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Journal of Integrative Neuroscience Jun 2022There has been increasing evidence that exercise therapy is effective in the treatment and prevention of major depression (MD). However, the basic molecular mechanisms...
The Molecular Mechanism of Exercise for Treatment of Patients with Major Depression: A Preliminary Report on the Dynamics of Metabolites of Nitric Oxide and Catecholamines.
BACKGROUND
There has been increasing evidence that exercise therapy is effective in the treatment and prevention of major depression (MD). However, the basic molecular mechanisms underlying the effects of exercise on MD remain unclear. We conducted a preliminary study to clarify the effect of exercise therapy on MD, focusing on the dynamics of nitric oxide (NO) and catecholamine metabolites, which have been found to be associated with MD.
METHODS
Eleven outpatients with mild to moderate MD and 37 healthy controls (HC) were included in the study. The participants' clinical records and questionnaires were screened for their past medical history. For their exercise therapy, the participants were instructed to walk the equivalent of 17.5 kcal/kg/week for 8 weeks. Blood samples were collected from all participants at baseline, 4 weeks, and 8 weeks after the start of exercise therapy, and plasma metabolites of NO (NOx), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were analyzed. We also assessed the 17-item Hamilton Rating Scale for Depression (HRSD-17) in patients with MD. A mixed-effects regression model was used to compare the mean values by time (baseline, 4, and 8 weeks) for the three corresponding groups (NOx, MHPG, and HVA).
RESULTS
HRSD-17 scores decreased significantly in the MD group after 8 weeks of exercise therapy. NOx and MHPG increased, but there was no significant change in HVA in the MD group after the exercise therapy. NOx decreased after exercise, and HVA increased significantly from baseline after 4 weeks of exercise but decreased after 8 weeks of exercise in the HC group.
CONCLUSIONS
The effects of exercise on NOx, MHPG, and HVA may differ between MD and HC. The potential mechanisms for the benefits of walking exercise in MD patients will be the subject for future research.
Topics: Catecholamines; Depression; Depressive Disorder, Major; Homovanillic Acid; Humans; Methoxyhydroxyphenylglycol; Nitric Oxide
PubMed: 35864774
DOI: 10.31083/j.jin2104123 -
Blood Biomarkers Predict the Cognitive Effects of Aripiprazole in Patients with Acute Schizophrenia.International Journal of Molecular... Mar 2017Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological...
Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing aripiprazole treatment. We evaluated cognitive function in 51 patients with schizophrenia using Brief Assessment of Cognition in Schizophrenia (BACS), as well as background information, psychiatric symptoms, plasma catecholamine metabolites-homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG)-, and serum brain-derived neurotrophic factor (BDNF). Multivariate analyses were performed in order to identify factors independently associated with cognitive function. Brain-derived neurotrophic factor levels, number of hospitalizations, and MHPG levels were associated with verbal memory and learning. Total hospitalization period and MHPG levels were associated with working memory. Age at first hospitalization and education were associated with motor speed. The number of hospital admissions, Positive and Negative Syndrome Scale negative subscale scores (PANSS-N), MHPG levels, BDNF levels, and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were associated with verbal fluency. Homovanillic acid and MHPG levels, duration of illness, and PANSS-N scores were associated with attention and processing speed. Brain-derived neurotrophic factor and MHPG levels were associated with executive function. These results suggest that treatment of psychiatric symptoms and cognitive dysfunction may be improved in patients treated with aripiprazole by controlling for these contributing factors.
Topics: Adult; Antipsychotic Agents; Aripiprazole; Biomarkers; Brain-Derived Neurotrophic Factor; Cognition; Executive Function; Female; Homovanillic Acid; Humans; Male; Memory, Short-Term; Methoxyhydroxyphenylglycol; Middle Aged; Schizophrenia
PubMed: 28272307
DOI: 10.3390/ijms18030568 -
Journal of Psychiatric Research Apr 2018Seasonal variations in neurotransmitter parameters have been previously reported in humans. However, these studies have involved small sample sizes and have not examined...
Seasonal variations in neurotransmitter parameters have been previously reported in humans. However, these studies have involved small sample sizes and have not examined possible relationships with meteorological variables. We compared cerebrospinal fluid (CSF) concentrations of the major monoamine neurotransmitter metabolites (5-HIAA, HVA, and MHPG) in 188 healthy controls (80 men, 108 women) in relationship to age, sex, BMI, and available meteorological variables. All subjects had a lumbar puncture (LP) performed at 9 a.m. after overnight stay. Meteorological data for the day prior to LP were obtained from the National Climatic Association and included the photoperiod, percent sunshine, temperature (max, min, mean), barometric pressure, relative humidity, amount of precipitation and sky cover. Results revealed differences across seasons and cross-seasons for CSF 5-HIAA (p ≤ .05), with post-hoc differences emerging between spring versus summer and fall and between x-spring and x-summer (p ≤ .05). Differences were also found across seasons for CSF HVA (p ≤ .05) with post-hoc differences between spring versus fall. CSF 5-HIAA was significantly inversely correlated with maximum (r = -.28, p ≤ .02), minimum (r = -.24, p ≤ .04), and mean temperature (r = -.28, p ≤ .02) in men. In women, 5-HIAA (r = -.22, p ≤ .02) and HVA (r = -.28, p ≤ .003) were significantly correlated with relative humidity. These data confirm previous findings of variations in serotonin and dopamine metabolites across the year and highlight possible underlying mechanisms involving meteorological changes, which may result in alterations in neurophysiology and behavior.
