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Neuropsychopharmacology : Official... Sep 2015Midbrain dopamine neurons are important mediators of reward and movement and are sensitive to cocaine-induced plasticity. After even a single injection of cocaine, there...
Midbrain dopamine neurons are important mediators of reward and movement and are sensitive to cocaine-induced plasticity. After even a single injection of cocaine, there is an increase in AMPA-dependent synaptic transmission. The present study examines cocaine-induced plasticity of mGluR-dependent currents in dopamine neurons in the substantia nigra. Activation of mGluR1 and mGluR5 resulted in a mixture of inward and outward currents mediated by a nonselective cation conductance and a calcium-activated potassium conductance (SK), respectively. A single injection of cocaine decreased the current activated by mGluR1 in dopamine neurons, and it had no effect on the size of the mGluR5-mediated current. When the injection of cocaine was preceded by treatment of the animals with a blocker of mGluR5 receptors (MPEP), cocaine no longer decreased the mGluR1 current. Thus, the activation of mGluR5 was required for the cocaine-mediated suppression of mGluR1-mediated currents in dopamine neurons. The results support the hypothesis that mGluR5 coordinates a reduction in mGluR1 functional activity after cocaine treatment.
Topics: Action Potentials; Animals; Cocaine; Dopamine Uptake Inhibitors; Dopaminergic Neurons; Excitatory Amino Acid Agents; Female; In Vitro Techniques; Iontophoresis; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Potassium Channel Blockers; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Small-Conductance Calcium-Activated Potassium Channels; Substantia Nigra
PubMed: 25829143
DOI: 10.1038/npp.2015.91 -
Biological Psychiatry Dec 1992The syndrome of chronic fatigue, feverishness, diffuse pains, and other constitutional complaints, often precipitated by an acute infectious illness and aggravated by...
The syndrome of chronic fatigue, feverishness, diffuse pains, and other constitutional complaints, often precipitated by an acute infectious illness and aggravated by physical and emotional stressors, has a lengthy history in the medical literature. The Centers for Disease Control (CDC) recently formulated a case definition, renaming the illness "chronic fatigue syndrome." Nevertheless, there remain few biological data that can validate the existence of this syndrome as distinct from a wide variety of other, largely psychiatric disorders, and little understanding of its pathogenesis. In the present study, basal plasma and cerebrospinal fluid levels of the monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) were determined in 19 patients meeting CDC research case criteria for chronic fatigue syndrome and in 17 normal individuals. Patients with chronic fatigue syndrome showed a significant reduction in basal plasma levels of MHPG and a significant increase in basal plasma levels of 5-HIAA. Although the functional significance of these findings has not been definitively elucidated, they are compatible with the clinical presentation of a syndrome associated with chronic lethargy and fatigue, and with evidence of persistent immune stimulation, and lend support to the idea that chronic fatigue syndrome represents a clinical entity with potential biological specificity.
Topics: Adult; Anxiety Disorders; Blood-Brain Barrier; Cohort Studies; Depressive Disorder; Fatigue Syndrome, Chronic; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Somatoform Disorders
PubMed: 1282370
DOI: 10.1016/0006-3223(92)90187-5 -
British Journal of Pharmacology Mar 19891. A novel method for measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by use of high performance liquid chromatography (h.p.l.c.) with...
Measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by h.p.l.c. with electrochemical detection, as an index of noradrenaline utilisation and presynaptic alpha 2-adrenoceptor function.
