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Neuron Aug 2017Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu) is a core pathophysiology of fragile X syndrome (FX); however, the...
Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1) hippocampus, which exhibit exaggerated mGlu-induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M) is excessively translated, and synthesis of M downstream of mGlu activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M activity normalizes core phenotypes in the Fmr1, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1 brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain.
Topics: Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Hippocampus; Long-Term Synaptic Depression; Methoxyhydroxyphenylglycol; Mice, Transgenic; Neurons; Protein Biosynthesis; Receptors, Metabotropic Glutamate
PubMed: 28772121
DOI: 10.1016/j.neuron.2017.07.013 -
Psychoneuroendocrinology Nov 1992Nicotine intake, menstrual and smoking withdrawal symptomatology, and baseline cortisol and MHPG were assessed in nine women smokers under conditions of ad lib smoking...
Nicotine intake, menstrual and smoking withdrawal symptomatology, and baseline cortisol and MHPG were assessed in nine women smokers under conditions of ad lib smoking and overnight abstinence in three menstrual phases (early follicular, mid-to-late follicular, and late luteal). A trend towards higher nicotine intake (p < 0.10) was observed in the mid-to-late follicular phase. Although menstrual symptomatology was not significantly elevated during the smoking abstinence condition overall, abstinence appeared to prevent the normal reduction in symptomatology during the mid-to-late follicular phase that occurred under conditions of ad lib smoking. Menstrual and withdrawal symptoms were highly correlated, and both were most pronounced during the late luteal/abstinence condition. The smoking-specific item "craving" reflected this pattern, though in attenuated form, suggesting that the observed exacerbation of withdrawal symptomatology was not simply due to generalized dysphoria, as queried in both instruments. MHPG was significantly elevated in the late luteal phase, whereas cortisol was significantly higher during ad lib smoking than during abstinence and tended to be highest in the mid-to-late follicular phase. Further investigation will be needed to determine the functional significance of these findings for understanding and treating smoking in women.
Topics: Adult; Estradiol; Female; Humans; Hydrocortisone; Menstrual Cycle; Methoxyhydroxyphenylglycol; Nicotine; Norepinephrine; Progesterone; Smoking; Smoking Cessation; Substance Withdrawal Syndrome
PubMed: 1287682
DOI: 10.1016/0306-4530(92)90021-x -
Life Sciences 1995Evidence from clinical studies suggests that the noradrenergic system may play a role in the pathophysiology of antidepressant- and neuroleptic-induced akathisia. In...
Evidence from clinical studies suggests that the noradrenergic system may play a role in the pathophysiology of antidepressant- and neuroleptic-induced akathisia. In limited previous neurochemical research, acute treatment with selective serotonin reuptake inhibitors (SSRIs) has been reported to increase rat brain norepinephrine (NE) turnover or release. We have examined the neurochemical effects of 2 hr, 4 day, and 20 day treatment with the SSRI fluoxetine, and the neuroleptic haloperidol, on regional brain monoamine metabolism. Short and long-term fluoxetine treatment produced substantial decreases (to 65-79% of control) in serotonin (5HT) turnover. However no effects of fluoxetine on mouse brain NE turnover--as assessed by forebrain, hypothalamus, and hindbrain 3-methoxy-4-hydroxyphenylglycol (MHPG) levels or MHPG/NE ratios--were observed. Acute (2 hr) fluoxetine also did not alter regional NE turnover in rat brain. In contrast, haloperidol tended to increase MHPG levels and MHPG/NE ratios in the mouse brain regions studied. The persistence of decreased 5HT turnover during fluoxetine treatment, the lack of an effect of fluoxetine on NE turnover, and the increased NE turnover seen after haloperidol may have important implications regarding drug responsivity and the mechanism of akathisia induction.
Topics: Animals; Brain; Dopamine; Fluoxetine; Haloperidol; Homovanillic Acid; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Mice; Norepinephrine; Rats; Serotonin; Species Specificity
PubMed: 7543647
DOI: 10.1016/0024-3205(95)02007-6 -
The International Journal of... Nov 2009Post-mortem studies document alterations in the central noradrenergic system in suicide. However, studies of non-fatal suicide attempts have, thus far, found no... (Comparative Study)
Comparative Study
Post-mortem studies document alterations in the central noradrenergic system in suicide. However, studies of non-fatal suicide attempts have, thus far, found no consistent relationship to the noradrenaline metabolite 3-methoxy-4-hydroxphenylglycol (MHPG) in cerebrospinal fluid (CSF). We therefore conducted a prospective study of CSF MHPG and suicidal acts in major depression and bipolar depression. CSF MHPG was assayed in 184 drug-free patients with DSM-IV major depressive disorder or bipolar disorder, presenting for treatment of a current depressive episode, who were then followed-up for up to 12 months. Survival analysis was conducted using Cox proportional hazards modelling to test association of CSF MHPG and future suicidal behaviour, and potential clinical mediators. Twenty-seven individuals made a suicide attempt (two fatal) in the follow-up period. Lower CSF MHPG predicted future suicide attempt or suicide (22% increase in hazard for each 10 pmol/ml lower MHPG, p=0.045). Lower CSF MHPG also correlated with higher medical lethality of future suicidal act (mean MHPG: 49+/-18 vs. 32+/-12 pmol/ml for low- vs. high-lethality, t=2.8, d.f.=25, p=0.009). Smoking and self-rated depression severity were also associated with lower CSF MHPG and with future suicide attempt, but were not statistically significant mediators in multivariate models. In conclusion, lower CSF MHPG is associated with short-term risk for future suicidal behaviour in the 12 months following a major depressive episode. Psychopathology that mediates the relationship between lower CSF MHPG and future suicidal behaviour needs to be identified.
