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Biological Psychiatry Sep 1991The relationship of plasma free homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) to early clinical response was prospectively studied in a new series of...
The relationship of plasma free homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) to early clinical response was prospectively studied in a new series of acutely psychotic inpatients given a fixed dose of perphenazine elixir for 10 days. Elevated pretreatment plasma HVA but not MHPG was significantly associated with good response. Change in HVA was correlated with a favorable response and a significant decline in MHPG was found in responders. Results suggest that HVA can provide a useful clinical predictor of response, and that both dopamine metabolism and noradrenergic functioning, as measured by plasma HVA and MHPG, are reduced in effective neuroleptic treatment.
Topics: Acute Disease; Adolescent; Adult; Bipolar Disorder; Chromatography, High Pressure Liquid; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Homovanillic Acid; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Perphenazine; Prognosis; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology
PubMed: 1932395
DOI: 10.1016/0006-3223(91)90309-a -
Disease Models & Mechanisms Jul 2013Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope...
Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.
Topics: Animals; Baroreflex; Behavior, Animal; Biological Transport; Catecholamines; Disease Models, Animal; Female; Gene Knock-In Techniques; Humans; Methoxyhydroxyphenylglycol; Mice; Mutant Proteins; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Postural Orthostatic Tachycardia Syndrome; Telemetry
PubMed: 23580201
DOI: 10.1242/dmm.012203 -
The Journal of Cardiovascular Nursing 2019Clinical response to left ventricular assist devices (LVADs), as measured by health-related quality of life, varies among patients after implantation; however, it is... (Comparative Study)
Comparative Study
BACKGROUND
Clinical response to left ventricular assist devices (LVADs), as measured by health-related quality of life, varies among patients after implantation; however, it is unknown which pathophysiological mechanisms underlie differences in clinical response by health-related quality of life.
OBJECTIVE
The purpose of this study was to compare changes in sympathetic markers (β-adrenergic receptor kinase-1 [βARK1], norepinephrine [NE], and 3,4-dihydroxyphenylglycol [DHPG]) between health-related quality of life clinical responders and nonresponders from pre- to post-LVAD implantation.
METHODS
We performed a secondary analysis on a subset of data from a cohort study of patients from pre- to 1, 3, and 6 months after LVAD implantation. Clinical response was defined as an increase of 5 points or higher on the Kansas City Cardiomyopathy Questionnaire Clinical Summary score from pre- to 6 months post-LVAD implantation. We measured plasma βARK1 level with an enzyme-linked immunosorbent assay and plasma NE and DHPG levels with high-performance liquid chromatography with electrochemical detection. Latent growth curve modeling was used to compare the trajectories of markers between groups.
RESULTS
The mean (SD) age of the sample (n = 39) was 52.9 (13.2) years, and most were male (74.4%) and received LVADs as bridge to transplantation (69.2%). Preimplantation plasma βARK1 levels were significantly higher in clinical responders (n = 19) than in nonresponders (n = 20) (P = .001), but change was similar after LVAD (P = .235). Preimplantation plasma DHPG levels were significantly lower in clinical responders than in nonresponders (P = .002), but the change was similar after LVAD (P = .881). There were no significant differences in plasma NE levels.
CONCLUSIONS
Preimplantation βARK1 and DHPG levels are differentiating factors between health-related quality of life clinical responders and nonresponders to LVAD, potentially signaling differing levels of sympathetic stimulation underlying clinical response.
Topics: Adult; Aged; Biomarkers; Cohort Studies; Female; G-Protein-Coupled Receptor Kinase 2; Heart-Assist Devices; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Quality of Life; Sympathetic Nervous System; Treatment Outcome
PubMed: 31094762
DOI: 10.1097/JCN.0000000000000580 -
American Journal of Physiology.... Aug 2000Endothelin (ET)-1 is a 21-amino acid peptide that induces a variety of biological activities, including vasoconstriction and cell proliferation, and its likely...
