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Sample records for ampt-induced monoamine depletion

  1. The combined depletion of monoamines alters the effectiveness of subthalamic deep brain stimulation.

    PubMed

    Faggiani, Emilie; Delaville, Claire; Benazzouz, Abdelhamid

    2015-10-01

    Non-motor symptoms of Parkinson's disease are under-studied and therefore not well treated. Here, we investigated the role of combined depletions of dopamine, norepinephrine and/or serotonin in the manifestation of motor and non-motor deficits in the rat. Then, we studied the impact of these depletions on the efficacy of deep brain stimulation of the subthalamic nucleus (STN-DBS). We performed selective depletions of dopamine, norepinephrine and serotonin, and the behavioral effects of different combined depletions were investigated using the open field, the elevated plus maze and the forced swim test. Bilateral dopamine depletion alone induced locomotor deficits associated with anxiety and mild "depressive-like" behaviors. Although additional depletions of norepinephrine and/or serotonin did not potentiate locomotor and anxiety disorders, combined depletions of the three monoamines dramatically exacerbated "depressive-like" behavior. STN-DBS markedly reversed locomotor deficits and anxiety behavior in animals with bilateral dopamine depletion alone. However, these improvements were reduced or lost by the additional depletion of norepinephrine and/or serotonin, indicating that the depletion of these monoamines may interfere with the antiparkinsonian efficacy of STN-DBS. Furthermore, our results showed that acute STN-DBS improved "depressive-like" disorder in animals with bilateral depletion of dopamine and also in animals with combined depletions of the three monoamines, which induced severe immobility in the forced swim test. Our data highlight the key role of monoamine depletions in the pathophysiology of anxiety and depressive-like disorders and provide the first evidence of their negative consequences on the efficacy of STN-DBS upon the motor and anxiety disorders in the context of Parkinson's disease. PMID:26206409

  2. Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l-fenfluramine administration to adult rats.

    PubMed

    Skelton, Matthew R; Blankenmeyer, Tracy L; Gudelsky, Gary A; Brown-Strittholt, Carrie A; Vorhees, Charles V; Williams, Michael T

    2004-12-15

    Fenfluramine (FEN) is a substituted amphetamine known for its anorectic effects, without the stimulatory or abuse potential associated with other amphetamine derivatives. FEN is a potent serotonin (5-HT) releaser and reuptake inhibitor and has been shown to cause depletions of 5-HT that can last days and even weeks after administration. Administration of FEN four times on a single day also causes a prolonged increase of corticosterone (CORT) that lasts approximately 72 h following the first FEN dose. This dosing regimen also produces deficits in sequential learning as measured in the Cincinnati water maze (CWM). Adrenalectomy blocks this effect but removes more than CORT. Accordingly, the purpose of this study was to determine whether inhibiting glucocorticoid production, by administration of the 11 beta-hydroxylase inhibitor metyrapone (MET), will similarly attenuate or eliminate the sequential learning deficits seen with FEN exposure. MET (50 mg/kg) injections were administered 90 min prior to and for 3 days after FEN (four doses given at 2-h intervals). Animals pretreated with MET and treated with FEN showed no sequential learning deficits when tested 1 week following FEN administration compared to FEN alone. The depletions of monoamines were similar following FEN administration, regardless of MET treatment. Taken together, this suggests that a potential mechanism for the sequential learning deficits in FEN-treated animals is a result of prolonged increases in CORT output. PMID:15484208

  3. Brain α2-adrenoceptors in monoamine-depleted rats: increased receptor density, G coupling proteins, receptor turnover and receptor mRNA

    PubMed Central

    Ribas, Catalina; Miralles, Antonio; Busquets, Xavier; García-Sevilla, Jesús A

    2001-01-01

    This study was designed to assess the molecular and cellular events involved in the up-regulation (and receptor supersensitivity) of brain α2-adrenoceptors as a result of chronic depletion of noradrenaline (and other monoamines) by reserpine. Chronic reserpine (0.25 mg kg−1 s.c., every 48 h for 6 – 14 days) increased significantly the density (Bmax values) of cortical α2-adrenoceptor agonist sites (34 – 48% for [3H]-UK14304, 22 – 32% for [3H]-clonidine) but not that of antagonist sites (11 – 18% for [3H]-RX821002). Competition of [3H]-RX821002 binding by (−)-adrenaline further indicated that chronic reserpine was associated with up-regulation of the high-affinity state of α2-adrenoceptors. In cortical membranes of reserpine-treated rats (0.25 mg kg−1 s.c., every 48 h for 20 days), the immunoreactivities of various G proteins (Gαi1/2, Gαi3, Gαo and Gαs) were increased (25 – 34%). Because the high-affinity conformation of the α2-adrenoceptor is most probably related to the complex with Gαi2 proteins, these results suggested an increase in signal transduction through α2-adrenoceptors (and other monoamine receptors) induced by chronic reserpine. After α2-adrenoceptor alkylation, the analysis of receptor recovery (Bmax for [3H]-UK14304) indicated that the increased density of cortical α2-adrenoceptors in reserpine-treated rats was probably due to a higher appearance rate constant of the receptor (Δr=57%) and not to a decreased disappearance rate constant (Δk=7%). Northern- and dot-blot analyses of RNA extracted from the cerebral cortex of saline- and reserpine-treated rats (0.25 mg kg−1, s.c., every 48 h for 20 days) revealed that reserpine markedly increased the expression of α2a-adrenoceptor mRNA in the brain (125%). This transcriptional activation of the receptor gene expression appears to be the cellular mechanism by which reserpine induces up-regulation in the density of brain α2-adrenoceptors

  4. Monoamines and sleep in Drosophila.

    PubMed

    Nall, Aleksandra; Sehgal, Amita

    2014-06-01

    Sleep is an important physiological state, but its function and regulation remain elusive. Drosophila melanogaster is a useful model organism for studying sleep because it has a well-established diurnal activity pattern, including consolidated periods of quiescence that share many characteristics with human sleep. Sleep behavior is regulated by circadian and homeostatic processes and is modulated by environmental and physiological context cues. These cues are communicated to sleep circuits by neurohormones and neuromodulators. A major class of neuromodulators, monoamines, has been found to be essential in various aspects of sleep regulation. Dopamine promotes arousal and sleep-dependent memory formation as well as daily activity. Octopamine, the insect homolog of norepinephrine, promotes wake and may play a role in circadian clock-dependent sleep and arousal. Serotonin promotes sleep and modulates circadian entrainment to light. The different monoamines each signal through multiple receptors in various brain regions in response to different conditions. How these separate circuits integrate their inputs into a single program of behavior is an open field of study for which Drosophila will continue to be a useful model. Monoamine biosynthetic pathways and receptors are conserved between flies and humans, and, thus far, their roles in modulating sleep also appear to be conserved. PMID:24886188

  5. Monoamine Oxidase Inhibitors: Clinical Review

    PubMed Central

    Remick, Ronald A.; Froese, Colleen

    1990-01-01

    Monoamine oxidase inhibitors (MAOIs) are effective antidepressant agents. They are increasingly and effectively used in a number of other psychiatric and non-psychiatric medical syndromes. Their potential for serious toxicity (i.e., hypertensive reaction) is far less than original reports suggest, and newer reversible substrate-specific MAOIs may offer even less toxicity. The author reviews the pharmacology, mechanism of action, clinical indications, and dosing strategies of MAOIs. The common MAOI side-effects (hypotension, weight gain, sexual dysfunction, insomnia, daytime sedation, myoclonus, and hypertensive episodes) are described and management techniques suggested. Recent clinical developments involving MAOIs are outlined. PMID:21233984

  6. A kinome wide screen identifies novel kinases involved in regulation of monoamine transporter function.

    PubMed

    Vuorenpää, Anne; Ammendrup-Johnsen, Ina; Jørgensen, Trine N; Gether, Ulrik

    2016-09-01

    The high affinity transporters for the monoamine neurotransmitters, dopamine, norepinephrine, and serotonin, play a key role in controlling monoaminergic neurotransmission. It is believed that the transporters (DAT, NET and SERT, respectively) are subject to tight regulation by the cellular signaling machinery to maintain monoaminergic homeostasis. Kinases constitute a pivotal role in cellular signaling, however, the regulation of monoamine transporters by the entire ensemble of kinases is unknown. Here, we perform a whole human kinome RNA interference screen to identify novel kinases involved in regulation of monoamine transporter function and surface expression. A primary screen in HEK 293 cells stably expressing DAT or SERT with siRNAs against 573 human kinases revealed 93 kinases putatively regulating transporter function. All 93 hits, which also included kinases previously implicated in monoamine transporter regulation, such as Protein kinase B (Akt) and mitogen-activated protein kinases (MAPK), were validated with a new set of siRNAs in a secondary screen. In this screen we assessed both changes in uptake and surface expression leading to selection of 11 kinases for further evaluation in HEK 293 cells transiently expressing DAT, SERT or NET. Subsequently, three kinases; salt inducible kinase 3 (SIK3), cAMP-dependent protein kinase catalytic subunit alpha (PKA C-α) and protein kinase X-linked (PrKX); were selected for additional exploration in catecholaminergic CATH.a differentiated cells (CAD) and rat chromocytoma (PC12) cells. Whereas SIK3 likely transcriptionally regulated expression of the three transfected transporters, depletion of PKA C-α was shown to decrease SERT function. Depletion of PrKX caused decreased surface expression and function of DAT without changing protein levels, suggesting that PrKX stabilizes the transporter at the cell surface. Summarized, our data provide novel insight into kinome regulation of the monoamine transporters and

  7. Behavioral effects of bidirectional modulation of brain monoamines by reserpine and d-amphetamine in zebrafish

    PubMed Central

    Kyzar, Evan; Stewart, Adam Michael; Landsman, Samuel; Collins, Christopher; Gebhardt, Michael; Robinson, Kyle; Kalueff, Allan V.

    2013-01-01

    Brain monoamines play a key role in the regulation of behavior. Reserpine depletes monoamines, and causes depression and hypoactivity in humans and rodents. In contrast, d-amphetamine increases brain monoamines’ levels, and evokes hyperactivity and anxiety. However, the effects of these agents on behavior and in relation to monoamine levels remain poorly understood, necessitating further experimental studies to understand their psychotropic action. Zebrafish (Danio rerio) are rapidly emerging as a promising model organism for drug screening and translational neuroscience research. Here, we have examined the acute and long-term effects of reserpine and d-amphetamine on zebrafish behavior in the novel tank test. Overall, d-amphetamine (5 and 10 mg/L) evokes anxiogenic-like effects in zebrafish acutely, but not 7 days later. In contrast, reserpine (20 and 40 mg/L) did not evoke overt acute behavioral effects, but markedly reduced activity 7 days later, resembling motor retardation observed in depression and/or Parkinson’s disease. Three-dimensional ‘temporal’ (X, Y, Time) reconstructions of zebrafish locomotion further supports these findings, confirming the utility of 3D-based video-tracking analyses in zebrafish models of drug action. Our results show that zebrafish are highly sensitive to drugs bi-directionally modulating brain monoamines, generally paralleling rodent and clinical findings. Collectively, this emphasizes the potential of zebrafish tests to model complex brain disorders associated with monoamine dysregulation. PMID:23827499

  8. Genetics of monoamine neurotransmitter disorders

    PubMed Central

    2015-01-01

    The monoamine neurotransmitter disorders are a heterogeneous group of inherited neurological disorders involving defects in the metabolism of dopamine, norepinephrine, epinephrine and serotonin. The inheritance of these disorders is mostly autosomal recessive. The neurological symptoms are primarily attributable to cerebral deficiency of dopamine, serotonin or both. The clinical presentations were highly variable and substantial overlaps exist. Evidently, laboratory investigations are crucial for accurate diagnosis. Measurement of neurotransmitter metabolites in cerebral spinal fluid (CSF) is the key to delineate the metabolic defects. Adjuvant investigations including plasma phenylalanine, urine pterins, urine 3-O-methyldopa (3-OMD) and serum prolactin are also helpful to establish the diagnosis. Genetic analyses are pivotally important to confirm the diagnosis which allows specific treatments, proper genetic counselling, prognosis prediction, assessment of recurrent risk in the family as well as prenatal diagnosis. Early diagnosis with appropriate treatment is associated with remarkable response and favourable clinical outcome in several disorders in this group. PMID:26835371

  9. Genetics of monoamine neurotransmitter disorders.

    PubMed

    Siu, Wai-Kwan

    2015-04-01

    The monoamine neurotransmitter disorders are a heterogeneous group of inherited neurological disorders involving defects in the metabolism of dopamine, norepinephrine, epinephrine and serotonin. The inheritance of these disorders is mostly autosomal recessive. The neurological symptoms are primarily attributable to cerebral deficiency of dopamine, serotonin or both. The clinical presentations were highly variable and substantial overlaps exist. Evidently, laboratory investigations are crucial for accurate diagnosis. Measurement of neurotransmitter metabolites in cerebral spinal fluid (CSF) is the key to delineate the metabolic defects. Adjuvant investigations including plasma phenylalanine, urine pterins, urine 3-O-methyldopa (3-OMD) and serum prolactin are also helpful to establish the diagnosis. Genetic analyses are pivotally important to confirm the diagnosis which allows specific treatments, proper genetic counselling, prognosis prediction, assessment of recurrent risk in the family as well as prenatal diagnosis. Early diagnosis with appropriate treatment is associated with remarkable response and favourable clinical outcome in several disorders in this group. PMID:26835371