1. A novel method for measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by use of high performance liquid chromatography (h.p.l.c.) with electrochemical detection is described. This technique incorporates an ethyl acetate purification procedure and uses 3-hydroxy-4-methoxyphenylglycol (iso-MHPG) as the internal standard. 2. Inhibition of monoamine oxidase by injection of tranylcypromine (5 and 10 mg kg-1) or pargyline (50 and 100 mg kg-1) markedly decreased brain MHPG concentrations. After injection of the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine (200 mg kg-1), there were time-dependent linear decreases in the concentrations of noradrenaline and MHPG in mouse brain. In addition, a very good correlation (r = 0.95, n = 30; P less than 0.001) was found between the concentrations of noradrenaline and MHPG present in the brains of the same mice after alpha-methyl-p-tyrosine treatment. 3. Mouse brain MHPG concentrations were dose-dependently reduced after administration of the alpha 2-adrenoceptor agonist, clonidine (1-3000 micrograms kg-1), and elevated by the antagonists, idazoxan (1 and 5 mg kg-1), and yohimbine (1 and 5 mg kg-1). Intracerebroventricular injection of the alpha 1-adrenoceptor agonist, phenylephrine (5-50 micrograms) dose-dependently increased MHPG levels. The alpha 1-adrenoceptor antagonist, prazosin, had no effect at the moderate dose of 1 mg kg-1, but increased MHPG concentrations at 5 mg kg-1. The beta-adrenoceptor agonist, clenbuterol (10-1000 micrograms kg-1) and the antagonist, pindolol (1 and 5 mg kg-1), were both without effect. 4. The decrease in brain MHPG concentrations induced by clonidine (100 micrograms kg-1) was prevented by prior injection of 1 mg kg-1 of idazoxan or yohimbine, but not by prazosin or pindolol. 5. MHPG levels were decreased after administration of the noradrenaline reuptake inhibitor desipramine (5 and 10 mg kg-1) and the non-selective monoamine reuptake inhibitors, sibutramine HCl (BTS 54 524; 1 and 3 mg kg-1) and amitryptyline (5 mg kg-1). However, the selective 5-hydroxytryptamine reuptake inhibitor, zimeldine (5 and 10 mg kg-1), was without effect. Dexamphetamine (1 and 5 mg kg-1) and methamphetamine (1 and 5 mg kg-1) both decreased brain MHPG concentrations in a dose-related fashion. 6. Overall the data show that MHPG can be used as a functional index of both presynaptic alpha 2-adrenoceptor activity and noradrenaline turnover and utilisation.
Topics: Animals; Brain Chemistry; Chromatography, High Pressure Liquid; Clonidine; Dextroamphetamine; Electrochemistry; Glycols; In Vitro Techniques; Indicators and Reagents; Methamphetamine; Methoxyhydroxyphenylglycol; Methyltyrosines; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors; Norepinephrine; Receptors, Adrenergic, alpha; alpha-Methyltyrosine
PubMed: 2541844
DOI: 10.1111/j.1476-5381.1989.tb11852.x -
Journal of Neurophysiology Jul 2010Recent biochemical and behavioral data implicate reactive oxygen species (ROS) in peripheral and spinal pain mechanisms. However, pain-related functions of ROS in the...
Recent biochemical and behavioral data implicate reactive oxygen species (ROS) in peripheral and spinal pain mechanisms. However, pain-related functions of ROS in the brain and mechanisms of pain-related ROS activation remain to be determined. Our previous studies showed that the amygdala plays a key role in emotional-affective pain responses and pain modulation. Hyperactivity of amygdala neurons in an animal pain model depends on group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5), but their signaling pathway remains to be determined. Here we tested the hypothesis that activation of group I mGluRs increases nociceptive processing in amygdala neurons through a mechanism that involves ROS. Extracellular single-unit recordings were made from neurons in the laterocapsular division of the central nucleus of the amygdala (CeLC) in anesthetized adult male rats. Administration of a group I mGluR agonist (DHPG) into the CeLC by microdialysis increased the responses to innocuous and noxious somatosensory (knee joint compression) and visceral (colorectal distention [CRD]) stimuli. A ROS scavenger (PBN) and a superoxide dismutase mimetic (TEMPOL) reversed the facilitatory effects of DHPG. An mGluR5 antagonist (MPEP) also inhibited the effects of DHPG on the responses to innocuous and noxious somatosensory and visceral stimuli, whereas an mGluR1 antagonist (LY367385) decreased only the responses to visceral stimulation. The results show for the first time that ROS mediate group I mGluR-induced facilitation of nociceptive processing in amygdala neurons. The antagonist data may suggest differential contributions of subtypes mGluR1 and mGluR5 to the processing of somatosensory and visceral nociceptive information in the amygdala.
Topics: Amygdala; Animals; Colon; Cyclic N-Oxides; Electrophysiological Phenomena; Free Radical Scavengers; Hindlimb; Joints; Male; Methoxyhydroxyphenylglycol; Microdialysis; Neurons; Nitric Oxide; Nociceptors; Pain; Patch-Clamp Techniques; Physical Stimulation; Protein Kinase C; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Metabotropic Glutamate; Rectum; Spin Labels
PubMed: 20463194
DOI: 10.1152/jn.00223.2010 -
Psychoneuroendocrinology Aug 2007Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and...
Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and investigate whether novelty seeking behavior is associated with differences in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the dopamine metabolite homovanillic acid (HVA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the neuropeptide corticotrophin-releasing factor (CRF). Monkeys were randomized early in life to either mild intermittent stress (IS) or no stress (NS) conditions, and subsequently presented with opportunities to interact with a familiar or novel object in a test box that was connected to each monkey's home cage. To further minimize the potentially stressful nature of the test situation, monkeys were acclimated to the test procedures prior to study initiation. Post-test plasma levels of cortisol in IS and NS monkeys did not differ significantly from baseline levels measured in undisturbed conditions. During testing, more IS than NS monkeys voluntarily left the home cage, and IS monkeys spent more time in the test box compared to NS monkeys. More IS than NS monkeys engaged in object exploration in the test box, and IS monkeys preferred to interact with the novel vs. familiar object. Novelty seeking was not associated with differences in 5HIAA, HVA, MHPG, or CRF, but correlated with differences in object exploration observed in a different test situation at an earlier age. These trait-like differences in novelty seeking appear to reflect mild early stress-induced adaptations that enhance curiosity and resilience.
Topics: Animals; Corticotropin-Releasing Hormone; Data Interpretation, Statistical; Exploratory Behavior; Homovanillic Acid; Hydroxyindoleacetic Acid; Individuality; Methoxyhydroxyphenylglycol; Saimiri; Stress, Psychological
PubMed: 17604913
DOI: 10.1016/j.psyneuen.2007.05.008 -
The Journal of Neuroscience : the... Mar 2005Ca2+ signals in neurons use specific temporal and spatial patterns to encode unambiguous information about crucial cellular functions. To understand the molecular basis... (Comparative Study)
Comparative Study
Ca2+ signals in neurons use specific temporal and spatial patterns to encode unambiguous information about crucial cellular functions. To understand the molecular basis for initiation and propagation of inositol 1,4,5-trisphosphate (InsP3)-mediated intracellular Ca2+ signals, we correlated the subcellular distribution of components of the InsP3 pathway with measurements of agonist-induced intracellular Ca2+ transients in cultured rat hippocampal neurons and pheochromocytoma cells. We found specialized domains with high levels of phosphatidylinositol-4-phosphate kinase (PIPKI) and chromogranin B (CGB), proteins acting synergistically to increase InsP3 receptor (InsP3R) activity and sensitivity. In contrast, Ca2+ pumps in the plasma membrane (PMCA) and sarco-endoplasmic reticulum as well as buffers that antagonize the rise in intracellular Ca2+ were distributed uniformly. By pharmacologically blocking phosphatidylinositol-4-kinase and PIPKI or disrupting the CGB-InsP3R interaction by transfecting an interfering polypeptide fragment, we produced major changes in the initiation site and kinetics of the Ca2+ signal. This study shows that a limited number of proteins can reassemble to form unique, spatially restricted signaling domains to generate distinctive signals in different regions of the same neuron. The finding that the subcellular location of initiation sites and protein microdomains was cell type specific will help to establish differences in spatiotemporal Ca2+ signaling in different types of neurons.
Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Calcium-Transporting ATPases; Carbachol; Cation Transport Proteins; Cells, Cultured; Cholinergic Agonists; Dose-Response Relationship, Drug; Drug Interactions; Embryo, Mammalian; Endoplasmic Reticulum; Enzyme Inhibitors; Hippocampus; Immunohistochemistry; Inositol 1,4,5-Trisphosphate Receptors; Intracellular Space; Methoxyhydroxyphenylglycol; Mitochondria; Nerve Growth Factor; Neurons; Parvalbumins; Peptide Fragments; Plasma Membrane Calcium-Transporting ATPases; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Metabotropic Glutamate; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Time Factors; Transfection
PubMed: 15772345
DOI: 10.1523/JNEUROSCI.4313-04.2005 -
Biological Psychiatry Mar 2000Consistent with many studies demonstrating enhanced reactivity of the sympathetic nervous system in posttraumatic stress disorder (PTSD), the administration of...