Endothelin (ET)-1 is a 21-amino acid peptide that induces a variety of biological activities, including vasoconstriction and cell proliferation, and its likely involvement in cardiovascular and other diseases has recently led to broad clinical trials of ET receptor antagonists. ET-1 is widely distributed in the central nervous system (CNS), where it is thought to regulate hormone and neurotransmitter release. Here we show that CNS responses to emotional and physical stressors are differentially affected in heterozygous ET-1-knockout mice, which exhibited diminished aggressive and autonomic responses toward intruders (emotional stressors) but responded to restraint-induced (physical) stress more intensely than wild-type mice. This suggests differing roles of ET-1 in the central pathways mediating responses to different types of stress. Hypothalamic levels of ET-1 and the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were both increased in wild-type mice subjected to intruder stress, whereas MHPG levels were not significantly affected in ET-1-knockout mice. Furthermore, immunohistochemical analysis showed that ET-1 and tyrosine hydroxylase, an enzyme in the catecholamine synthesis pathway, were colocalized within certain neurons of the hypothalamus and amygdala. Our findings suggest that ET-1 modulates central coordination of stress responses in close association with catecholamine metabolism.
Topics: Animals; Brain; Catecholamines; Endothelin-1; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Reference Values; Stress, Physiological
PubMed: 10938240
DOI: 10.1152/ajpregu.2000.279.2.R515 -
The Journal of Neuroscience : the... Mar 2013Cajal-Retzius cells are a class of neurons believed to play critical roles during cortical development. However, their network computational functions remain poorly...
Cajal-Retzius cells are a class of neurons believed to play critical roles during cortical development. However, their network computational functions remain poorly understood. Although work in the neocortex and hippocampus has shown that Cajal-Retzius cells receive predominantly, if not exclusively, spontaneous GABA(A) receptor-mediated input, the cellular sources originating these events remain unclear. However, a precise definition of the presynaptic GABAergic interneurons contacting Cajal-Retzius cells is important to understand the microcircuits and network patterns controlling their activation. Here, we have taken advantage of electrophysiological and anatomical techniques applied to mouse hippocampal slices in vitro to directly address this question. Our paired recording experiments indicate that Cajal-Retzius cells receive small-amplitude, kinetically slow synaptic input from stratum lacunosum-moleculare interneurons, anatomically identified as neurogliaform cells. In addition, a convergence of optogenetic, electrophysiological, and pharmacological experiments shows that Cajal-Retzius cells receive GABAergic input from oriens lacunosum-moleculare cells and that this input has different physiological properties (i.e., larger amplitude and faster kinetics) from the one provided by neurogliaform cells. Last, we show that GABAergic evoked synaptic input onto Cajal-Retzius cells may either increase their excitability and trigger action potentials or inhibit spontaneous firing by depolarization block. We propose that the specific type of response depends on both the membrane potential of Cajal-Retzius cells and the kinetics of the received GABAergic input. In conclusion, we have unraveled a novel hippocampal microcircuit with complex GABAergic synaptic signaling, which we suggest may play a role in the refinement of the hippocampal network and connections during development.
Topics: Age Factors; Animals; Animals, Newborn; Biophysics; Channelrhodopsins; Electric Stimulation; Excitatory Amino Acid Antagonists; Female; GABA Antagonists; Green Fluorescent Proteins; Hippocampus; In Vitro Techniques; Interneurons; Light; Male; Membrane Potentials; Methoxyhydroxyphenylglycol; Mice; Mice, Transgenic; Mutation; Nerve Net; Neural Inhibition; Optogenetics; Patch-Clamp Techniques; Proteins; Pyridazines; Quinoxalines; RNA, Untranslated; Receptors, CXCR4; Sodium Channel Blockers; Somatostatin; Synaptic Potentials; Tetrodotoxin; Valine; gamma-Aminobutyric Acid
PubMed: 23536064
DOI: 10.1523/JNEUROSCI.5680-12.2013 -
Journal of Neurochemistry May 2009Glutamate (Glu) is the major excitatory transmitter in the vertebrate brain. Ligand-gated and G protein-coupled Glu receptors present in glial cells are presumably...