  10. Drugs related to monoamine oxidase activity.

    PubMed

    Fišar, Zdeněk

    2016-08-01

    Progress in understanding the role of monoamine neurotransmission in pathophysiology of neuropsychiatric disorders was made after the discovery of the mechanisms of action of psychoactive drugs, including monoamine oxidase (MAO) inhibitors. The increase in monoamine neurotransmitter availability, decrease in hydrogen peroxide production, and neuroprotective effects evoked by MAO inhibitors represent an important approach in the development of new drugs for the treatment of mental disorders and neurodegenerative diseases. New drugs are synthesized by acting as multitarget-directed ligands, with MAO, acetylcholinesterase, and iron chelation as targets. Basic information is summarized in this paper about the drug-induced regulation of monoaminergic systems in the brain, with a focus on MAO inhibition. Desirable effects of MAO inhibition include increased availability of monoamine neurotransmitters, decreased oxidative stress, decreased formation of neurotoxins, induction of pro-survival genes and antiapoptotic factors, and improved mitochondrial functions. PMID:26944656

  11. Effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor, on monoamine system in mice and rats.

    PubMed

    Xue, Rui; He, Xin-Hua; Yuan, Li; Chen, Hong-Xia; Zhang, Li-Ming; Yong, Zheng; Yu, Gang; Fan, Shi-Yong; Li, Yun-Feng; Zhong, Bo-Hua; Zhang, You-Zhi

    2016-01-01

    Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS) model. Results in pharmacological models indicated that acute administration of 071031B at 5-20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo. PMID:26318675

  12. Imaging Monoamine Oxidase in the Human Brain

    SciTech Connect

    Fowler, J. S.; Volkow, N. D.; Wang, G-J.; Logan, Jean

    1999-11-10

    Positron emission tomography (PET) studies mapping monoamine oxidase in the human brain have been used to measure the turnover rate for MAO B; to determine the minimum effective dose of a new MAO inhibitor drug lazabemide and to document MAO inhibition by cigarette smoke. These studies illustrate the power of PET and radiotracer chemistry to measure normal biochemical processes and to provide information on the effect of drug exposure on specific molecular targets.

  13. Safflower extracts functionally regulate monoamine transporters.

    PubMed

    Zhao, Gang; Zheng, Xiang-Wei; Gai, Yue; Chu, Wen-Jing; Qin, Guo-Wei; Guo, Li-He

    2009-07-01

    Safflower (HH), the dry flower of Carthamus tinctorius L., has long been used to empirically treat neuropsychological disorders such as stroke and major depression in traditional Chinese medicine, and recently been proven effective for regulating levels of dopamine and serotonin in new-born rat brain. The present study assessed whether HH would be bioactive for functionally regulating monoamine transporters using in vitro drug-screening cell lines. Our current results showed that all solvent-extracted HH fractions, in different degrees, markedly increased both dopamine uptake by Chinese hamster ovary (CHO) cells stably expressing dopamine transporter (DAT) and norepinephrine uptake by CHO cells expressing norepinephrine transporter (NET), and also showed that chloroform (HC), ethyl acetate (HE), and n-butyl alcohol extract strikingly depressed serotonin uptake by CHO cells expressing serotonin transporter (SERT); wherein, the potencies of ethanol extract, HC, HE, and aqueous extract to up-regulate dopamine/norepinephrine uptake and potency of HE to inhibit serotonin uptake were relatively stronger. Further investigation revealed that the enhancement of dopamine/norepinephrine uptake by HC and HE was dependent of DAT/NET activity, and the HE-induced inhibition of serotonin uptake was typical of competition. Thus, HH extracts are novel monoamine transporter modulators functioning as DAT/NET activators and/or SERT inhibitors, and would likely improve neuropsychological disorders through regulating monoamine-transporter activity. PMID:19527825

  14. Monoamine Reuptake Inhibitors in Parkinson's Disease

    PubMed Central

    Huot, Philippe; Fox, Susan H.; Brotchie, Jonathan M.

    2015-01-01

    The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia. PMID:25810948

  15. Effect of contraceptive steroids on monoamine oxidase activity

    PubMed Central

    Southgate, Jennifer; Collins, G. G. S.; Pryse-Davies, J.; Sandler, M.

    1969-01-01

    Cyclical variations in monoamine oxidase activity during the human menstrual cycle, specific to the endometrium and modified in women undergoing contraceptive steroid treatment, may reflect changes in hormonal environment. Treatment of rats with individual constituents of the contraceptive pill causes analogous changes: oestrogens inhibit and progestogens potentiate uterine monoamine oxidase activity. ImagesFig. 2Fig. 3

  16. Molecular aspects of monoamine oxidase B.

    PubMed

    Ramsay, Rona R

    2016-08-01

    Monoamine oxidases (MAO) influence the monoamine levels in brain by virtue of their role in neurotransmitter breakdown. MAO B is the predominant form in glial cells and in platelets. MAO B structure, function and kinetics are described as a background for the effect of alterations in its activity on behavior. The need to inhibit MAO B to combat decreased brain amines continues to drive the search for new drugs. Reversible and irreversible inhibitors are now designed using data-mining, computational screening, docking and molecular dynamics. Multi-target ligands designed to combat the elevated activity of MAO B in Alzheimer's and Parkinson's Diseases incorporate MAO inhibition (usually irreversible) as well as iron chelation, antioxidant or neuroprotective properties. The main focus of drug design is the catalytic activity of MAO, but the imidazoline I2 site in the entrance cavity of MAO B is also a pharmacological target. Endogenous regulation of MAO B expression is discussed briefly in light of new studies measuring mRNA, protein, or activity in healthy and degenerative samples, including the effect of DNA methylation on the expression. Overall, this review focuses on examples of recent research on the molecular aspects of the expression, activity, and inhibition of MAO B. PMID:26891670

  17. Visualization of monoamine oxidase in human brain

    SciTech Connect

    Fowler, J.S.; Volkow, N.D.; Wang, G.J.; Pappas, N.; Shea, C.; MacGregor, R.R.; Logan, J.

    1996-12-31

    Monoamine oxidase is a flavin enzyme which exists in two subtypes, MAO A and MAO B. In human brain MAO B predominates and is largely compartmentalized in cell bodies of serotonergic neurons and glia. Regional distribution of MAO B was determined by positron computed tomography with volunteers after the administration of deuterium substituted [11C]L-deprenyl. The basal ganglia and thalamus exhibited the greatest concentrations of MAO B with intermediate levels in the frontal cortex and cingulate gyrus while lowest levels were observed in the parietal and temporal cortices and cerebellum. We observed that brain MAO B increases with are in health normal subjects, however the increases were generally smaller than those revealed with post-mortem studies.

  18. Monoamine oxidase and agitation in psychiatric patients.

    PubMed

    Nikolac Perkovic, Matea; Svob Strac, Dubravka; Nedic Erjavec, Gordana; Uzun, Suzana; Podobnik, Josip; Kozumplik, Oliver; Vlatkovic, Suzana; Pivac, Nela

    2016-08-01

    Subjects with schizophrenia or conduct disorder display a lifelong pattern of antisocial, aggressive and violent behavior and agitation. Monoamine oxidase (MAO) is an enzyme involved in the degradation of various monoamine neurotransmitters and neuromodulators and therefore has a role in various psychiatric and neurodegenerative disorders and pathological behaviors. Platelet MAO-B activity has been associated with psychopathy- and aggression-related personality traits, while variants of the MAOA and MAOB genes have been associated with diverse clinical phenotypes, including aggressiveness, antisocial problems and violent delinquency. The aim of the study was to evaluate the association of platelet MAO-B activity, MAOB rs1799836 polymorphism and MAOA uVNTR polymorphism with severe agitation in 363 subjects with schizophrenia and conduct disorder. The results demonstrated significant association of severe agitation and smoking, but not diagnosis or age, with platelet MAO-B activity. Higher platelet MAO-B activity was found in subjects with severe agitation compared to non-agitated subjects. Platelet MAO-B activity was not associated with MAOB rs1799836 polymorphism. These results suggested the association between increased platelet MAO-B activity and severe agitation. No significant association was found between severe agitation and MAOA uVNTR or MAOB rs1799836 polymorphism, revealing that these individual polymorphisms in MAO genes are not related to severe agitation in subjects with schizophrenia and conduct disorder. As our study included 363 homogenous Caucasian male subjects, our data showing this negative genetic association will be a useful addition to future meta-analyses. PMID:26851573

  19. Regulation of the vesicular monoamine transporter-2: a novel mechanism for cocaine and other psychostimulants.

    PubMed

    Brown, J M; Hanson, G R; Fleckenstein, A E

    2001-03-01

    The plasmalemmal dopamine (DA) transporter (DAT) is a principal site of action for cocaine. This report presents the novel finding that in addition to inhibiting DAT function, cocaine administration rapidly alters vesicular DA transport. Specifically, cocaine treatment abruptly and reversibly increased both the V(max) of DA uptake and the B(max) of vesicular monoamine transporter-2 (VMAT-2) ligand (dihydrotetrabenazine) binding, as assessed ex vivo in purified rat striatal synaptic vesicles. Selective inhibitors of the DAT (amfonelic acid and GBR12935), but not the plasmalemmal serotonin transporter (fluoxetine), also increased vesicular DA uptake. Moreover, DA depletion resulting from administration of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine had cocaine-like effects. Conversely, administration of the DA-releasing agent methamphetamine rapidly decreased vesicular uptake. Taken together, these data demonstrate for the first time ex vivo that cocaine treatment rapidly alters vesicular monoamine transport, and suggest that alterations in cytoplasmic DA concentrations contribute to stimulant-induced changes in vesicular DA uptake. Hence, the VMAT-2 may be an important target for developing strategies to treat not only cocaine addiction but also other disorders involving alterations in neuronal DA disposition, including Parkinson's disease. PMID:11181904

  20. Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain.

    PubMed

    Oishi, R; Shishido, S; Yamori, M; Saeki, K

    1994-02-01

    To compare in vivo effects of eleven compounds of different classes of histamine H1-receptor antagonists (alcoholamines: diphenhydramine, carbinoxamine, and clemastine; ethylenediamines: mepyramine, tripelennamine, and clemizole; alkylamines: triprolidine and chlorpheniramine; piperazines: meclizine and homochlorcyclizine; phenothiazines: promethazine) on neuronal uptake of dopamine (DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT), the effects on the turnover of these monoamines were examined in the mouse brain, based on the alpha-methyl-p-tyrosine-induced depletion of DA and NA or probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The DA turnover was reduced remarkably by diphenhydramine, tripelennamine, and promethazine, and also significantly by chlorpheniramine, mepyramine, clemizole, and homochlorcyclizine, at doses used in the ordinary animal experiments. The 5-HT turnover was reduced markedly by mepyramine, tripelennamine, and chlorpheniramine. In contrast, the NA turnover was increased by promethazine and homochlorcyclizine, possibly due to their antagonistic effects on alpha-adrenoceptors. These results suggest that (1) the degree of inhibition of the uptake of DA and 5-HT by histamine H1-receptor antagonists is considerably different, (2) most H1-antagonists have little influence on NA uptake and some compounds enhance NA release, and that (3) carbinoxamine, clemastine, triprolidine, and meclizine have comparatively weak influences on monoamine metabolism. These effects on brain monoamine systems may be related to some central actions of histamine H1-receptor antagonists, such as an addiction to these compounds combined with opioids. PMID:7513381

  1. Monoamine receptor agonists, acting preferentially at presynaptic autoreceptors and heteroreceptors, downregulate the cell fate adaptor FADD in rat brain cortex.

    PubMed

    García-Fuster, M Julia; García-Sevilla, Jesús A

    2015-02-01

    FADD is a crucial adaptor of death receptors that can engage apoptosis or survival actions (e.g. neuroplasticity) through its phosphorylated form (p-FADD). Although FADD was shown to participate in receptor mechanisms related to drugs of abuse, little is known on its role in the signaling of classic neurotransmitters (dopamine, noradrenaline, and serotonin) in brain. This study assessed the modulation of FADD (and p-FADD/FADD ratio, as an index of neuroplasticity) and FLIP-L (a neuroprotective FADD interacting partner), as well as the role of MEK-ERK signaling, after activation of monoamine auto/heteroreceptors by selective agonists in rat cortex. Acute depletion of monoamines with reserpine, but not with AMPT or PCPA, reduced FADD (28%) and increased p-FADD/FADD ratio (1.34-fold). Activation of presynaptic α2A-adrenoceptors (UK-14304 and clonidine), 5-HT1A receptors (8-OH-DPAT), and D2 dopamine receptor (bromocriptine) dose-dependently decreased FADD (up to 54%) and increased p-FADD (up to 29%) and p-FADD/FADD ratios (up to 2.93-fold), through specific receptor mechanisms. Activation of rat 5-HT1B autoreceptor in axon terminals by CP-94253 did not modulate FADD forms. Activation of postsynaptic D1 dopamine receptor by SKF-81297 also reduced FADD (25%) and increased p-FADD (32%). Disruption of MEK-ERK activation with SL327 did not modify clonidine (α2A-adrenoceptor)-induced FADD inhibition, indicating that agonist effect was not dependent on ERK signaling. The various monoamine receptor agonists and antagonists did not alter FLIP-L content, or the activation of executioner caspase-3 and PARP-1 cleavage, indicating that the agonists attenuated apoptotic signals and promoted neuroplasticity through FADD regulation. These novel results indicate that inhibition of pro-apoptotic FADD adaptor could function as a common signaling step in the initial activation of monoamine receptors in the brain. PMID:25286119

  2. MONOAMINE OXIDASE: RADIOTRACER DEVELOPMENT AND HUMAN STUDIES.

    SciTech Connect

    FOWLER,J.S.; LOGAN,J.; VOLKOW,N.D.; WANG,G.J.; MACGREGOR,R.R.; DING,Y.S.