Topics: Adult; Biomarkers; Bipolar Disorder; Cohort Studies; Depressive Disorder, Major; Female; Follow-Up Studies; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Predictive Value of Tests; Prospective Studies; Risk Factors; Suicide, Attempted; Time Factors
PubMed: 19573266
DOI: 10.1017/S1461145709990228 -
British Journal of Pharmacology Jul 1986The effects of the Ca2+-channel blockers verapamil and nimodipine, on the behavioural signs of naloxone (1 mg kg-1)-induced abstinence syndrome in morphine-dependent...
The effects of the Ca2+-channel blockers verapamil and nimodipine, on the behavioural signs of naloxone (1 mg kg-1)-induced abstinence syndrome in morphine-dependent rats, were evaluated. The content of noradrenaline (NA) and of its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured, using high performance liquid chromatography and electrochemical detection or gas chromatography-mass spectrometry, in various brain regions of these animals. Possible interactions of nimodipine and verapamil with opioid receptors were evaluated by examining their ability to displace [3H]-naloxone binding to brain membranes. Verapamil (5, 10 and 50 mg kg-1) and nimodipine (1, 5 and 10 mg kg-1) dose-dependently reduced most of the signs of morphine abstinence. Naloxone-precipitated abstinence decreased the NA content in the cortex, hippocampus, brainstem and cerebellum. In the same brain regions the content of MHPG increased, suggesting an increased release of the amine during morphine abstinence. Nimodipine (10 mg kg-1 i.v.) did not change the content of NA or MHPG in the cortex, hippocampus and brainstem. However, nimodipine pre-treatment markedly reduced the changes in NA and MHPG content induced by the abstinence syndrome. Neither verapamil nor nimodipine displaced [3H]-naloxone from its binding sites. These results suggest that Ca2+-channel blockers suppress the behavioural and neurochemical expressions of morphine abstinence by a mechanism that differs from those of opioids or alpha 2-adrenoceptor agonists.
Topics: Animals; Behavior, Animal; Brain Chemistry; Calcium Channel Blockers; Methoxyhydroxyphenylglycol; Morphine; Morphine Dependence; Naloxone; Nicotinic Acids; Nimodipine; Norepinephrine; Rats; Receptors, Opioid; Substance Withdrawal Syndrome; Verapamil
PubMed: 3017487
DOI: 10.1111/j.1476-5381.1986.tb10236.x -
International Journal of Molecular... Oct 2022Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor...
Prenatal SAMe Treatment Induces Changes in Brain Monoamines and in the Expression of Genes Related to Monoamine Metabolism in a Mouse Model of Social Hierarchy and Depression, Probably via an Epigenetic Mechanism.
Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found that prenatal treatment with SAMe of Submissive (Sub) mice that serve as a model for depression alleviated many of the behavioral depressive symptoms. In the present study, we treated pregnant Sub mice with 20 mg/kg of SAMe on days 12-15 of gestation and studied the levels of monoamines and the expression of genes related to monoamines metabolism in their prefrontal cortex (PFC) at the age of 3 months. The data were compared to normal saline-treated Sub mice that exhibit depressive-like symptoms. SAMe increased the levels of serotonin in the PFC of female Sub mice but not in males. The levels of 5-HIAA were not changed. SAMe increased the levels of dopamine and of DOPAC in males and females but increased the levels of HVA only in females. The levels of norepinephrine and its metabolite MHPG were unchanged. SAMe treatment changed the expression of several genes involved in the metabolism of these monoamines, also in a sex-related manner. The increase in several monoamines induced by SAMe in the PFC may explain the alleviation of depressive-like symptoms. Moreover, these changes in gene expression more than 3 months after treatment probably reflect the beneficial effects of SAMe as an epigenetic modulator in the treatment of depression.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Biogenic Monoamines; Brain; Catecholamines; Depression; Dopamine; Epigenesis, Genetic; Female; Hierarchy, Social; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Mice; Norepinephrine; Saline Solution; Serotonin
PubMed: 36233200
DOI: 10.3390/ijms231911898 -
Journal of Neuroscience Research Apr 2017Type 5 metabotropic glutamate receptors (mGluR5) activate protein kinase C (PKC) via coupling to G protein signaling. We have previously demonstrated that the epsilon...