BACKGROUND
Consistent with many studies demonstrating enhanced reactivity of the sympathetic nervous system in posttraumatic stress disorder (PTSD), the administration of yohimbine, a noradrenergic alpha(2)-antagonist, has been shown to increase core symptoms of PTSD and to induce greater increases in plasma 3-methyl-4-hydroxy-phenyl-glycol (MHPG) in subjects with PTSD compared with healthy control subjects. In turn, neuropeptide Y (NPY) has been shown to inhibit the release of norepinephrine from sympathetic noradrenergic neurons.
METHODS
In the following study, plasma NPY responses to yohimbine and placebo were measured in a subgroup of 18 subjects with PTSD and 8 healthy control subjects who participated in the previous study of the effect of yohimbine on plasma MHPG.
RESULTS
The PTSD subjects had lower baseline plasma NPY and blunted yohimbine-stimulated increases in plasma NPY compared with the healthy control subjects. Within the PTSD group, baseline plasma NPY levels correlated negatively with combat exposure scale scores, baseline PTSD and panic symptoms, and yohimbine-stimulated increases in MHPG and systolic blood pressure.
CONCLUSIONS
This study suggests that combat stress-induced decreases in plasma NPY may mediate, in part, the noradrenergic system hyperreactivity observed in combat-related PTSD. The persistence of this decrease in plasma NPY may contribute to symptoms of hyperarousal and the expression of exaggerated alarm reactions, anxiety reactions, or both in combat veterans with PTSD long after war.
Topics: Adrenergic alpha-Antagonists; Adult; Blood Pressure; Heart Rate; Humans; Male; Methoxyhydroxyphenylglycol; Neuropeptide Y; Panic Disorder; Psychiatric Status Rating Scales; Severity of Illness Index; Stress Disorders, Post-Traumatic; Warfare; Yohimbine
PubMed: 10715359
DOI: 10.1016/s0006-3223(99)00185-7 -
Proceedings of the National Academy of... Sep 2001Cyclin-dependent kinase 5 (Cdk5) is a multifunctional neuronal protein kinase that is required for neurite outgrowth and cortical lamination and that plays an important...
Cyclin-dependent kinase 5 (Cdk5) is a multifunctional neuronal protein kinase that is required for neurite outgrowth and cortical lamination and that plays an important role in dopaminergic signaling in the neostriatum through phosphorylation of Thr-75 of DARPP-32 (dopamine and cAMP-regulated phosphoprotein, molecular mass 32 kDa). Casein kinase 1 (CK1) has been implicated in a variety of cellular functions such as DNA repair, circadian rhythm, and intracellular trafficking. In the neostriatum, CK1 has been found to phosphorylate Ser-137 of DARPP-32. However, first messengers for the regulation of Cdk5 or CK1 have remained unknown. Here we report that both Cdk5 and CK1 are regulated by metabotropic glutamate receptors (mGluRs) in neostriatal neurons. (S)-3,5-dihydroxyphenylglycine (DHPG), an agonist for group I mGluRs, increased Cdk5 and CK1 activities in neostriatal slices, leading to the enhanced phosphorylation of Thr-75 and Ser-137 of DARPP-32, respectively. The effect of DHPG on Thr-75, but not on Ser-137, was blocked by a Cdk5-specific inhibitor, butyrolactone. In contrast, the effects of DHPG on both Thr-75 and Ser-137 were blocked by CK1-7 and IC261, specific inhibitors of CK1, suggesting that activation of Cdk5 by mGluRs requires CK1 activity. In support of this possibility, the DHPG-induced increase in Cdk5 activity, measured in extracts of neostriatal slices, was abolished by CK1-7 and IC261. Treatment of acutely dissociated neurons with DHPG enhanced voltage-dependent Ca(2+) currents. This enhancement was eliminated by either butyrolactone or CK1-7 and was absent in DARPP-32 knockout mice. Together these results indicate that a CK1-Cdk5-DARPP-32 cascade may be involved in the regulation by mGluR agonists of Ca(2+) channels.