    2000-09-28

    PET is uniquely capable of providing information on biochemical transformations in the living human body. Although most of the studies of monoamine oxidase (MAO) have focused on measurements in the brain, the role of peripheral MAO as a phase 1 enzyme for the metabolism of drugs and xenobiotics is gaining attention (Strolin Benedetti and Tipton, 1998; Castagnoli et al., 1997.). MAO is well suited for this role because its concentration in organs such as kidneys, liver and digestive organs is high sometimes exceeding that in the brain. Knowledge of the distribution of the MAO subtypes within different organs and different cells is important in determining which substrates (and which drugs and xenobiotics) have access to which MAO subtypes. The highly variable subtype distribution with different species makes human studies even more important. In addition, the deleterious side effects of combining MAO inhibitors with other drugs and with foodstuffs makes it important to know the MAO inhibitory potency of different drugs both in the brain and in peripheral organs (Ulus et al., 2000). Clearly PET can play a role in answering these questions, in drug research and development and in discovering some of the factors which contribute to the highly variable MAO levels in different individuals.

  3. Therapeutic potential of monoamine transporter substrates.

    PubMed

    Rothman, Richard B; Baumann, Michael H

    2006-01-01

    Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (alpha-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions. PMID:17017961

  4. Monoamine transporters: insights from molecular dynamics simulations

    PubMed Central

    Grouleff, Julie; Ladefoged, Lucy Kate; Koldsø, Heidi; Schiøtt, Birgit

    2015-01-01

    The human monoamine transporters (MATs) facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia, and Parkinson’s disease. Inhibition of the MATs is thus an important strategy for treatment of such diseases. The MATs are sodium-coupled transport proteins belonging to the neurotransmitter/Na+ symporter (NSS) family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the MATs, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors. PMID:26528185

  5. Cerebrospinal fluid monoamine metabolites and suicide.

    PubMed

    Jokinen, Jussi; Nordström, Anna-Lena; Nordström, Peter

    2009-01-01

    Prospective studies of the serotonergic system and suicide report that low 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and a history of attempted suicide predict suicide risk. Low CSF homovanillic acid (HVA) is reported to be associated with past and future lethality of suicide attempts but not with suicide. The interrelationships between monoamine metabolites, violent method, suicide intent and lethality of suicidal behaviour are complex. We hypothesized that CSF 5-HIAA and HVA levels are related to suicide intent, violence and lethality of suicidal behaviour. Fifteen male suicide attempters admitted to a psychiatric ward at the Karolinska University Hospital and eight healthy male volunteers were submitted to lumbar puncture and CSF 5-HIAA and HVA were assayed. Suicide intent with the Beck Suicide Intent Scale (SIS), lethality and violence of suicidal behaviour were assessed. All patients were followed up for causes of death. Six suicides and one fatal accident were identified with death certificates. Mean CSF 5-HIAA but not CSF HVA differed between suicides and survivors. Violent suicides had higher suicide intent and CSF 5-HIAA than non-violent suicides. In violent suicides, CSF 5-HIAA levels were negatively correlated with SIS. Greater suicide intent may be associated with greater aggressive intent and predicts a violent suicide method. PMID:19034712

  6. Bupropion increases striatal vesicular monoamine transport.

    PubMed

    Rau, Kristi S; Birdsall, Elisabeth; Hanson, Jarom E; Johnson-Davis, Kamisha L; Carroll, F Ivy; Wilkins, Diana G; Gibb, James W; Hanson, Glen R; Fleckenstein, Annette E

    2005-11-01

    The vesicular monoamine transporter-2 (VMAT-2) is principally involved in regulating cytoplasmic dopamine (DA) concentrations within terminals by sequestering free DA into synaptic vesicles. This laboratory previously identified a correlation between striatal vesicular DA uptake through VMAT-2 and inhibition of the DA transporter (DAT). For example, administration of methylphenidate (MPD), a DAT inhibitor, increases vesicular DA uptake through VMAT-2 in a purified vesicular preparation; an effect associated with a redistribution of VMAT-2 protein within DA terminals. The purpose of this study was to determine if other DAT inhibitors, including bupropion, similarly affect VMAT-2. Results revealed bupropion rapidly, reversibly, and dose-dependently increased vesicular DA uptake; an effect also associated with VMAT-2 protein redistribution. The bupropion-induced increase in vesicular DA uptake was prevented by pretreatment with eticlopride, a DA D2 receptor antagonist, but not by SCH23390, a DA D1 receptor antagonist. We previously reported that MPD post-treatment prevents persistent DA deficits associated with multiple methamphetamine (METH) administrations. Although bupropion attenuated the METH-induced reduction in VMAT-2 activity acutely, it did not prevent the long-term dopaminergic toxicity or the METH-induced redistribution of VMAT-2 protein. The findings from this study demonstrate similarities and differences in the mechanism by which MPD and bupropion affect striatal dopaminergic nerve terminals. PMID:16005476

  7. Monoamine oxidase: Radiotracer chemistry and human studies

    DOE PAGESBeta

    Fowler, Joanna S.; Logan, Jean; Shumay, Elena; Alia-Klein, Nelly; Wang, Gene-Jack; Volkow, Nora D.

    2015-03-01

    Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serot onin, norepinephrine and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson’s disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 since the first radiotracers were developed and the first PET images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variablesmore » which have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological and psychiatric disorders; (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers which are currently used and possible new applications.« less

  8. Monoamine oxidase: Radiotracer chemistry and human studies

    SciTech Connect

    Fowler, Joanna S.; Logan, Jean; Shumay, Elena; Alia-Klein, Nelly; Wang, Gene-Jack; Volkow, Nora D.

    2015-03-01

    Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serot onin, norepinephrine and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson’s disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 since the first radiotracers were developed and the first PET images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variables which have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological and psychiatric disorders; (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers which are currently used and possible new applications.

  9. Monoamine transporter inhibitors and substrates as treatments for stimulant abuse.

    PubMed

    Howell, Leonard L; Negus, S Stevens

    2014-01-01

    The acute and chronic effects of abused psychostimulants on monoamine transporters and associated neurobiology have encouraged development of candidate medications that target these transporters. Monoamine transporters, in general, and dopamine transporters, in particular, are critical molecular targets that mediate abuse-related effects of psychostimulants such as cocaine and amphetamine. Moreover, chronic administration of psychostimulants can cause enduring changes in neurobiology reflected in dysregulation of monoamine neurochemistry and behavior. The current review will evaluate evidence for the efficacy of monoamine transporter inhibitors and substrates to reduce abuse-related effects of stimulants in preclinical assays of stimulant self-administration, drug discrimination, and reinstatement. In considering deployment of monoamine transport inhibitors and substrates as agonist-type medications to treat stimulant abuse, the safety and abuse liability of the medications are an obvious concern, and this will also be addressed. Future directions in drug discovery should identify novel medications that retain efficacy to decrease stimulant use but possess lower abuse liability and evaluate the degree to which efficacious medications can attenuate or reverse neurobiological effects of chronic stimulant use. PMID:24484977

  10. Monoamine Transporter Inhibitors and Substrates as Treatments for Stimulant Abuse

    PubMed Central

    Howell, Leonard L.; Negus, S. Stevens

    2015-01-01

    The acute and chronic effects of abused psychostimulants on monoamine transporters and associated neurobiology have encouraged development of candidate medications that target these transporters. Monoamine transporters in general, and dopamine transporters in particular, are critical molecular targets that mediate abuse-related effects of psychostimulants such as cocaine and amphetamine. Moreover, chronic administration of psychostimulants can cause enduring changes in neurobiology reflected in dysregulation of monoamine neurochemistry and behavior. The current review will evaluate evidence for the efficacy of monoamine transporter inhibitors and substrates to reduce abuse-related effects of stimulants in preclinical assays of stimulant self-administration, drug discrimination and reinstatement. In considering deployment of monoamine transport inhibitors and substrates as agonist-type medications to treat stimulant abuse, the safety and abuse liability of the medications are an obvious concern, and this will also be addressed. Future directions in drug discovery should identify novel medications that retain efficacy to decrease stimulant use but possess lower abuse liability, and evaluate the degree to which efficacious medications can attenuate or reverse neurobiological effects of chronic stimulant use. PMID:24484977

  11. Monoamine oxidase inhibitory activities of heterocyclic chalcones.

    PubMed

    Minders, Corné; Petzer, Jacobus P; Petzer, Anél; Lourens, Anna C U

    2015-11-15

    Studies have shown that natural and synthetic chalcones (1,3-diphenyl-2-propen-1-ones) possess monoamine oxidase (MAO) inhibition activities. Of particular importance to the present study is a report that a series of furanochalcones acts as MAO-B selective inhibitors. Since the effect of heterocyclic substitution, other than furan (and more recently thiophene, piperidine and quinoline) on the MAO inhibitory properties of the chalcone scaffold remains unexplored, the aim of this study was to synthesise and evaluate further heterocyclic chalcone analogues as inhibitors of the human MAOs. For this purpose, heterocyclic chalcone analogues that incorporate pyrrole, 5-methylthiophene, 5-chlorothiophene and 6-methoxypyridine substitution were examined. Seven of the nine synthesised compounds exhibited IC50 values <1 μM for the inhibition of MAO-B, with all compounds exhibiting higher affinities for MAO-B compared to the MAO-A isoform. The most potent MAO-B inhibitor (4h) displays an IC50 value of 0.067 μM while the most potent MAO-A inhibitor (4e) exhibits an IC50 value of 3.81 μM. It was further established that selected heterocyclic chalcones are reversible and competitive MAO inhibitors. 4h, however, may exhibit tight-binding to MAO-B, a property linked to its thiophene moiety. We conclude that high potency chalcones such as 4h represent suitable leads for the development of MAO-B inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders. PMID:26432037

  12. Effect of Alkaloids Isolated from Phyllodium pulchellum on Monoamine Levels and Monoamine Oxidase Activity in Rat Brain

    PubMed Central

    Cai, Lu; Wang, Chao; Dong, Pei-pei; Zhang, Bao-jing; Zhang, Hou-Li; Huang, Shan-shan; Zhang, Bo; Yu, Sheng-ming; Zhong, Ming; Ma, Xiao-Chi

    2016-01-01

    Phyllodium pulchellum (P. pulchellum) is a folk medicine with a significant number of bioactivities. The aim of this study was to investigate the effects displayed by alkaloids fractions, isolated from the roots of P. pulchellum, on neurotransmitters monoamine levels and on monoamine oxidase (MAO) activity. Six alkaloids, which had indolealkylamine or β-carboline skeleton, were obtained by chromatographic technologies and identified by spectroscopic methods such as NMR and MS. After treatment with alkaloids of P. pulchellum, the reduction of DA levels (54.55%) and 5-HT levels (35.01%) in rat brain was observed by HPLC-FLD. The effect of alkaloids on the monoamines metabolism was mainly related to MAO inhibition, characterized by IC50 values of 37.35 ± 6.41 and 126.53 ± 5.39 μg/mL for MAO-A and MAO-B, respectively. The acute toxicity indicated that P. pulchellum extract was nontoxic. PMID:27195015

  13. Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters.

    PubMed

    Bermingham, Daniel P; Blakely, Randy D

    2016-10-01

    Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and disruption of clearance and reuptake has significant effects on physiology and behavior and has been linked to a number of neuropsychiatric disorders. To ensure adequate and dynamic control of these transporters, multiple modes of control have evolved to regulate their activity and trafficking. Central to many of these modes of control are the actions of protein kinases, whose actions can be direct or indirectly mediated by kinase-modulated protein interactions. Here, we summarize the current state of our understanding of how protein kinases regulate monoamine transporters through changes in activity, trafficking, phosphorylation state, and interacting partners. We highlight genetic, biochemical, and pharmacological evidence for kinase-linked control of DAT, NET, and SERT and, where applicable, provide evidence for endogenous activators of these pathways. We hope our discussion can lead to a more nuanced and integrated understanding of how neurotransmitter transporters are controlled and may contribute to disorders that feature perturbed monoamine signaling, with an ultimate goal of developing better therapeutic strategies. PMID:27591044

  14. Expression cloning of a reserpine-sensitive vesicular monoamine transporter.

    PubMed Central

    Erickson, J D; Eiden, L E; Hoffman, B J

    1992-01-01

    A cDNA for a rat vesicular monoamine transporter, designated MAT, was isolated by expression cloning in a mammalian cell line (CV-1). The cDNA sequence predicts a protein of 515 amino acids with 12 putative membrane-spanning domains. The characteristics of [3H]serotonin accumulation by CV-1 cells expressing the cDNA clone suggested sequestration by an intracellular compartment. In cells permeabilized with digitonin, uptake was ATP dependent with an apparent Km of 1.3 microM. Uptake was abolished by the proton-translocating ionophore carbonylcyanide p-trifluoromethoxyphenylhydrazone and with tri-(n-butyl)tin, an inhibitor of the vacuolar H(+)-ATPase. The rank order of potency to inhibit uptake was reserpine > tetrabenazine > serotonin > dopamine > norepinephrine > epinephrine. Direct comparison of [3H]monoamine uptake indicated that serotonin was the preferred substrate. Photolabeling of membranes prepared from CV-1 cells expressing MAT with 7-azido-8-[125I]iodoketanserin revealed a predominant tetrabenazine-sensitive photolabeled glycoprotein with an apparent molecular mass of approximately 75 kDa. The mRNA that encodes MAT was present specifically in monoamine-containing cells of the locus coeruleus, substantia nigra, and raphe nucleus of rat brain, each of which expresses a unique plasma membrane reuptake transporter. The MAT cDNA clone defines a vesicular monoamine transporter representing a distinct class of neurotransmitter transport molecules. Images PMID:1438304

  15. The Designer Methcathinone Analogs, Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue

    PubMed Central

    Baumann, Michael H; Ayestas, Mario A; Partilla, John S; Sink, Jacqueline R; Shulgin, Alexander T; Daley, Paul F; Brandt, Simon D; Rothman, Richard B; Ruoho, Arnold E; Cozzi, Nicholas V

    2012-01-01

    The nonmedical use of ‘designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study. PMID:22169943

  16. The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue.

    PubMed

    Baumann, Michael H; Ayestas, Mario A; Partilla, John S; Sink, Jacqueline R; Shulgin, Alexander T; Daley, Paul F; Brandt, Simon D; Rothman, Richard B; Ruoho, Arnold E; Cozzi, Nicholas V

    2012-04-01

    The nonmedical use of 'designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study. PMID:22169943

  17. Alteration of enteric monoamines with monoamine receptors and colonic dysmotility in 6-hydroxydopamine-induced Parkinson's disease rats.