Topics: Adult; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Seasons; Sex Factors; Weather; Young Adult
PubMed: 29427844
DOI: 10.1016/j.jpsychires.2018.01.004 -
International Journal of Molecular... Jan 2016ortho-Quinones are produced in vivo through the oxidation of catecholic substrates by enzymes such as tyrosinase or by transition metal ions. Neuromelanin, a dark...
ortho-Quinones are produced in vivo through the oxidation of catecholic substrates by enzymes such as tyrosinase or by transition metal ions. Neuromelanin, a dark pigment present in the substantia nigra and locus coeruleus of the brain, is produced from dopamine (DA) and norepinephrine (NE) via an interaction with cysteine, but it also incorporates their alcoholic and acidic metabolites. In this study we examined the metabolic fate of ortho-quinones derived from the catecholamine metabolites, 3,4-dihydroxyphenylethanol (DOPE), 3,4-dihydroxyphenylethylene glycol (DOPEG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylmandelic acid (DOMA). The oxidation of catecholic substrates by mushroom tyrosinase was followed by UV-visible spectrophotometry. HPLC analysis after reduction with NaBH₄ or ascorbic acid enabled measurement of the half-lives of ortho-quinones and the identification of their reaction products. Spectrophotometric examination showed that the ortho-quinones initially formed underwent extensive degradation at pH 6.8. HPLC analysis showed that DOPE-quinone and DOPEG-quinone degraded with half-lives of 15 and 30 min at pH 6.8, respectively, and >100 min at pH 5.3. The major product from DOPE-quinone was DOPEG which was produced through the addition of a water molecule to the quinone methide intermediate. DOPEG-quinone yielded a ketone, 2-oxo-DOPE, through the quinone methide intermediate. DOPAC-quinone and DOMA-quinone degraded immediately with decarboxylation of the ortho-quinone intermediates to form 3,4-dihydroxybenzylalcohol (DHBAlc) and 3,4-dihydroxybenzaldehyde (DHBAld), respectively. DHBAlc-quinone was converted to DHBAld with a half-life of 9 min, while DHBAld-quinone degraded rapidly with a half-life of 3 min. This study confirmed the fact that ortho-quinones from DOPE, DOPEG, DOPAC and DOMA are converted to quinone methide tautomers as common intermediates, through proton rearrangement or decarboxylation. The unstable quinone methides afford stable alcoholic or carbonyl products.
Topics: Catecholamines; Fungal Proteins; Isomerism; Methoxyhydroxyphenylglycol; Monophenol Monooxygenase; Phenylethyl Alcohol; Quinones
PubMed: 26828480
DOI: 10.3390/ijms17020164 -
Learning & Memory (Cold Spring Harbor,... Sep 2020Cannabinoid receptors are widely expressed throughout the hippocampal formation, but are particularly dense in the dentate gyrus (DG) subregion. We, and others, have...
Cannabinoid receptors are widely expressed throughout the hippocampal formation, but are particularly dense in the dentate gyrus (DG) subregion. We, and others, have shown in mice that cannabinoid type 1 receptors (CB1Rs) are involved in a long-term depression (LTD) that can be induced by prolonged 10 Hz stimulation of the medial perforant path (MPP)-granule cell synaptic input to the DG. Here, we extend this work to examine the involvement of CB1Rs in other common forms of LTD in the hippocampus of juvenile male and female Sprague-Dawley rats (). We found, as in mice, that prolonged 10 Hz stimulation (6000 pulses) could reliably induce a form of LTD that was dependent upon CB1R activation. In addition, we also discovered a role for both CB1R and mGluR proteins in LTD induced with 1 Hz low-frequency stimulation (1 Hz-LTD; 900 pulses) and in LTD induced by bath application of the group I mGluR agonist (RS)-3,5-Dihydroxyphenylglycine (DHPG; DHPG-LTD). This study elucidates an essential role for endocannabinoid receptors in a number of forms of LTD in the rat DG, and identifies a novel role for CB1Rs as potential therapeutic targets for conditions that involve impaired LTD in the DG.
Topics: Animals; Dentate Gyrus; Electric Stimulation; Female; Long-Term Synaptic Depression; Male; Methoxyhydroxyphenylglycol; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Metabotropic Glutamate
PubMed: 32817304
DOI: 10.1101/lm.050666.119 -
Journal of Neurophysiology Sep 2016Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and...
Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9. Interestingly, HDACi incubation also increased levels of Ac-H3K9 and triggered GABAergic and glutamatergic plasticities in DA neurons of saline-treated rats. Our results suggest that acute morphine-induced changes in VTA DA activity and synaptic transmission engage HDAC2 activity locally in the VTA to maintain synaptic modifications through histone hypoacetylation.
Topics: Animals; Animals, Newborn; Benzoxazines; Calcium Channel Blockers; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Histone Deacetylase 2; Histone Deacetylase Inhibitors; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Methoxyhydroxyphenylglycol; Morphine; Morpholines; Naphthalenes; Narcotics; Neuronal Plasticity; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Tyrosine 3-Monooxygenase; Ventral Tegmental Area
PubMed: 27306674
DOI: 10.1152/jn.00238.2016 -
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 -
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