Topics: Animals; Calcium Channels; Casein Kinases; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases; Dopamine and cAMP-Regulated Phosphoprotein 32; Enzyme Inhibitors; In Vitro Techniques; Kinetics; Male; Membrane Potentials; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Neostriatum; Nerve Tissue Proteins; Neurons; Patch-Clamp Techniques; Phosphoproteins; Phosphorylation; Phosphoserine; Phosphothreonine; Protein Kinases; Receptors, Metabotropic Glutamate
PubMed: 11572969
DOI: 10.1073/pnas.191353898 -
Journal of Neurophysiology Jan 2004The laterocapsular division of the central nucleus of the amygdala (CeA) is now defined as the "nociceptive amygdala" because of its high content of neurons that respond... (Comparative Study)
Comparative Study
The laterocapsular division of the central nucleus of the amygdala (CeA) is now defined as the "nociceptive amygdala" because of its high content of neurons that respond to painful stimuli. The majority of these neurons become sensitized in a model of arthritis pain. Here we address the role of G protein-coupled group I metabotropic glutamate receptor subtypes mGluR1 and mGluR5 in nociceptive processing under normal conditions and in pain-related sensitization. Extracellular single-unit recordings were made from 65 CeA neurons in anesthetized rats. Each neuron's responses to brief mechanical stimuli, background activity, receptive field size, and threshold were measured before and after induction of the kaolin/carrageenan mono-arthritis in one knee and before and during applications of agonists and antagonists into the CeA by microdialysis. All neurons received excitatory input from the knee(s) and responded most strongly to noxious stimuli. Before arthritis, a group I mGluR1 and mGluR5 agonist (DHPG, n = 10) potentiated the responses to innocuous and noxious stimuli. This effect was mimicked by an mGluR5 agonist (CHPG, n = 15). In the arthritis pain state (>6 h after induction), the facilitatory effects of DHPG (n = 9), but not CHPG (n = 7), increased. An mGluR1 antagonist (CPCCOEt) had no effect before arthritis (n = 12) but inhibited the responses of sensitized neurons in the arthritis pain state (n = 8). An mGluR5 antagonist (MPEP) inhibited brief nociceptive responses under normal conditions (n = 19) and prolonged nociception in arthritis (n = 8). These data suggest a change of mGluR1 function and activation in the amygdala in pain-related sensitization, whereas mGluR5 is involved in brief as well as prolonged nociception.
Topics: Action Potentials; Amygdala; Animals; Arthritis; Chromones; Dose-Response Relationship, Drug; Glycine; Kaolin; Male; Methoxyhydroxyphenylglycol; Neurons; Phenylacetates; Physical Stimulation; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate
PubMed: 13679408
DOI: 10.1152/jn.00485.2003 -
Journal of Psychopharmacology (Oxford,... Oct 2014Suppressing anxiety and fear memory relies on bidirectional projections between the medial prefrontal cortex and the amygdala. Positive allosteric modulators of mGluR5...
Suppressing anxiety and fear memory relies on bidirectional projections between the medial prefrontal cortex and the amygdala. Positive allosteric modulators of mGluR5 improve cognition in animal models of schizophrenia and retrieval of newly formed associations such as extinction of fear-conditioned behaviour. The increase in neuronal network activities of the medial prefrontal cortex is influenced by both mGluR1 and mGluR5; however, it is not well understood how they modulate network activities and downstream information processing. To map mGluR5-mediated network activity in relation to its emergence as a viable cognitive enhancer, we tested group I mGluR compounds on medial prefrontal cortex network activity via multi-electrode array neuronal spiking and whole-cell patch clamp recordings. Results indicate that mGluR5 activation promotes feed-forward inhibition that depends on recruitment of neuronal activity by carbachol-evoked up states. The rate of neuronal spiking activity under the influence of carbachol was reduced by the mGluR5 positive allosteric modulator, N-(1,3-Diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide (VU-29), and enhanced by the mGluR5 negative allosteric modulator, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP). Spontaneous inhibitory post-synaptic currents were increased upon application of carbachol and in combination with VU-29. These results emphasize a bias towards tonic mGluR5-mediated inhibition that might serve as a signal-to-noise enhancer of sensory inputs projected from associated limbic areas onto the medial prefrontal cortex neuronal microcircuit.
Topics: Action Potentials; Allosteric Regulation; Animals; Benzamides; Carbachol; Drug Synergism; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Inhibitory Postsynaptic Potentials; Male; Methoxyhydroxyphenylglycol; Neural Pathways; Prefrontal Cortex; Pyrazoles; Pyridines; Rats; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Thiazoles
PubMed: 25031220
DOI: 10.1177/0269881114542856