UNLABELLED
Glutamate (Glu) is the major excitatory transmitter in the vertebrate brain. Ligand-gated and G protein-coupled Glu receptors present in glial cells are presumably involved in neuronal function. Activation of Bergmann glial Glu receptors triggers a membrane to nuclei signaling cascade that regulates gene expression at the transcriptional and translational levels. Sry-related high-mobility group box (Sox10), a member of the conserved high-mobility group box transcription factor family is expressed in neural crest stem cells and in a subset of neural crest-derived lineages that include glial, but not neuronal cells. To gain insight into the role of Sox10 in Bergmann glial cells, we explored its expression and regulation. We demonstrate herein that Sox10 is expressed in Bergmann glial cells and that its DNA binding activity, mRNA, and protein levels as well as its transcriptional behavior augments upon the activation of metabotropic Glu receptors. Increase in Sox10-DNA complexes and Sox10 mRNA and protein levels were found upon exposure to Glu. Over-expression of Sox10 leads to transcriptional repression in reporter gene assays and in one of its target genes: the chick kainate binding protein gene. These findings add a new perspective into glial glutamatergic signaling and suggest the participation of Sox10 in cerebellar glutamatergic transactions.
KEYWORDS
Bergmann glial cells, glutamate, metabotropic glutamate receptors, signaling, Sox10, transcriptional control.
Topics: Analysis of Variance; Animals; Basic Helix-Loop-Helix Transcription Factors; Cells, Cultured; Cerebellum; Chick Embryo; Chromones; Electrophoretic Mobility Shift Assay; Gene Expression; Gene Expression Regulation, Developmental; Glutamic Acid; Methoxyhydroxyphenylglycol; Neuroglia; RNA, Messenger; SOXE Transcription Factors; Serpins; Time Factors; Transfection
PubMed: 19425178
DOI: 10.1111/j.1471-4159.2009.06017.x -
Parkinsonism & Related Disorders Feb 2009Diseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac...
BACKGROUND
Diseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac sympathetic denervation, as reflected by low myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity. We studied the impact of such denervation on cardiac chronotropic and inotropic function.
METHODS
Cardiac inotropic function was assessed by the pre-ejection period index and the systolic time ratio index in response to the directly acting beta-adrenoceptor agonist, isoproterenol, and to the indirectly acting sympathomimetic amine, tyramine, in patients with PD+NOH or PAF (PD+NOH/PAF group, N=13). We compared the results to those in patients with multiple system atrophy, which usually entails NOH with normal cardiac sympathetic innervation (MSA, N=15), and in normal control subjects (N=5).
RESULTS
The innervated and denervated groups did not differ in baseline mean pre-ejection period index or systolic time ratio index. Tyramine increased cardiac contractility in the MSA patients and controls but not in the PD+NOH/PAF group. For similar heart rate responses, the PD+NOH/PAF group required less isoproterenol (p<0.01) and had lower plasma isoproterenol levels (p<0.01) than did the MSA group.
CONCLUSIONS
Among patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol. This pattern suggests that cardiac denervation is associated with decreased ability to release endogenous norepinephrine from sympathetic nerves and with supersensitivity of cardiac beta-adrenoreceptors.
Topics: Adrenergic beta-Agonists; Aged; Autonomic Nervous System Diseases; Blood Pressure; Dopamine; Female; Heart; Hemodynamics; Humans; Hypotension, Orthostatic; Isoproterenol; Male; Methoxyhydroxyphenylglycol; Norepinephrine; Parkinson Disease; Radionuclide Imaging; Statistics, Nonparametric; Sympathectomy; Sympathomimetics; Tyramine
PubMed: 18514012
DOI: 10.1016/j.parkreldis.2008.04.002 -
Brain Research Oct 2015Metabotropic and ionotropic glutamate receptors are closely clustered in postsynaptic membranes and are believed to interact actively with each other to control...
Metabotropic and ionotropic glutamate receptors are closely clustered in postsynaptic membranes and are believed to interact actively with each other to control excitatory synaptic transmission. Metabotropic glutamate receptor 5 (mGluR5), for example, has been well documented to potentiate ionotropic NMDA receptor activity, although underlying mechanisms are poorly understood. In this study, we investigated the role of mGluR5 in regulating trafficking and subcellular distribution of NMDA receptors in adult rat striatal neurons. We found that the mGluR1/5 agonist DHPG concentration-dependently increased NMDA receptor GluN1 and GluN2B subunit expression in the surface membrane. Meanwhile, DHPG reduced GluN1 and GluN2B levels in the intracellular compartment. The effect of DHPG was blocked by an mGluR5 selective antagonist MTEP but not by an mGluR1 selective antagonist 3-MATIDA. Pretreatment with an inhibitor or a specific inhibitory peptide for synapse-enriched Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) also blocked the DHPG-stimulated redistribution of GluN1 and GluN2B. In addition, DHPG enhanced CaMKIIα activity and elevated GluN2B phosphorylation at a CaMKII-sensitive site (serine 1303). These results demonstrate that mGluR5 regulates trafficking of NMDA receptors in striatal neurons. Activation of mGluR5 appears to induce rapid trafficking of GluN1 and GluN2B to surface membranes through a signaling pathway involving CaMKII.
