule. In the rat, the precursor consists of a 169-residue polypeptide containing in its C-terminal region one copy each of neurotensin and neuromedin N. Four Lys-Arg sequences which are thought to represent putative processing sites occur in the precursor molecule. Of these sites, the three that are closest to the C-terminus flank and separate neurotensin and neuromedin N. The fourth precedes a neuromedin N-like sequence. The present studies were aimed at determining the extent to which each of these four dibasic sites is cleaved and at identifying and quantifying the intermediate and mature products to which this cleavage gives rise in extracts from whole rat brain, hippocampus and globus pallidus. This was achieved by means of radioimmunoassays specific for sequences of the neurotensin/neuromedin N precursor that are adjacent to the dibasic processing sites used in combination with high pressure liquid chromatography and arginine-directed trypsin digestion of tissue extracts. In all tissue extracts, it was found that the three most C-terminal dibasic processing sites in the neurotensin/neuromedin N precursor are processed to a similar extent, whereas the dibasic site that precedes the neuromedin N-like sequence is processed to a lesser extent. As reported previously, the globus pallidus was shown to contain proportionally lower levels of neuromedin N than other brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Post-translational processing of the neurotensin/neuromedin N precursor in the central nervous system of the rat--II. Immunohistochemical localization of maturation products.

The neurotensin/neuromedin N precursor molecule possesses four lysine-arginine dibasic residues which represent potential sites of cleavage by proteolytic maturation enzymes. As shown in the preceding paper, all of these dibasic residues are cleaved to a variable extent in rat brain. The aim of the present study was to localize immunohistochemically the resulting maturation products using site-specific antibodies directed against neurotensin, as well as against the exposed KLPLVL (K6L) and EKEEVI (E6I) sequences of the precursor. In a first set of experiments, each antigen was singly labelled in serial adjacent sections through the rat brain using a peroxidase-antiperoxidase technique. In a second series of experiments, neurotensin and either E61 or K6L antigens were double labelled in pairs using indirect immunofluorescence and visualized by confocal microscopy. In both types of preparations, immunoreactivity for all three antigens was detected in nerve cell bodies and axon terminals. In the absence of colchicine pretreatment, labelled nerve cell bodies were sparse in both neurotensin- and E6I-immunostained material and virtually undetectable in K6L-immunoreacted sections. By contrast, terminal immunostaining was intense and comparable in distribution for both neurotensin and E6I in most regions examined. K6L axonal labelling showed the same topographic pattern as that of E6I and neurotensin but was consistently weaker, except in the globus pallidus, where both E6I- and K6L-immunoreactive arbors were more widespread than those of neurotensin. These results suggest that the cleavage of the dibasic sites adjacent to the E6I and K6L sequences is more extensive in certain brain regions than in others. Colchicine pretreatment markedly increased the number of neurotensin- and, to a lesser extent. E6I-immunoreactive perikarya throughout the rat brain. However, it only marginally augmented the number of K6L-immunoreactive cell bodies, which remained sparse throughout. These results suggest that the maturation cleavages exposing the E6I and K6L sequences occur further distal to the cell body than the one giving rise to neurotensin. Both E6I- and K6L-immunoreactive perikarya were essentially confined to areas displaying neurotensin immunoreactivity. Furthermore, E6I and K6L antigens were shown in double labeling experiments to be present in the same cells as neurotensin, indicating that even if it is quantitatively different among brain regions, the basic pattern of neurotensin/neuromedin N precursor processing remains qualitatively similar throughout the brain.

Animals↗
PubMed1994

Synthesis of a biologically active fluorescent probe for labeling neurotensin receptors.