    PubMed

    Zhang, Xiaoli; Li, Yun; Liu, Chenzhe; Fan, Ruifang; Wang, Ping; Zheng, Lifei; Hong, Feng; Feng, Xiaoyan; Zhang, Yue; Li, Lisheng; Zhu, Jinxia

    2015-08-01

    Constipation is common in Parkinson's disease (PD), in which monoamines (dopamine [DA], norepinephrine [NE], and 5-hydroxytryptamine [5-HT]) play an important role. Rats microinjected with 6-hydroxydopamine (6-OHDA) into the bilateral substantia nigra (SN) exhibit constipation, but the role of monoamines and their receptors is not clear. In the present study, colonic motility, monoamine content, and the expression of monoamine receptors were examined using strain gauge force transducers, ultraperformance liquid chromatography tandem mass spectrometry, immunofluorescence, and Western blot. The 6-OHDA rats displayed a significant reduction in dopaminergic neurons in the SN and a decreased time on rota-rod test and a marked decrease in daily fecal production and fecal water content. The amplitude of colonic spontaneous contraction was obviously decreased in 6-OHDA rats. Blocking D1-like receptor and β3-adrenoceptor (β3-AR) significantly reduced the inhibition of DA and NE on the colonic motility, respectively, whereas the 5-HT and 5-HT4 receptor agonists promoted the colonic motility. Moreover, DA content was increased in the colonic muscularis externa of 6-OHDA rats. The protein expression of β3-ARs was notably upregulated, but 5-HT4 receptors were significantly decreased in the colonic muscularis externa of 6-OHDA rats. We conclude that enhanced DA and β3-ARs and decreased 5-HT4 receptors may be contributed to the colonic dysmotility and constipation observed in 6-OHDA rats. PMID:25766133

  18. SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine ☆

    PubMed Central

    Lawal, Hakeem O.; Krantz, David E.

    2012-01-01

    The exocytotic release of neurotransmitters requires active transport into synaptic vesicles and other types of secretory vesicles. Members of the SLC18 family perform this function for acetylcholine (SLC18A3, the vesicular acetylcholine transporter or VAChT) and monoamines such as dopamine and serotonin (SLC18A1 and 2, the vesicular monoamine transporters VMAT1 and 2, respectively). To date, no specific diseases have been attributed to a mutation in an SLC18 family member; however, polymorphisms in SLC18A1 and SLC18A2 may confer risk for some neuropsychiatric disorders. Additional members of this family include SLC18A4, expressed in insects, and SLC18B1, the function of which is not known. SLC18 is part of the Drug:H+ Antiporter-1 Family (DHA1, TCID 2.A.1.2) within the Major Facilitator Superfamily (MFS, TCID 2.A.1). PMID:23506877

  19. Designing modulators of monoamine transporters using virtual screening techniques

    PubMed Central

    Mortensen, Ole V.; Kortagere, Sandhya

    2015-01-01

    The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective monoamine neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. Despite the availability of several potent and selective MAT substrates and inhibitors the continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to identify novel ways of targeting and modulating the MATs. Designing novel modulators of MAT function have been limited by the lack of three dimensional structure information of the individual MATs. However, crystal structures of LeuT, a bacterial homolog of MATs, in a substrate-bound occluded, substrate-free outward-open, and an apo inward-open state and also with competitive and non-competitive inhibitors have been determined. In addition, several structures of the Drosophila DAT have also been resolved. Together with computational modeling and experimental data gathered over the past decade, these structures have dramatically advanced our understanding of several aspects of SERT, NET, and DAT transporter function, including some of the molecular determinants of ligand interaction at orthosteric substrate and inhibitor binding pockets. In addition progress has been made in the understanding of how allosteric modulation of MAT function can be achieved. Here we will review all the efforts up to date that has been made through computational approaches employing structural models of MATs to design small molecule modulators to the orthosteric and allosteric sites using virtual screening techniques. PMID:26483692

  20. Structures and Mechanism of the Monoamine Oxidase Family

    PubMed Central

    Gaweska, Helena; Fitzpatrick, Paul F.

    2011-01-01

    Members of the monoamine oxidase family of flavoproteins catalyze the oxidation of primary and secondary amines, polyamines, amino acids, and methylated lysine side chains in proteins. The enzymes have similar overall structures, with conserved FAD-binding domains and varied substrate-binding sites. Multiple mechanisms have been proposed for the catalytic reactions of these enzymes. The present review compares the structures of different members of the family and the various mechanistic proposals. PMID:22022344

  1. Cerebrospinal Fluid Levels of Monoamine Metabolites in the Epileptic Baboon

    PubMed Central

    Szabó, C. Ákos; Patel, Mayuri; Uteshev, Victor V.

    2016-01-01

    The baboon represents a natural model for genetic generalized epilepsy and sudden unexpected death in epilepsy (SUDEP). In this retrospective study, cerebrospinal fluid (CSF) monoamine metabolites and scalp electroencephalography (EEG) were evaluated in 263 baboons of a pedigreed colony. CSF monoamine abnormalities have been linked to reduced seizure thresholds, behavioral abnormalities and SUDEP in various animal models of epilepsy. The levels of 3-hydroxy-4-methoxyphenylglycol, 5-hydroxyindolacetic acid and homovanillic acid in CSF samples drawn from the cisterna magna were analyzed using high-performance liquid chromatography. These levels were compared between baboons with seizures (SZ), craniofacial trauma (CFT) and asymptomatic, control (CTL) baboons, between baboons with abnormal and normal EEG studies. We hypothesized that the CSF levels of major monoaminergic metabolites (i.e., dopamine, serotonin and norepinephrine) associate with the baboons’ electroclinical status and thus can be used as clinical biomarkers applicable to seizures/epilepsy. However, despite apparent differences in metabolite levels between the groups, usually lower in SZ and CFT baboons and in baboons with abnormal EEG studies, we did not find any statistically significant differences using a logistic regression analysis. Significant correlations between the metabolite levels, especially between 5-HIAA and HVA, were preserved in all electroclinical groups. While we were not able to demonstrate significant differences in monoamine metabolites in relation to seizures or EEG markers of epilepsy, we cannot exclude the monoaminergic system as a potential source of pathogenesis in epilepsy and SUDEP. A prospective study evaluating serial CSF monoamine levels in baboons with recently witnessed seizures, and evaluation of abnormal expression and function of monoaminergic receptors and transporters within epilepsy-related brain regions, may impact the electroclinical status. PMID:26924854

  2. DEPLETED URANIUM TECHNICAL WORK

    EPA Science Inventory

    The Depleted Uranium Technical Work is designed to convey available information and knowledge about depleted uranium to EPA Remedial Project Managers, On-Scene Coordinators, contractors, and other Agency managers involved with the remediation of sites contaminated with this mater...

  3. Monoamines in the brain cerebrospinal fluid of facial pain patients.

    PubMed Central

    Bouckoms, A. J.; Sweet, W. H.; Poletti, C.; Lavori, P.; Carr, D.; Matson, W.; Gamache, P.; Aronin, N.

    1992-01-01

    The purpose of the study was to assay monoamines in cerebrospinal fluid (CSF) obtained from the trigeminal cistern of 64 patients with intractable facial pain. The CSF was analyzed for homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), end-product markers of activity for the dopamine, serotonin, and norepinephrine systems, respectively. HVA averaged 121 ng/mL in these facial pain patients, compared to 150 to 550 ng/mL in 10 studies of ventricular brain CSF in assorted psychiatric and pain patients. 5-HIAA averaged 29 to ng/mL in our facial pain patients compared to 60 to 120 ng/mL in nine studies of ventricular brain CSF in assorted psychiatric and neurological patients. Trigeminal cistern CSF MHPG averaged 9 ng/mL, similar to the range of 13 studies of lumbar CSF of assorted psychiatric and pain diagnoses. These results indicate that (1) the electrochemical detection method provides a unique way of accurately measuring nanogram concentrations of multiple monoamines in a little as 0.25 mL of CSF; (2) trigeminal cistern and posterior fossa brain CSF monoamine metabolites reflect a different profile of dopaminergic and serotonergic functioning in these facial pain patients from that previously reported with lumbar CSF measurements of other patients; and (3) trigeminal sensory ganglion or brain dopamine and serotonin systems may be concomitantly dysfunctional in intractable facial pain. PMID:7504420

  4. Monoamine mediation of the morphine-induced activation of mice

    PubMed Central

    Carroll, Bernard J.; Sharp, Peter T.

    1972-01-01

    1. The dose-response relationship for hyperactivity in grouped mice following the injection of morphine sulphate has been established. 2. The activation response can be modified by drugs which affect either catecholamines or indoleamines. 3. The monoamine precursors L-DOPA and 5-hydroxytryptophan potentiate the response. 4. The monoamine synthesis inhibitors α-methyl-p-tyrosine and p-chlorophenylalanine reduce the response. 5. Inhibition of monoamine oxidase activity by pargyline caused a great increase in the response. The simultaneous administration of reserpine resulted in a further potentiation. 6. Reserpine blocked the response whenever it was given alone, either before, with or after the injection of morphine. 7. Blockade of α-adrenoceptors with phentolamine or phenoxybenzamine reduced the response. 8. Blockade of tryptaminergic receptors with methysergide or cinanserin also antagonized the response. 9. The major tranquillizers haloperidol and chlorpromazine reduced the response. Haloperidol was especially effective in this regard. 10. The tricyclic antidepressant drug imipramine potentiated the response. 11. The morphine antagonist nalorphine completely prevented the response. 12. The anticholinergic agent atropine and the antihistaminic drug mepyramine did not affect the response. 13. We conclude that dopamine, noradrenaline and 5-hydroxytryptamine are all involved in the normal activation response of grouped mice to morphine, with dopaminergic mechanisms being of primary importance. PMID:4263794

  5. Olfactory bulb monoamine concentrations vary with time of day.

    PubMed

    Corthell, J T; Stathopoulos, A M; Watson, C C; Bertram, R; Trombley, P Q

    2013-09-01

    The olfactory bulb (OB) has been recently identified as a circadian oscillator capable of operating independently of the master circadian pacemaker, the suprachiasmatic nuclei of the hypothalamus. OB oscillations manifest as rhythms in clock genes, electrical activity, and odor sensitivity. Dopamine, norepinephrine, and serotonin have been shown to modulate olfactory information processing by the OB and may be part of the mechanism that underlies diurnal changes in olfactory sensitivity. Rhythmic release of these neurotransmitters could generate OB rhythms in electrical activity and olfactory sensitivity. We hypothesized that these monoamines were rhythmically released in the OB. To test our hypotheses, we examined monoamine levels in the OB, over the course of a day, by high-performance liquid chromatography coupled to electrochemical detection. We observed that dopamine and its metabolite, 3-4-dihydroxyphenylacetic acid, rhythmically fluctuate over the day. In contrast, norepinephrine is arrhythmic. Serotonin and its metabolite hydroxyindoleacetic acid appear to rhythmically fluctuate. Each of these monoamines has been shown to alter OB circuit behavior and influence odor processing. Rhythmic release of serotonin may be a mechanism by which the suprachiasmatic nuclei communicate, indirectly, with the OB. PMID:23727009

  6. Role of monoamine transporters in mediating psychostimulant effects.

    PubMed

    Riddle, Evan L; Fleckenstein, Annette E; Hanson, Glen R

    2005-01-01

    Monoamine transporters such as the dopamine (DA) transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2) are critical regulators of DA disposition within the brain. Alterations in DA disposition can lead to conditions such as drug addiction, Parkinson's disease, and schizophrenia, a fact that underscores the importance of understanding DAergic signaling. Psychostimulants alter DAergic signaling by influencing both DAT and VMAT-2, and although the effects of these drugs result in increased levels of synaptic DA, the mechanisms by which this occurs and the effects that these drugs exert on DAT and VMAT-2 vary. Many psychostimulants can be classified as releasers (ie, amphetamine analogs) or uptake blockers (ie, cocaine-like drugs) based on the mechanism of their acute effects on neurotransmitter flux through the DAT. Releasers and uptake blockers differentially modulate the activity and subcellular distribution of monoamine transporters, a phenomenon likely related to the neurotoxic potential of these drugs to DAergic neurons. This article will review some of the recent findings whereby releasers and uptake blockers alter DAT and VMAT-2 activity and how these alterations may be involved in neurotoxicity, thus providing insight on the neurodegeneration observed in Parkinson's disease. PMID:16594636