Type 5 metabotropic glutamate receptors (mGluR5) activate protein kinase C (PKC) via coupling to G protein signaling. We have previously demonstrated that the epsilon isoform of PKC (PKCɛ) is a critical downstream target of mGluR5 in regulating behavioral and biochemical responses to alcohol. Recent evidence suggests that PKC-mediated phosphorylation of mGluR5 can lead to receptor desensitization and internalization. We therefore sought to examine the specific involvement of PKCɛ in the regulation of mGluR5 surface expression in the nucleus accumbens (NAc), a key regulator of alcohol-associated behaviors. Coronal brain sections from male Wistar rats were analyzed for either colocalization of mGluR5 and PKCɛ via immunohistochemistry or changes in mGluR5 surface expression and PKCɛ phosphorylation following local application of PKCɛ translocation activator or inhibitor peptides and/or an orthosteric mGluR5 agonist. We observed colocalization of mGluR5 and PKCɛ in the NAc. We also showed that intra-NAc infusion of the PKCɛ translocation inhibitor ɛV1-2 increased mGluR5 surface expression under baseline conditions. Stimulation of mGluR5 with an orthosteric agonist DHPG, dose dependently increased ERK1/2 and PKCɛ phosphorylation as well as mGluR5 internalization in acute NAc slices. Finally, we observed that activation of PKCɛ translocation with Tat-ΨɛRACK peptide mediates agonist-independent mGluR5 internalization, whereas PKCɛ translocation inhibitor ɛV1-2 prevents agonist-dependent internalization of mGluR5 in NAc slice preparations. These findings suggest that the subcellular localization of mGluR5 in the NAc is regulated by PKCɛ under basal and stimulation conditions, which may influence the role of mGluR5-PKCɛ signaling in alcohol-related behaviors. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Biotinylation; Calnexin; Dose-Response Relationship, Drug; Enzyme Activators; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Gene Expression Regulation; In Vitro Techniques; Male; Methoxyhydroxyphenylglycol; Nucleus Accumbens; Peptides; Phosphorylation; Protein Biosynthesis; Protein Kinase C-epsilon; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Syntaxin 1
PubMed: 27546836
DOI: 10.1002/jnr.23868 -
CNS Neuroscience & Therapeutics May 2016SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT.
METHODS
Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry.
RESULTS
Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings.
CONCLUSION
CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.
Topics: Adult; Biogenic Monoamines; Biomarkers, Pharmacological; Chromatography, High Pressure Liquid; Cyclohexanols; Dimethylamines; Dose-Response Relationship, Drug; Double-Blind Method; Duloxetine Hydrochloride; Electrocardiography; Female; Healthy Volunteers; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neurotransmitter Agents; Neurotransmitter Uptake Inhibitors; Tandem Mass Spectrometry; Time Factors; Young Adult
PubMed: 26849844
DOI: 10.1111/cns.12513 -
The Journal of Neuroscience : the... Feb 2012Fragile X syndrome is caused by the loss of fragile X mental retardation protein (FMRP), which represses and reversibly regulates the translation of a subset of mRNAs in...
Fragile X syndrome is caused by the loss of fragile X mental retardation protein (FMRP), which represses and reversibly regulates the translation of a subset of mRNAs in dendrites. Protein synthesis can be rapidly stimulated by mGluR-induced and protein phosphatase 2a (PP2A)-mediated dephosphorylation of FMRP, which is coupled to the dissociation of FMRP and target mRNAs from miRNA-induced silencing complexes. Here, we report the rapid ubiquitination and ubiquitin proteasome system (UPS)-mediated degradation of FMRP in dendrites upon DHPG (3,5-dihydroxyphenylglycine) stimulation in cultured rat neurons. Using inhibitors to PP2A and FMRP phosphomutants, degradation of FMRP was observed to depend on its prior dephosphorylation. Translational induction of an FMRP target, postsynaptic density-95 mRNA, required both PP2A and UPS. Thus, control of FMRP levels at the synapse by dephosphorylation-induced and UPS-mediated degradation provides a mode to regulate protein synthesis.
Topics: Analysis of Variance; Animals; Boronic Acids; Bortezomib; Cells, Cultured; Dendrites; Disks Large Homolog 4 Protein; Drosophila Proteins; Embryo, Mammalian; Enzyme Inhibitors; Female; Fragile X Mental Retardation Protein; Gene Expression Regulation; Green Fluorescent Proteins; Hippocampus; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Leupeptins; Male; Membrane Proteins; Methoxyhydroxyphenylglycol; Mutation; Neurons; Okadaic Acid; Phosphoprotein Phosphatases; Phosphorylation; Protein Biosynthesis; Pyrazines; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Serine; Signal Transduction; Synapses; Transfection; Ubiquitination
PubMed: 22357842
DOI: 10.1523/JNEUROSCI.5057-11.2012 -
Revue Medicale de Liege May 1986
Review
Topics: Antidepressive Agents; Apomorphine; Clonidine; Contingent Negative Variation; Depression; Dexamethasone; Diagnosis, Differential; Female; Growth Hormone; Humans; Hydrocortisone; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Pregnancy; Saliva; Sleep, REM
PubMed: 2425409
DOI: No ID Found