We synthesized a fluorescent derivative of the tridecapeptide neurotensin (NT), with the aim of providing a new tool for the pharmacological characterization and anatomic localization of NT receptors in mammalian brain. Fluoresceinylated NT (N alpha-fluoresceinyl thiocarbamyl (FTC)-[Glu1]NT; fluo-NT) was synthesized using solid-phase methodology and purified to 99% homogeneity by preparative high-pressure liquid chromatography (HPLC). Analytical HPLC, acidic and carboxypeptidase Y hydrolysis, and fast atom bombardment-mass spectroscopy confirmed that the purified compound was selectively labeled on the [Glu1] terminus and that a single FTC moiety was coupled to each molecule of [Glu1]NT. Flow cytometric analysis of the binding of fluo-NT to SN17 septal neuroblastoma cells indicated that the fluorescent derivative bound neural NT receptors with an affinity comparable to that of monoiodinated NT([125I]-NT). Competition experiments on mouse brain membrane preparations showed fluo-NT to inhibit specific [125I]-NT binding with a coefficient of inhibition (KI) virtually identical to that of the native peptide (0.67 vs 0.55 nM). Conventional epifluorescence and confocal microscopic analysis of specific fluo-NT binding to sections of the rat midbrain revealed a topographic distribution of the bound fluorescent ligand similar to that previously observed with autoradiography using [125I]-NT. However, fluo-NT provided markedly higher cell resolution and enabled, in particular, the detection of hitherto unnoted intracytoplasmic receptor clusters. Binding of fluo-NT to live SN17 hybrid cells indicated that the fluorescent ligand had retained its ability to internalize in vivo and confirmed that this internalization process was both time- and temperature-dependent. In sum, the present study demonstrates that fluo-NT is applicable to both the pharmacological study of NT binding sites using flow cytometry and to the regional and cellular localization of these sites by conventional epifluorescence and confocal microscopy.

Amino Acids↗
PubMed1994

Neurotensin promotes oscillatory bursting behavior and is internalized in basal forebrain cholinergic neurons.

Cholinergic neurons of the basal forebrain magnocellular complex (BF) constitute the primary source of ACh to the cerebral cortex and are thought to be instrumental in mediating cortical activation and plasticity. Recent light and electron microscopic studies have revealed a selective association of receptors for the neuropeptide neurotensin (NT) with BF cholinergic neurons, suggesting that this peptide may be playing a key role in the control of BF cholinergic function. In the present study, we have investigated by means of intracellular recording in guinea pig brain slices the neuromodulatory actions of NT on the intrinsic excitability of BF cholinergic neurons that were identified electrophysiologically by their low-threshold discharge, slow afterhyperpolarization, and transient outward rectification (TOR). In all cholinergic neurons tested (n = 39), bath application of NT (20-200 nM for 1-4 min) produced, via a direct mechanism, a membrane potential depolarization associated with a decrease in apparent input conductance. Most significantly, NT led to the emergence of a very prominent slow rhythmic bursting pattern that could shape into complex spindle-like sequences that were intrinsically generated by the cholinergic cells. These NT actions were also accompanied by a reduction of both the slow afterhyperpolarization and TOR. Bursting oscillations relied on the activation of Ca2+ conductances as opposed to Na+ conductances, since they were absent during Ca(2+)-conductance block with Mn2+, but still occurred in the presence of the Na(+)-channel blocker TTX. NT actions were specific, since they could be reproduced by application of the active (NT 8-13) but not of the inactive (NT 1-8) fragment of the peptide. Identification of the BF cholinergic neurons as direct NT targets was further provided by confocal laser scanning microscopic demonstration of internalization of a fluoresceinylated derivative of NT (fluo-NT) within biocytin-filled, electrophysiologically identified cholinergic neurons. The results demonstrate the electrophysiological functionality of NT receptors on BF cholinergic neurons and the existence of a receptor-mediated internalization of NT in these cells. They also suggest that the peptide is an important player in the control of BF function and, in particular, in the generation of forebrain network oscillations.

Acetylcholine↗
PubMed1993

[125I]azido-DTLET as a tool for selective covalent labeling of delta-opioid receptors in rat brain sections.