  7. Androgen receptor and monoamine oxidase polymorphism in wild bonobos.

    PubMed

    Garai, Cintia; Furuichi, Takeshi; Kawamoto, Yoshi; Ryu, Heungjin; Inoue-Murayama, Miho

    2014-12-01

    Androgen receptor gene (AR), monoamine oxidase A gene (MAOA) and monoamine oxidase B gene (MAOB) have been found to have associations with behavioral traits, such as aggressiveness, and disorders in humans. However, the extent to which similar genetic effects might influence the behavior of wild apes is unclear. We examined the loci AR glutamine repeat (ARQ), AR glycine repeat (ARG), MAOA intron 2 dinucleotide repeat (MAin2) and MAOB intron 2 dinucleotide repeat (MBin2) in 32 wild bonobos, Pan paniscus, and compared them with those of chimpanzees, Pan troglodytes, and humans. We found that bonobos were polymorphic on the four loci examined. Both loci MAin2 and MBin2 in bonobos showed a higher diversity than in chimpanzees. Because monoamine oxidase influences aggressiveness, the differences between the polymorphisms of MAin2 and MBin2 in bonobos and chimpanzees may be associated with the differences in aggression between the two species. In order to understand the evolution of these loci and AR, MAOA and MAOB in humans and non-human primates, it would be useful to conduct future studies focusing on the potential association between aggressiveness, and other personality traits, and polymorphisms documented in bonobos. PMID:25606465

  8. "Ping-pong gaze" secondary to monoamine oxidase inhibitor overdose.

    PubMed

    Attaway, Amy; Sroujieh, Laila; Mersfelder, Tracey L; Butler, Christopher; Ouellette, Daniel

    2016-01-01

    An infrequent manifestation of monoamine oxidase inhibitor (MAOI) toxicity is "ping-pong gaze" (PPG). We describe the case of a 26-year-old female who was found unresponsive after taking 40 tablets of phenelzine. On presentation to the hospital, her eyes were moving in characteristic "ping pong" fashion. After 6 hours her gaze terminated. The following day her neurologic exam was benign and she had no long-term sequelae. While the etiology of PPG is unknown, it is most often seen with irreversible structural brain damage. However, a detailed literature review revealed that previous cases of MAOI toxicity where the patient survived have all had complete neurologic recovery. PMID:27127395

  9. The Role of Monoamine Oxidase Inhibitors in Current Psychiatric Practice

    PubMed Central

    Fiedorowicz, Jess G.; Swartz, Karen L.

    2007-01-01

    The use of monoamine oxidase inhibitors (MAOIs) by psychiatrists has declined over the past several decades with the expansion of psychiatrists’ pharmacologic armamentarium. This trend has also been driven by concern about food and drug interactions and side effects, as well as waning physician experience with these medications. Many psychiatrists, in fact, never prescribe MAOIs. Recent research has liberalized the MAOI diet and identified symptom presentations more likely to respond to these medications. Thus, clinicians must continue to familiarize themselves with the properties of and indications for prescribing MAOIs. PMID:15552546

  10. The genetics of major depression: Moving beyond the monoamine hypothesis

    PubMed Central

    Shyn, Stanley I.; Hamilton, Steven P.

    2009-01-01

    SYNOPSIS Efforts to unlock the biology of major depressive disorder (MDD) are proceeding on multiple fronts. In this article, we review our current understanding of epidemiologic evidence for a heritable component to MDD risk, as well as recent advances in linkage, candidate gene, and genome-wide association analyses of MDD and related disease subtypes and endophenotypes. While monoamine signaling has preoccupied the bulk of scientific investigation to date, non-traditional gene candidates such as PCLO and GRM7 are now emerging and beginning to change the landscape for future human and animal research on depression. PMID:20159343

  11. Monoamine oxidase A (MAO A) inhibitors decrease glioma progression.

    PubMed

    Kushal, Swati; Wang, Weijun; Vaikari, Vijaya Pooja; Kota, Rajesh; Chen, Kevin; Yeh, Tzu-Shao; Jhaveri, Niyati; Groshen, Susan L; Olenyuk, Bogdan Z; Chen, Thomas C; Hofman, Florence M; Shih, Jean C

    2016-03-22

    Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective therapy is then available. Monoamine Oxidase A (MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. This study shows that MAO A expression is increased in human glioma tissues and cell lines. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. NMI was localized specifically to the tumor. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. NMI can also be used as a non-invasive imaging tool. Thus has a dual function for both therapy and diagnosis. PMID:26871599

  12. A review of monoamine transporter-ligand interactions.

    PubMed

    Immadisetty, Kalyan; Madura, Jeffry D

    2013-12-01

    Transporters of the monoamines serotonin, dopamine, and norepinephrine are plasma membrane proteins belonging to the neurotransmitter sodium symporter family (NSS). Monoamine transporters (MATs) by facilitating reuptake of neurotransmitters from the synapse into the presynaptic nerve terminal, regulate neurotransmitter chemical signaling and maintain homeostasis. MATs are targets for several psychostimulants such as cocaine and amphetamine; and also for drugs treating several psychiatric disorders such as depression, attention deficit hyperactivity disorder, Parkinson's disease, and schizophrenia. Since, currently available treatment has several limitations and side effects, novel treatment is highly desired. Efforts to develop better treatment have been hampered by the lack of crystal structures for MATs. However, leucine transporter (LeuTAa), a bacterial protein from Aquifex aeolicus, belonging to the same NSS family as MATs has recently been crystallized. LeuTAa is used as a template to develop homology models of MATs, which facilitates understanding of the structure, function and pharmacology of MATs. Experimental methods for drug discovery demand a significant amount of time, effort and money. Efficient utilization of computational techniques hastens the process of drug discovery and also significantly reduces the cost. Assessing the binding affinity of drugs to the receptors is a key aspect of drug design. Free energy calculations compliment the experiment by quantitatively assessing the affinity of ligands to receptors. These methods are highly beneficial in the lead identification and optimization stages of rational drug design. We review the currently available free energy methods to treat protein-ligand interactions along with several free energy studies performed on MATs. PMID:24138394

  13. Proteins interacting with monoamine transporters: current state and future challenges.

    PubMed

    Sager, Jonathan J; Torres, Gonzalo E

    2011-08-30

    Plasma membrane and vesicular transporters for the biogenic amines, dopamine, norepinephrine, and serotonin, represent a group of proteins that play a crucial role in the regulation of neurotransmission. Clinically, mono amine transporters are the primary targets for the actions of many therapeutic agents used to treat mood disorders, as well as the site of action for highly addictive psychostimulants such as cocaine, amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine. Over the past decade, the use of approaches such as yeast two-hybrid and proteomics has identified a multitude of transporter interacting proteins, suggesting that the function and regulation of these transporters are more complex than previously anticipated. With the increasing number of interacting proteins, the rules dictating transporter synthesis, assembly, targeting, trafficking, and function are beginning to be deciphered. Although many of these protein interactions have yet to be fully characterized, current knowledge is beginning to shed light on novel transporter mechanisms involved in monoamine homeostasis, the molecular actions of psychostimulants, and potential disease mechanisms. While future studies resolving the spatial and temporal resolution of these, and yet unknown, interactions will be needed, the realization that monoamine transporters do not work alone opens the path to a plethora of possible pharmacological interventions. PMID:21797260

  14. Monoamine oxidase A (MAO A) inhibitors decrease glioma progression

    PubMed Central

    Vaikari, Vijaya Pooja; Kota, Rajesh; Chen, Kevin; Yeh, Tzu-Shao; Jhaveri, Niyati; Groshen, Susan L.; Olenyuk, Bogdan Z.; Chen, Thomas C.; Hofman, Florence M.; Shih, Jean C.

    2016-01-01

    Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective therapy is then available. Monoamine Oxidase A (MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. This study shows that MAO A expression is increased in human glioma tissues and cell lines. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. NMI was localized specifically to the tumor. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. NMI can also be used as a non-invasive imaging tool. Thus has a dual function for both therapy and diagnosis. PMID:26871599

  15. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis

    PubMed Central

    Wu, Jason Boyang; Shao, Chen; Li, Xiangyan; Li, Qinlong; Hu, Peizhen; Shi, Changhong; Li, Yang; Chen, Yi-Ting; Yin, Fei; Liao, Chun-Peng; Stiles, Bangyan L.; Zhau, Haiyen E.; Shih, Jean C.; Chung, Leland W.K.

    2014-01-01

    Tumors from patients with high-grade aggressive prostate cancer (PCa) exhibit increased expression of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines. Despite the association between MAOA and aggressive PCa, it is unclear how MAOA promotes PCa progression. Here, we found that MAOA functions to induce epithelial-to-mesenchymal transition (EMT) and stabilize the transcription factor HIF1α, which mediates hypoxia through an elevation of ROS, thus enhancing growth, invasiveness, and metastasis of PCa cells. Knockdown and overexpression of MAOA in human PCa cell lines indicated that MAOA induces EMT through activation of VEGF and its coreceptor neuropilin-1. MAOA-dependent activation of neuropilin-1 promoted AKT/FOXO1/TWIST1 signaling, allowing FOXO1 binding at the TWIST1 promoter. Importantly, the MAOA-dependent HIF1α/VEGF-A/FOXO1/TWIST1 pathway was activated in high-grade PCa specimens, and knockdown of MAOA reduced or even eliminated prostate tumor growth and metastasis in PCa xenograft mouse models. Pharmacological inhibition of MAOA activity also reduced PCa xenograft growth in mice. Moreover, high MAOA expression in PCa tissues correlated with worse clinical outcomes in PCa patients. These findings collectively characterize the contribution of MAOA in PCa pathogenesis and suggest that MAOA has potential as a therapeutic target in PCa. PMID:24865426

  16. Brain monoamine oxidase A activity predicts trait aggression.

    PubMed

    Alia-Klein, Nelly; Goldstein, Rita Z; Kriplani, Aarti; Logan, Jean; Tomasi, Dardo; Williams, Benjamin; Telang, Frank; Shumay, Elena; Biegon, Anat; Craig, Ian W; Henn, Fritz; Wang, Gene-Jack; Volkow, Nora D; Fowler, Joanna S

    2008-05-01

    The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression. PMID:18463263

  17. Methamphetamine administration reduces hippocampal vesicular monoamine transporter-2 uptake.

    PubMed

    Rau, Kristi S; Birdsall, Elisabeth; Volz, Trent J; Riordan, James A; Baucum, Anthony J; Adair, Brian P; Bitter, Rebecca; Gibb, James W; Hanson, Glen R; Fleckenstein, Annette E

    2006-08-01

    Repeated high-dose injections of methamphetamine (METH) rapidly decrease dopamine uptake by the vesicular monoamine transporter-2 (VMAT-2) associated with dopaminergic nerve terminals, as assessed in nonmembrane-associated vesicles purified from striata of treated rats. The purpose of this study was to determine whether METH similarly affects vesicular uptake in the hippocampus; a region innervated by both serotonergic and noradrenergic neurons and profoundly affected by METH treatment. Results revealed that repeated high-dose METH administrations rapidly (within 1 h) reduced hippocampal vesicular dopamine uptake, as assessed in vesicles purified from treated rats. This reduction was likely associated with serotonergic nerve terminals because METH did not further reduce vesicular monoamine uptake in para-chloroamphetamine-lesioned animals. Pretreatment with the serotonin transporter inhibitor fluoxetine blocked both this acute effect on VMAT-2 and the decrease in serotonin content observed 7 days after METH treatment. In contrast, there was no conclusive evidence that METH affected vesicular dopamine uptake in noradrenergic neurons or caused persistent noradrenergic deficits. These findings suggest a link between METH-induced alterations in serotonergic hippocampal vesicular uptake and the persistent hippocampal serotonergic deficits induced by the stimulant. PMID:16687477

  18. Brain Monoamine Oxidase-A Activity Predicts Trait Aggression

    PubMed Central

    Alia-Klein, Nelly; Goldstein, Rita Z.; Kriplani, Aarti; Logan, Jean; Tomasi, Dardo; Williams, Benjamin; Telang, Frank; Shumay, Elena; Biegon, Anat; Craig, Ian W.; Henn, Fritz; Wang, Gene-Jack; Volkow, Nora D.; Fowler, Joanna S.

    2008-01-01

    The genetic deletion of monoamine oxidase A (MAO A, an enzyme which breaks down the monoamine neurotransmitters norepinephrine, serotonin and dopamine) produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, MIM 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in-vivo in healthy non-smoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the Multidimensional Personality Questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than a third of the variability. Since trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression. PMID:18463263

  19. BEHAVIORAL OUTCOMES OF MONOAMINE OXIDASE DEFICIENCY: PRECLINICAL AND CLINICAL EVIDENCE

    PubMed Central

    Bortolato, Marco; Shih, Jean C.