Topics: Analysis of Variance; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Corpus Striatum; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Agents; Gene Expression; In Vitro Techniques; Male; Methoxyhydroxyphenylglycol; Neurons; Phosphorylation; Pyridines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, N-Methyl-D-Aspartate; Thiazoles
PubMed: 26256252
DOI: 10.1016/j.brainres.2015.07.053 -
Journal of Nutritional Science and... 2018The effect of soy and casein peptide intake on the metabolism of amino acids and monoamine neurotransmitters in the serum and brain were examined in C57BL/6 mice. Acute... (Comparative Study)
Comparative Study
The effect of soy and casein peptide intake on the metabolism of amino acids and monoamine neurotransmitters in the serum and brain were examined in C57BL/6 mice. Acute oral administration of soy peptide (0.026 g/30 g body weight) caused a notable increase in tyrosine, a catecholamine precursor, in the serum and cerebral cortex, whereas casein peptide administration at the same dose led to an increase in tyrosine in the serum, but not in the cerebral cortex. In addition to tyrosine, soy peptide administration also led to an effective augmentation of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), a principal metabolite of noradrenaline, and significant facilitation of noradrenergic turnover in the cerebral cortex, brainstem, and hippocampus compared to the vehicle control. Casein peptide administration also led to an increase in MHPG only in the cerebral cortex, and caused facilitation of noradrenergic turnover in the cerebral cortex and brainstem. These in vivo observations suggest that both soy and casein peptide intake at this concentration can lead to an increased availability of tyrosine and stimulation of noradrenergic turnover in the brain.
Topics: Animals; Brain; Brain Stem; Caseins; Catecholamines; Cerebral Cortex; Hippocampus; Male; Methoxyhydroxyphenylglycol; Mice, Inbred C57BL; Neurotransmitter Agents; Norepinephrine; Peptides; Soybean Proteins; Tyrosine
PubMed: 30381622
DOI: 10.3177/jnsv.64.329 -
International Journal of Molecular... Jan 2022Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the...
Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the β-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play a critical pathogenetic role in MS. CD4 T cells obtained from twenty-five relapsing-remitting MS patients and sixteen healthy subjects were cultured ex vivo with norepinephrine and/or β-adrenoreceptor antagonist or agonist, followed by a cytokine production analysis using ELISA. Norepinephrine suppressed IL-17 and IFN-γ production by the anti-CD3/anti-CD28-microbead-stimulated CD4 T cells in both groups. Blockade of the β-adrenoreceptor with the specific antagonist ICI 118.551 enhanced norepinephrine-mediated IL-17 suppression but decreased its inhibitory effect on IFN-γ production in MS patients. In contrast, the β-adrenoreceptor agonist formoterol did not influence norepinephrine's inhibitory effect on cytokine production in both groups. The blockade of the β-adrenoreceptor, even in the absence of exogenous norepinephrine, suppressed IL-17 production but did not influence IFN-γ production in both groups. Conversely, β-adrenoreceptor activation by formoterol decreased IFN-γ production and did not affect IL-17 production in both groups. These data illustrate the inhibitory effect of norepinephrine on IL-17 and IFN-γ production by CD4 T cells in MS. The inhibitory effect of norepinephrine on IFN-γ production by CD4 T cells in MS could be mediated via β-adrenoreceptor activation.
Topics: Adult; CD4-Positive T-Lymphocytes; Case-Control Studies; Cytokines; Epinephrine; Female; Humans; Interferon-gamma; Interleukin-17; Male; Methoxyhydroxyphenylglycol; Multiple Sclerosis; Norepinephrine; Receptors, Adrenergic, beta-2; T-Lymphocytes
PubMed: 35054851
DOI: 10.3390/ijms23020668