The binding kinetics and pharmacological selectivity of the photoaffinity delta-opioid ligand [125I]azido-DTLET (Tyr-D-Thr-Gly-Phe(pN3)-Leu-Thr) were investigated in serial frozen sections from rat neostriatum prior to ultraviolet irradiation (i.e., in conditions of reversibility). Scatchard analysis of saturation binding experiments indicated that [125I]azido-DTLET binds to both a high (KD = 5.04 nM) and a low (KD = 38 nM) affinity site. Binding to the low-affinity site was no longer detectable in the presence of unlabeled [D-Ala2,N-MePhe4,Gly-Ol5]enkephalin (DAGO), suggesting that this site corresponds to mu-opioid receptors. This interpretation was further supported by the dose-dependent inhibition of the binding of [3H]DAGO by non-radioactive azido-DTLET. Binding to the high-affinity site was totally inhibited, in a dose-dependent fashion, by a variety of opioid drugs among which delta-opioid ligands showed the highest order of potency. It is concluded that, in the nanomolar range, [125I]azido-DTLET constitutes a highly selective tool for covalent labeling of delta-opioid receptors in rat brain sections.

Affinity Labels↗
PubMed1993

Short- and long-term effects of nucleus basalis magnocellularis lesions on cortical levels of somatostatin and its receptors in the rat.

Cognitive and histological alterations in human Alzheimer's disease (AD) are correlated with selective neuronal loss in nucleus basalis of Meynert. In search of an animal model of AD-linked neurochemical deficits, we examined the effects of short- (2 weeks) and long- (3 and 6 months) term lesions of the nucleus basalis magnocellularis (NBM) on somatostatinergic parameters in rat forebrain. NBM lesions were performed by unilateral injection of ibotenic acid into the NBM. Cortical choline-acetyl transferase (ChAT) activity and acetylcholinesterase staining in the NBM remained significantly decreased ipsi- as compared to contralaterally up to 6 months after the placement of the lesion. Somatostatin (SRIF) content was increased by 120% in the ipsilateral frontal cortex 6 months post-lesion but not at shorter time intervals. Levels of neuropeptide Y (which is extensively co-localized with SRIF in the forebrain) were not significantly altered after unilateral NBM lesions at any time point. A 30% decrease in SRIF binding capacity as well as a marked reduction of SRIF inhibition of adenylate cyclase, indicative of a loss of functional SRIF receptors, was observed in ipsilateral versus contralateral frontal cortex on brain tissue homogenates after short-term unilateral NBM lesion. By film radioautography, the loss in SRIF binding sites was localized to both superficial and deep layers of the frontal cortex. This loss persisted up to 3 months but was no longer apparent after 6 months due to a decrease in SRIF binding capacity on the contralateral side.

Adenylyl Cyclase Inhibitors↗
PubMed1993

Ultrastructural localization of neurotensin immunoreactivity in the stellate ganglion of the cat.

The morphological features and cellular relationships of neurotensin-containing axon terminals were studied at light and electron microscopic levels in the cat stellate ganglion using peroxidase and immunogold immunocytochemistry. By light microscopy, neurotensin immunoreactivity was detected within thin varicose fibres distributed throughout the ganglion. Immunoreactive fibres were no longer apparent following chronic deafferentation of the ganglion indicating that they were of extrinsic origin. Ultrastructural analysis of peroxidase immunostained material confirmed the presence of neurotensin immunoreactivity within a subpopulation of axonal varicosities which made synaptic contacts with the dendrites of ganglion cells. Within labelled varicosities neurotensin immunoreactivity was found by both immunoperoxidase and immunogold methods to be concentrated within large dense core vesicles 80-120 nm in diameter. These large dense core vesicles were characteristically distant from the active zone, in keeping with a possible extrasynaptic release of the peptide.

Animals↗
PubMed1993

Pathologic effect of estradiol on the hypothalamus.

Estradiol provides physiological signals to the brain throughout life that are indispensable for the development and regulation of reproductive function. In addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major component.

Animals↗