    2012-01-01

    Monoamine oxidase (MAO) isoenzymes A and B are mitochondrial-bound proteins, catalyzing the oxidative deamination of monoamine neurotransmitters as well as xenobiotic amines. Although they derive from a common ancestral progenitor gene, are located at X-chromosome and display 70% structural identity, their substrate preference, regional distribution, and physiological role are divergent. In fact, while MAO-A has high affinity for serotonin and norepinephrine, MAO-B primarily serves the catabolism of 2-phenylethylamine (PEA) and contributes to the degradation of other trace amines and dopamine. Convergent lines of preclinical and clinical evidence indicate that variations in MAO enzymatic activity—due to either genetic or environmental factors—can exert a profound influence on behavioral regulation and play a role in the pathophysiology of a large spectrum of mental and neurodegenerative disorders, ranging from antisocial personality disorder to Parkinson’s disease. Over the past few years, numerous advances have been made in our understanding of the phenotypical variations associated with genetic polymorphisms and mutations of the genes encoding for both isoenzymes. In particular, novel findings on the phenotypes of MAO-deficient mice are highlighting novel potential implications of both isoenzymes in a broad spectrum of mental disorders, ranging from autism and anxiety to impulse-control disorders and ADHD. These studies will lay the foundation for future research on the neurobiological and neurochemical bases of these pathological conditions, as well as the role of gene × environment interactions in the vulnerability to several mental disorders. PMID:21971001

  20. Water Depletion Threatens Agriculture

    NASA Astrophysics Data System (ADS)

    Brauman, K. A.; Richter, B. D.; Postel, S.; Floerke, M.; Malsy, M.

    2014-12-01

    Irrigated agriculture is the human activity that has by far the largest impact on water, constituting 85% of global water consumption and 67% of global water withdrawals. Much of this water use occurs in places where water depletion, the ratio of water consumption to water availability, exceeds 75% for at least one month of the year. Although only 17% of global watershed area experiences depletion at this level or more, nearly 30% of total cropland and 60% of irrigated cropland are found in these depleted watersheds. Staple crops are particularly at risk, with 75% of global irrigated wheat production and 65% of irrigated maize production found in watersheds that are at least seasonally depleted. Of importance to textile production, 75% of cotton production occurs in the same watersheds. For crop production in depleted watersheds, we find that one half to two-thirds of production occurs in watersheds that have not just seasonal but annual water shortages, suggesting that re-distributing water supply over the course of the year cannot be an effective solution to shortage. We explore the degree to which irrigated production in depleted watersheds reflects limitations in supply, a byproduct of the need for irrigation in perennially or seasonally dry landscapes, and identify heavy irrigation consumption that leads to watershed depletion in more humid climates. For watersheds that are not depleted, we evaluate the potential impact of an increase in irrigated production. Finally, we evaluate the benefits of irrigated agriculture in depleted and non-depleted watersheds, quantifying the fraction of irrigated production going to food production, animal feed, and biofuels.

  1. Halo Star Lithium Depletion

    SciTech Connect

    Pinsonneault, M. H.; Walker, T. P.; Steigman, G.; Narayanan, Vijay K.

    1999-12-10

    The depletion of lithium during the pre-main-sequence and main-sequence phases of stellar evolution plays a crucial role in the comparison of the predictions of big bang nucleosynthesis with the abundances observed in halo stars. Previous work has indicated a wide range of possible depletion factors, ranging from minimal in standard (nonrotating) stellar models to as much as an order of magnitude in models that include rotational mixing. Recent progress in the study of the angular momentum evolution of low-mass stars permits the construction of theoretical models capable of reproducing the angular momentum evolution of low-mass open cluster stars. The distribution of initial angular momenta can be inferred from stellar rotation data in young open clusters. In this paper we report on the application of these models to the study of lithium depletion in main-sequence halo stars. A range of initial angular momenta produces a range of lithium depletion factors on the main sequence. Using the distribution of initial conditions inferred from young open clusters leads to a well-defined halo lithium plateau with modest scatter and a small population of outliers. The mass-dependent angular momentum loss law inferred from open cluster studies produces a nearly flat plateau, unlike previous models that exhibited a downward curvature for hotter temperatures in the 7Li-Teff plane. The overall depletion factor for the plateau stars is sensitive primarily to the solar initial angular momentum used in the calibration for the mixing diffusion coefficients. Uncertainties remain in the treatment of the internal angular momentum transport in the models, and the potential impact of these uncertainties on our results is discussed. The 6Li/7Li depletion ratio is also examined. We find that the dispersion in the plateau and the 6Li/7Li depletion ratio scale with the absolute 7Li depletion in the plateau, and we use observational data to set bounds on the 7Li depletion in main-sequence halo

  2. Changes in monoamine concentrations in mouse brain associated with ethanol dependence and withdrawal

    PubMed Central

    Griffiths, P.J.; Littleton, J.M.; Ortiz, A.

    1974-01-01

    1 Chronic administration of ethanol to mice by inhalation induced tolerance to ethanol and produced an increase in the concentration of brain monoamines. 2 Withdrawal of ethanol from dependent mice caused behavioural changes associated with a further transient rise in brain monoamine concentrations which then declined to control levels. 3 Inhibition of the withdrawal syndrome by the administration of ethanol postponed the changes in monoamines associated with withdrawal. 4 Administration of inhibitors of catecholamine synthesis before withdrawal of ethanol modified the withdrawal syndrome. PMID:4475606

  3. Effects of high-dose fenfluramine treatment on monoamine uptake sites in rat brain: Assessment using quantitative autoradiography

    SciTech Connect

    Appel, N.M.; Mitchell, W.M.; Contrera, J.F.; De Souza, E.B. )

    1990-01-01

    Fenfluramine is an amphetamine derivative that in humans is used primarily as an anorectic agent in the treatment of obesity. In rats, subchronic high-dose d,l-fenfluramine treatment (24 mg/kg subcutaneously, twice daily for 4 days) causes long-lasting decreases in brain serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid, and high-affinity 5HT uptake sites. Moreover, this high-dose treatment regimen causes both selective long-lasting decreases in fine-caliber 5HT-immunoreactive axons and appearance of other 5HT-immunoreactive axons with morphology characteristic of degenerating axons. Determination of the potential neurotoxic effects of fenfluramine treatment using immunohistochemistry is limited from the perspectives that staining is difficult to quantify and that it relies on presence of the antigen (in this case 5HT), and the 5HT-depleting effects of fenfluramine are well known. In the present study, we used quantitative in vitro autoradiography to assess, in detail, the density and regional distribution of (3H)paroxetine-labeled 5HT and (3H)mazindol-labeled catecholamine uptake sites in response to the high-dose fenfluramine treatment described above. Because monoamine uptake sites are concentrated on monoamine-containing nerve terminals, decreases in uptake site density would provide a quantitative assessment of potential neurotoxicity resulting from this fenfluramine treatment regimen. Marked decreases in densities of (3H)paroxetine-labeled 5HT uptake sites occurred in brain regions in which fenfluramine treatment decreased the density of 5HT-like immunostaining when compared to saline-treated control rats. These included cerebral cortex, caudate putamen, hippocampus, thalamus, and medial hypothalamus.

  4. Quantitative structure-activity studies on monoamine oxidase inhibitors.

    PubMed

    Johnson, C L

    1976-05-01

    Quantitative structure-activity studies were carried out on a series of N-isopropylaryl hydrazides which inhibits monoamine oxidase (MAO). The inhibitory potencies of these compounds of MAO were found to correlate with the electron-withdrawing capacity of the aryl ring substituents as estimated by both empirical Hammet sigma constants and electronic indices from molecular orbital calculations. Based on these correlations and previously published data on other classes of MAO inhibitors, a general model for the inhibitor pharmacophore is proposed: potent MAO of an aromatic ring; electron-withdrawing groups on the aromatic ring or replacing the phenyl ring with certain types of heterocyclic rings will tend to increase the potency. PMID:1271400

  5. Amphetamines, new psychoactive drugs and the monoamine transporter cycle

    PubMed Central

    Sitte, Harald H.; Freissmuth, Michael

    2015-01-01

    In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects. PMID:25542076

  6. Aggression and personality: association with amino acids and monoamine metabolites.

    PubMed

    Møller, S E; Mortensen, E L; Breum, L; Alling, C; Larsen, O G; Bøge-Rasmussen, T; Jensen, C; Bennicke, K

    1996-03-01

    Associations in 52 normal individuals were examined between plasma and cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and tyrosine, and concentrations of monoamine metabolites in the CSF, and scores on an aggression questionnaire, the Kinsey Institute Reaction List II, and the Eysenck Personality Questionnaire. There was a significantly positive correlation between CSF 5-hydroxyindoleacetic acid (5-HIAA) levels and extroverted aggression scores, and a significantly negative correlation between CSF 5-HIAA levels and introverted aggression scores. Males showed higher plasma Trp concentrations than females, and significantly positive correlations between plasma Trp concentrations and scores on extroverted aggression and the Eysenck E scale. Males, furthermore, showed a significantly negative correlation between CSF Trp levels and scores on the Eysenck P scale, and a significantly positive correlation between concentrations of 3-methoxy-4-hydroxy-phenylglycol in CSF and scores on moral aggression. These results suggest that central serotonin influences aggression in normal individuals through effects on personality. PMID:8685288

  7. Ammonia causes decreased brain monoamines in fathead minnows (Pimephales promelas)

    USGS Publications Warehouse

    Ronan, P.J.; Gaikowski, M.P.; Hamilton, S.J.; Buhl, K.J.; Summers, C.H.

    2007-01-01

    Hyperammonemia, arising from variety of disorders, leads to severe neurological dysfunction. The mechanisms of ammonia toxicity in brain are not completely understood. This study investigated the effects of ammonia on monoaminergic systems in brains of fathead minnows (Pimephales promelas). Fish serve as a good model system to investigate hyperammonemic effects on brain function since no liver manipulations are necessary to increase endogenous ammonia concentrations. Using high performance liquid chromatography with electrochemical detection, monoamines and some associated metabolites were measured from whole brain homogenate. Adult males were exposed for 48??h to six different concentrations of ammonia (0.01-2.36??mg/l unionized) which bracketed the 96-h LC50 for this species. Ammonia concentration-dependent decreases were found for the catecholamines (norepinephrine and dopamine) and the indoleamine serotonin (5-HT). After an initial increase in the 5-HT precursor 5-hydroxytryptophan it too decreased with increasing ammonia concentrations. There were also significant increases in the 5-HIAA/5-HT and DOPAC/DA ratios, often used as measures of turnover. There were no changes in epinephrine (Epi) or monoamine catabolites (DOPAC, 5-HIAA) at any ammonia concentrations tested. Results suggest that ammonia causes decreased synthesis while also causing increased release and degradation. Increased release may underlie behavioral reactions to ammonia exposure in fish. This study adds weight to a growing body of evidence demonstrating that ammonia leads to dysfunctional monoaminergic systems in brain which may underlie neurological symptoms associated with human disorders such as hepatic encephalopathy. ?? 2007 Elsevier B.V. All rights reserved.

  8. Functional genetic variants in the vesicular monoamine transporter 1 (VMAT1) modulate emotion processing

    PubMed Central

    Lohoff, Falk W.; Hodge, Rachel; Narasimhan, Sneha; Nall, Aleksandra; Ferraro, Thomas N.; Mickey, Brian J.; Heitzeg, Mary M.; Langenecker, Scott A.; Zubieta, Jon-Kar; Bogdan, Ryan; Nikolova, Yuliya S.; Drabant, Emily; Hariri, Ahmad R.; Bevilacqua, Laura; Goldman, David; Doyle, Glenn A.

    2012-01-01

    SUMMARY Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits, and risk for psychopathology. PMID:23337945

  9. Disruption of subcellular Arc/Arg 3.1 mRNA expression in striatal efferent neurons following partial monoamine loss induced by methamphetamine

    PubMed Central

    Barker-Haliski, Melissa L.; Oldenburger, Katharina; Keefe, Kristen A.

    2012-01-01

    The immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) is provocative in the context of neuroplasticity because of its experience-dependent regulation and mRNA transport to and translation at activated synapses. Normal rats have more preproenkephalin-negative (ppe-neg; presumed striatonigral) neurons with cytoplasmic Arc mRNA than ppe-positive (ppe-pos; striatopallidal) neurons, despite equivalent numbers of these neurons showing novelty-induced transcriptional activation of Arc. Furthermore, rats with partial monoamine loss induced by methamphetamine (METH) show impaired Arc mRNA expression in both ppe-neg and ppe-pos neurons relative to normal animals following response-reversal learning. In this study, Arc expression induced by exposure to a novel environment was used to assess transcriptional activation and cytoplasmic localization of Arc mRNA in striatal efferent neuron subpopulations subsequent to METH-induced neurotoxicity. Partial monoamine depletion significantly altered Arc expression. Specifically, basal Arc expression was elevated, but novelty-induced transcriptional activation was abolished. Without novelty-induced Arc transcription, METH-pretreated rats also had fewer neurons with cytoplasmic Arc mRNA expression, with the effect being greater for ppe-neg neurons. Thus, METH-induced neurotoxicity substantially alters striatal efferent neuron function at the level of Arc transcription, suggesting a long-term shift in basal ganglia neuroplasticity processes subsequent to METH-induced neurotoxicity. Such changes potentially underlie striatally-based learning deficits associated with METH-induced neurotoxicity. PMID:22978492

  10. Depleted uranium disposal options.

    SciTech Connect

    Biwer, B. M.; Ranek, N. L.; Goldberg, M.; Avci, H. I.

    2000-04-01

    Depleted uranium hexafluoride (UF{sub 6}) has been produced in the United States since the 1940s as part of both the military program and the civilian nuclear energy program. The U.S. Department of Energy (DOE) is the agency responsible for managing most of the depleted UF{sub 6} that has been produced in the United States. The total quantity of depleted UF{sub 6} that DOE has to or will have to manage is approximately 700,000 Mg. Studies have been conducted to evaluate the various alternatives for managing this material. This paper evaluates and summarizes the alternative of disposal as low-level waste (LLW). Results of the analysis indicate that UF{sub 6} needs to be converted to a more stable form, such as U{sub 3}O{sub 8}, before disposal as LLW. Estimates of the environmental impacts of disposal in a dry environment are within the currently applicable standards and regulations. Of the currently operating LLW disposal facilities, available information indicates that either of two DOE facilities--the Hanford Site or the Nevada Test Site--or a commercial facility--Envirocare of Utah--would be able to dispose of up to the entire DOE inventory of depleted UF{sub 6}.

  11. Cholesterol depletion induces autophagy

    SciTech Connect

    Cheng, Jinglei; Ohsaki, Yuki; Tauchi-Sato, Kumi; Fujita, Akikazu; Fujimoto, Toyoshi . E-mail: tfujimot@med.nagoya-u.ac.jp

    2006-12-08

    Autophagy is a mechanism to digest cells' own components, and its importance in many physiological and pathological processes is being recognized. But the molecular mechanism that regulates autophagy is not understood in detail. In the present study, we found that cholesterol depletion induces macroautophagy. The cellular cholesterol in human fibroblasts was depleted either acutely using 5 mM methyl-{beta}-cyclodextrin or 10-20 {mu}g/ml nystatin for 1 h, or metabolically by 20 {mu}M mevastatin and 200 {mu}M mevalonolactone along with 10% lipoprotein-deficient serum for 2-3 days. By any of these protocols, marked increase of LC3-II was detected by immunoblotting and by immunofluorescence microscopy, and the increase was more extensive than that caused by amino acid starvation, i.e., incubation in Hanks' solution for several hours. The induction of autophagic vacuoles by cholesterol depletion was also observed in other cell types, and the LC3-positive membranes were often seen as long tubules, >50 {mu}m in length. The increase of LC3-II by methyl-{beta}-cyclodextrin was suppressed by phosphatidylinositol 3-kinase inhibitors and was accompanied by dephosphorylation of mammalian target of rapamycin. By electron microscopy, autophagic vacuoles induced by cholesterol depletion were indistinguishable from those seen after amino acid starvation. These results demonstrate that a decrease in cholesterol activates autophagy by a phosphatidylinositol 3-kinase-dependent mechanism.

  12. Revisiting Antarctic Ozone Depletion

    NASA Astrophysics Data System (ADS)

    Grooß, Jens-Uwe; Tritscher, Ines; Müller, Rolf

    2015-04-01

    Antarctic ozone depletion is known for almost three decades and it has been well settled that it is caused by chlorine catalysed ozone depletion inside the polar vortex. However, there are still some details, which need to be clarified. In particular, there is a current debate on the relative importance of liquid aerosol and crystalline NAT and ice particles for chlorine activation. Particles have a threefold impact on polar chlorine chemistry, temporary removal of HNO3 from the gas-phase (uptake), permanent removal of HNO3 from the atmosphere (denitrification), and chlorine activation through heterogeneous reactions. We have performed simulations with the Chemical Lagrangian Model of the Stratosphere (CLaMS) employing a recently developed algorithm for saturation-dependent NAT nucleation for the Antarctic winters 2011 and 2012. The simulation results are compared with different satellite observations. With the help of these simulations, we investigate the role of the different processes responsible for chlorine activation and ozone depletion. Especially the sensitivity with respect to the particle type has been investigated. If temperatures are artificially forced to only allow cold binary liquid aerosol, the simulation still shows significant chlorine activation and ozone depletion. The results of the 3-D Chemical Transport Model CLaMS simulations differ from purely Lagrangian longtime trajectory box model simulations which indicates the importance of mixing processes.

  13. Early attempts to visualize cortical monoamine nerve terminals.

    PubMed

    Hökfelt, Tomas

    2016-08-15

    The Falck-Hillarp, formaldehyde fluorescence method for the demonstration of monoamine neurons in a microscope was established in Lund, Sweden and published in 1962. In the same year Hillarp moved to Karolinska Institutet in Stockholm. Two years later Dahlström and Fuxe published the famous supplement in Acta Physiologica Scandinavica, describing the distribution of the dopamine, noradrenaline and serotonin cell groups in the rat brain. This landmark paper also represented an important contribution to an emerging discipline in neuroscience - chemical neuroanatomy. During the following years several modifications of the original method were developed, attempting to solve some shortcomings, one being the reproducible demonstration of noradrenaline nerve terminals in cortical regions. One result was the paper focused on in the present article, which also describes other efforts in the same direction going on in parallel, primarily, in Lund and Stockholm. As a result there was, in the mid 1970s, a fairly complete knowledge of the catecholamine systems in the rat brain. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID:26806405

  14. 2-Benzylidene-1-indanone derivatives as inhibitors of monoamine oxidase.

    PubMed

    Nel, Magdalena S; Petzer, Anél; Petzer, Jacobus P; Legoabe, Lesetja J

    2016-10-01

    In the present study, a series of twenty-two 2-benzylidene-1-indanone derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The 2-benzylidene-1-indanone derivatives are structurally related to a series of benzylideneindanone derivatives which has previously been found to be MAO-B inhibitors. This study finds that the 2-benzylidene-1-indanones are MAO-B specific inhibitors with IC50 values <2.74μM. Among the compounds evaluated, twelve compounds exhibited IC50<0.1μM and may be considered as high potency inhibitors. The 2-benzylidene-1-indanone derivatives also inhibited MAO-A with the most potent inhibition exhibited by 5g (IC50=0.131μM). An analysis of the structure-activity relationships for MAO-B inhibition show that substitution on the A-ring with a 5-hydroxy group and on the B-ring with halogens and the methyl group yield high potency inhibition. It may therefore be concluded that 2-benzylidene-1-indanone analogues are promising leads for design of therapies for disorders such as Parkinson's disease. PMID:27578245

  15. Alcohol and violence: neuropeptidergic modulation of monoamine systems

    PubMed Central

    Miczek, Klaus A.; DeBold, Joseph F.; Hwa, Lara S.; Newman, Emily L.; de Almeida, Rosa M. M.

    2015-01-01

    Neurobiological processes underlying the epidemiologically-established link between alcohol and several types of social, aggressive, and violent behavior remain poorly understood. Acute low doses of alcohol, as well as withdrawal from long-term alcohol use, may lead to escalated aggressive behavior in a subset of individuals. An urgent task will be to disentangle the host of interacting genetic and environmental risk factors in individuals that are predisposed to engage in escalated aggressive behavior. The modulation of 5-hydroxytryptamine impulse flow by gamma-aminobutyric acid (GABA) and glutamate, acting via distinct ionotropic and metabotropic receptor subtypes in the dorsal raphe nucleus during alcohol consumption, is of critical significance in the suppression and escalation of aggressive behavior. In anticipation and reaction to aggressive behavior, neuropeptides such as corticotropin-releasing factor, neuropeptide Y, opioid peptides, and vasopressin interact with monoamines, GABA, and glutamate to attenuate and amplify aggressive behavior in alcohol-consuming individuals. These neuromodulators represent novel molecular targets for intervention that await clinical validation. Intermittent episodes of brief social defeat during aggressive confrontations are sufficient to cause long-lasting neuroadaptations that can lead to the escalation of alcohol consumption. PMID:26285061

  16. Regulation of Monoamine Transporters: Role of Transporter Phosphorylation

    PubMed Central

    Ramamoorthy, Sammanda; Shippenberg, Toni S.; Jayanthi, Lankupalle D.

    2010-01-01

    Presynaptic biogenic amine transporters mediate reuptake of released amines from the synapse, thus regulating serotonin, dopamine and norepinephrine neurotransmission. Medications utilized in the treatment of depression, attention deficit-hyperactivity disorder and other psychiatric disorders possess high affinity for amine transporters. In addition, amine transporters are targets for psychostimulants. Altered expression of biogenic amine transporters has long been implicated in several psychiatric and degenerative disorders. Therefore, appropriate regulation and maintenance of biogenic amine transporter activity is critical for the maintenance of normal amine homoeostasis. Accumulating evidence suggests that cellular protein kinases and phosphatases regulate amine transporter expression, activity, trafficking and degradation. Amine transporters are phosphoproteins that undergo dynamic control under the influence of various kinase and phosphatase activities. This review presents a brief overview of the role of amine transporter phosphorylation in the regulation of amine transport in the normal and diseased brain. Understanding the molecular mechanisms by which phosphorylation events affect amine transporter activity is essential for understanding the contribution of transporter phosphorylation to the regulation of monoamine neurotransmission and for identifying potential new targets for the treatment of various brain diseases. PMID:20951731

  17. Monoamine oxidases and alcoholism. II. Studies in alcoholic families

    SciTech Connect

    Suarez, B.K.; Hampe, C.L.; Parsian, A.; Cloninger, C.R.

    1995-10-09

    Thirty-five alcoholic families have been studied to investigate the relationship between DNA markers at the monoamine oxidase (MAO) loci and (1) platelet activity levels and (2) alcoholism. A quantitative linkage analysis failed to reveal any evidence that the variation in activity levels cosegregates with the DNA markers. A sib-pair analysis did not reveal a significant excess of MAO haplotype sharing among alcoholic sibs, although the deviation from random sharing was in the direction consistent with an X-linked component. A reanalysis of platelet MAO activity levels in a subset of these families revealed that the lower levels previously found in alcoholics is more likely due to the differences between males and females. Only among males and only when a {open_quotes}broad{close_quotes} definition of alcoholism is used (and MAO activity levels are transformed to normality) does it appear that alcoholics have depressed activities compared to nonalcoholics. Finally, when the confounding due to gender difference is removed, no differences between type I and type II alcoholics are found in these families. 63 refs., 6 tabs.

  18. Alcohol and violence: neuropeptidergic modulation of monoamine systems.

    PubMed

    Miczek, Klaus A; DeBold, Joseph F; Hwa, Lara S; Newman, Emily L; de Almeida, Rosa M M

    2015-09-01

    Neurobiological processes underlying the epidemiologically established link between alcohol and several types of social, aggressive, and violent behavior remain poorly understood. Acute low doses of alcohol, as well as withdrawal from long-term alcohol use, may lead to escalated aggressive behavior in a subset of individuals. An urgent task will be to disentangle the host of interacting genetic and environmental risk factors in individuals who are predisposed to engage in escalated aggressive behavior. The modulation of 5-hydroxytryptamine impulse flow by gamma-aminobutyric acid (GABA) and glutamate, acting via distinct ionotropic and metabotropic receptor subtypes in the dorsal raphe nucleus during alcohol consumption, is of critical significance in the suppression and escalation of aggressive behavior. In anticipation and reaction to aggressive behavior, neuropeptides such as corticotropin-releasing factor, neuropeptide Y, opioid peptides, and vasopressin interact with monoamines, GABA, and glutamate to attenuate and amplify aggressive behavior in alcohol-consuming individuals. These neuromodulators represent novel molecular targets for intervention that await clinical validation. Intermittent episodes of brief social defeat during aggressive confrontations are sufficient to cause long-lasting neuroadaptations that can lead to the escalation of alcohol consumption. PMID:26285061

  19. 3-Coumaranone derivatives as inhibitors of monoamine oxidase

    PubMed Central

    Van Dyk, Adriaan S; Petzer, Jacobus P; Petzer, Anél; Legoabe, Lesetja J

    2015-01-01

    The present study examines the monoamine oxidase (MAO) inhibitory properties of a series of 20 3-coumaranone [benzofuran-3(2H)-one] derivatives. The 3-coumaranone derivatives are structurally related to series of α-tetralone and 1-indanone derivatives, which have recently been shown to potently inhibit MAO, with selectivity for MAO-B (in preference to the MAO-A isoform). 3-Coumaranones are similarly found to selectively inhibit human MAO-B with half-maximal inhibitory concentration (IC50) values of 0.004–1.05 µM. Nine compounds exhibited IC50<0.05 µM for the inhibition of MAO-B. For the inhibition of human MAO-A, IC50 values ranged from 0.586 to >100 µM, with only one compound possessing an IC50<1 µM. For selected 3-coumaranone derivatives, it is established that MAO-A and MAO-B inhibition are reversible since dialysis of enzyme–inhibitor mixtures almost completely restores enzyme activity. On the basis of the selectivity profiles and potent action, it may be concluded that the 3-coumaranone derivatives are suitable leads for the development of selective MAO-B inhibitors as potential treatment for disorders such as Parkinson’s disease and Alzheimer’s disease. PMID:26491258

  20. Low monoamine oxidase B in peripheral organs in smokers

    PubMed Central

    Fowler, Joanna S.; Logan, Jean; Wang, Gene-Jack; Volkow, Nora D.; Telang, Frank; Zhu, Wei; Franceschi, Dinko; Pappas, Naomi; Ferrieri, Richard; Shea, Colleen; Garza, Victor; Xu, Youwen; Schlyer, David; Gatley, S. John; Ding, Yu-Shin; Alexoff, David; Warner, Donald; Netusil, Noelwah; Carter, Pauline; Jayne, Millard; King, Payton; Vaska, Paul

    2003-01-01

    One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,l-[11C]deprenyl and deuterium-substituted l-[11C]deprenyl (l-[11C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke. PMID:12972641

  1. Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation

    PubMed Central

    McDermott, Rose; Tingley, Dustin; Cowden, Jonathan; Frazzetto, Giovanni; Johnson, Dominic D. P.

    2009-01-01

    Monoamine oxidase A gene (MAOA) has earned the nickname “warrior gene” because it has been linked to aggression in observational and survey-based studies. However, no controlled experimental studies have tested whether the warrior gene actually drives behavioral manifestations of these tendencies. We report an experiment, synthesizing work in psychology and behavioral economics, which demonstrates that aggression occurs with greater intensity and frequency as provocation is experimentally manipulated upwards, especially among low activity MAOA (MAOA-L) subjects. In this study, subjects paid to punish those they believed had taken money from them by administering varying amounts of unpleasantly hot (spicy) sauce to their opponent. There is some evidence of a main effect for genotype and some evidence for a gene by environment interaction, such that MAOA is less associated with the occurrence of aggression in a low provocation condition, but significantly predicts such behavior in a high provocation situation. This new evidence for genetic influences on aggression and punishment behavior complicates characterizations of humans as “altruistic” punishers and supports theories of cooperation that propose mixed strategies in the population. It also suggests important implications for the role of individual variance in genetic factors contributing to everyday behaviors and decisions. PMID:19168625

  2. Cataplexy and monoamine oxidase deficiency in Norrie disease.

    PubMed

    Vossler, D G; Wyler, A R; Wilkus, R J; Gardner-Walker, G; Vlcek, B W

    1996-05-01

    Norrie disease (ND) is an X-linked recessive disorder causing ocular atrophy, mental retardation, deafness, and dysmorphic features. Virtually absent monoamine oxidase (MAO) type-A and -B activity has been found in some boys with chromosome deletions. We report the coexistence of cataplexy and abnormal REM sleep organization with ND. Three related boys, referred for treatment of medically refractory atonic spells and apneas, underwent extended EEG-video-polysomnographic monitoring. They demonstrated attacks of cataplexy and inappropriate periods of REM sleep during which they were unarousable. One boy also had generalized tonic-clonic seizures. Previous testing revealed that all three have complete ND gene deletions. In all subjects, platelet MAO-B activity was absent, serum serotonin levels were markedly increased, and plasma catecholamine levels were normal. Data from the canine narcolepsy syndrome model implicate abnormal catecholaminergic and cholinergic activities in the pathogenesis of cataplexy. Our findings suggest that abnormal MAO activity or an imbalance between serotonin and other neurotransmitter levels may be involved in the pathogenesis of human cataplexy. PMID:8628463

  3. Reye's syndrome: salicylate and mitochondrial monoamine oxidase function

    SciTech Connect

    Faraj, B.A.; Caplan, D.; Lolies, P.

    1986-03-01

    It has been suggested that aspirin is somehow linked with the onset of Reye's syndrome (RS). A general feature of Reye's syndrome is severe impairment of mitochondrial monoamine oxidase (MAO) function. The main objective of this investigation was to study the effect of salicylate on platelet mitochondrial MAO activity in three groups: group A (healthy children, n = 21) and group C (healthy adults, n = 10). Platelet MAO was measured by radio-enzymatic technique with /sup 14/C-tyramine as a substrate. The results showed that salicyclate (10 mM) had a 20 to 60 percent inhibitory effect on platelet MAO function in only 1, 3 and 2 of the subjects in group A, B and C. Furthermore, there was an association between low enzyme activity and salicylate MAO inhibitory effect in these subjects. These preliminary findings suggest that salicylate may induce deterioration in mitochondrial function in susceptible individuals and that the assessment of salicylate MAO inhibitory effect may identify those who may be at risk to develop aspirin poisoning and Reye's syndrome.

  4. Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors

    PubMed Central

    Chiuccariello, Lina; Cooke, Robert G; Miler, Laura; Levitan, Robert D; Baker, Glen B; Kish, Stephen J; Kolla, Nathan J; Rusjan, Pablo M; Houle, Sylvain; Wilson, Alan A

    2016-01-01

    Background: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer’s, and Parkinson’s Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. Methods: Major depressive episode (MDE) subjects underwent [11C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. Results: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300–600mg daily (n = 11), 83.75±5.52% for moclobemide at 900–1200mg daily (n = 9), and 86.82±6.89% for phenelzine at 45–60mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean ‘a’: 88.62±2.38%, mean ‘b’: 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45–60mg) and higher-dose moclobemide (900–1200mg) compared to lower-dose moclobemide [300–600mg; F(7,16) = 3.94, p = 0.01]. Conclusions: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300–600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets. PMID:26316187

  5. Ozone depletion by hydrofluorocarbons

    NASA Astrophysics Data System (ADS)

    Hurwitz, Margaret M.; Fleming, Eric L.; Newman, Paul A.; Li, Feng; Mlawer, Eli; Cady-Pereira, Karen; Bailey, Roshelle

    2015-10-01

    Atmospheric concentrations of hydrofluorocarbons (HFCs) are projected to increase considerably in the coming decades. Chemistry climate model simulations forced by current projections show that HFCs will impact the global atmosphere increasingly through 2050. As strong radiative forcers, HFCs increase tropospheric and stratospheric temperatures, thereby enhancing ozone-destroying catalytic cycles and modifying the atmospheric circulation. These changes lead to a weak depletion of stratospheric ozone. Simulations with the NASA Goddard Space Flight Center 2-D model show that HFC-125 is the most important contributor to HFC-related atmospheric change in 2050; its effects are comparable to the combined impacts of HFC-23, HFC-32, HFC-134a, and HFC-143a. Incorporating the interactions between chemistry, radiation, and dynamics, ozone depletion potentials (ODPs) for HFCs range from 0.39 × 10-3 to 30.0 × 10-3, approximately 100 times larger than previous ODP estimates which were based solely on chemical effects.

  6. The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain.

    PubMed

    Nagai, Fumiko; Nonaka, Ryouichi; Satoh Hisashi Kamimura, Kanako

    2007-03-22

    We developed a reproducible, simple, and small-scale method for determining the re-uptake and release of monoamines (dopamine, serotonin (5-HT) and norepinephrine) using rat brain synaptosomes. These assays were then applied to study the effects of different kinds of non-medically used psychoactive drugs on monoamine re-uptake and release. The phenethylamine derivatives, 4-fluoroamphetamine, 2-methylamino-3,4-methylene-dioxy-propiophenone (methylone), 1-(1,3-benzodioxol-5-yl)-2-butanamine (BDB), and N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), had strong inhibitory effects on the re-uptake of dopamine, 5-HT and norepinephrine. 4-Fluoroamphetamine, methylone and BDB also strongly increased the release of the three monoamines, but MBDB increased 5-HT and norepinephrine release, but had little effect on dopamine release. However, 2,5-dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-ethylphenethylamine (2C-E), 2,5-dimethoxy-4-chlorophenethylamine (2C-C), 2,4,5-trimethoxyamphetamine (TMA-2) and 2,4,6-trimethoxyamphetamine (TMA-6), which are methoxylated phenethylamine derivatives, slightly influenced the re-uptake and release of monoamines. Alpha-metyltryptamine (AMT), a tryptamine derivative, was one of the strongest re-uptake inhibitors and releasers of the three monoamines. The tryptamine derivative, 5-methoxy-alpha-methyltryptamine (5-MeO-AMT), also strongly inhibited re-uptake and increased the release of the three monoamines. N,N-dipropyltryptamine (DPT), 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), 5-methoxy-N,N-methylisopropyltryptamine (5-MeO-MIPT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) inhibited monoamine re-uptake, but had a few effects on monoamine release. 1-(3-Chlorophenyl)piperazine (3CPP) and 1-(methoxyphenyl)piperazine (4MPP), which are piperazine derivatives, inhibited monoamine re-uptake and accelerated their release. The results suggest that some designer drugs strongly act on the central nerve system to the same

  7. Effects of serotonin and catecholamine depletion on interleukin-6 activation and mood in human volunteers.

    PubMed

    Harrison, Ben J; Olver, James S; Norman, Trevor R; Nathan, Pradeep J

    2002-08-01

    There is increasing evidence that depression and related neurotic illnesses are associated with alterations in immune function that may contribute to their pathogenesis. For example, clinical and experimental studies have shown that abnormal HPA-axis activation and monoamine neurotransmission may be related to an increased release of proinflammatory cytokines from stimulated lymphocytes in the periphery and brain. In the present investigation, the effects of tryptophan depletion (TD) on unstimulated plasma interleukin-6 (IL-6) concentrations were investigated in order to determine whether acute changes in serotonin (5-HT) neurotransmission would induce a proinflammatory response in healthy individuals. The effects of TD were compared with the analogous procedure of tyrosine depletion (TPD), which reduces catecholamine metabolism in humans. Thirteen female participants completed three experimental sessions: TD, TPD and a balanced-control condition (B). Mood-ratings and blood sampling were performed at baseline and 5 h after the administration of the mixtures. Analyses revealed that TD and TPD markedly reduced tryptophan and tyrosine/phenylalanine levels, respectively. No changes in plasma IL-6 production or ratings of lowered mood were observed, however, subjects did report feeling more fatigued after TD. These findings indicate that a transient disruption in global monoamine function does not stimulate a proinflammatory response of IL-6 in normal volunteers. PMID:12404674

  8. Monoamines and their metabolites in the avian brain.

    PubMed

    Juorio, A V; Vogt, M

    1967-04-01

    1. In the avian brain, a high concentration of dopamine was found in a sharply contoured region of the nucleus basalis which may or may not have included the nucleus entopeduncularis, and therefore lay within the palaeostriatum of the nomenclature of Crosby and Huber. This was thus the only region which may be considered biochemically homologous to the mammalian corpus striatum. For purposes of macroscopic identification only, the region is described here as the ;anterior part of the nucleus basalis'. The concentration of dopamine was 3 mug/g in the pigeon, about the same in the duck and chicken, and 7.5 mug/g in the finch. In the pigeon this region also contained some noradrenaline; the quantity of 5-hydroxytryptamine (1.4 mug/g) and 5-hydroxyindolylacetic acid (0.6 mug/g) was larger than in any other part of the brain.2. In the brain of the pigeon and the chicken, the highest concentrations of noradrenaline (1.5 and 1.4 mug/g) were found in the hypothalamus.3. The concentration of adrenaline was higher in the avian than in the mammalian brain. In the hypothalamus, it ranged from 0.4 mug/g in the pigeon to 1 mug/g in the chicken.4. Fluorescence microscopy, using the formaldehyde condensation method, showed, in the anterior part of the nucleus basalis, a large area of diffuse green-yellow fluorescence, similar in appearance to the fluorescence of the striatum of the rat. In addition this part of the brain contained a small region of fluorescent fibres and varicosities. It is suggested that the diffuse fluorescence was produced by dopamine. It was absent from brains of reserpine-treated pigeons.5. In the pigeon, reserpine, tetrabenazine and prenylamine produced a decrease in the concentration of brain monoamines, an effect which was comparable to that seen in mammals. Yet, none of these drugs raised the concentration of homovanillic acid, but they increased that of 5-hydroxyindolylacetic acid; these drugs raise the concentration of both acids in mammalian brain.6

  9. Predicting Monoamine Oxidase Inhibitory Activity through Ligand-Based Models

    PubMed Central

    Vilar, Santiago; Ferino, Giulio; Quezada, Elias; Santana, Lourdes; Friedman, Carol

    2013-01-01

    The evolution of bio- and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that “similar molecules have similar biological properties” that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure-Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes’ function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer’s and Parkinson’s disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action. PMID:23231398

  10. Greater Monoamine Oxidase A Binding in Alcohol Dependence

    PubMed Central

    Matthews, Brittany A.; Kish, Stephen J.; Xu, Xin; Boileau, Isabelle; Rusjan, Pablo M.; Wilson, Alan A.; DiGiacomo, Dan; Houle, Sylvain; Meyer, Jeffrey H.

    2016-01-01

    Background Alcohol dependence (AD) is a multiorgan disease in which excessive oxidative stress and apoptosis are implicated. Monoamine oxidase A (MAO-A) is an important enzyme on the outer mitochondrial membrane that participates in the cellular response to oxidative stress and mitochondrial toxicity. It is unknown whether MAO-A levels are abnormal in AD. We hypothesized that MAO-A VT, an index of MAO-A level, is elevated in the prefrontal cortex (PFC) during AD, because markers of greater oxidative stress and apoptosis are reported in the brain in AD and a microarray analysis reported greater MAO-A messenger RNA in the PFC of rodents exposed to alcohol vapor. Methods Sixteen participants with alcohol dependence and 16 healthy control subjects underwent [11C]-harmine positron emission tomography. All were nonsmoking, medication- and drug-free, and had no other past or present psychiatric or medical illnesses. Results MAO-A VT was significantly greater in the PFC (37%, independent samples t test, t30 = 3.93, p < .001), and all brain regions analyzed (mean 32%, multivariate analysis of variance, F7,24 = 3.67, p = .008). Greater duration of heavy drinking correlated positively with greater MAO-A VT in the PFC (r = .67, p = .005) and all brain regions analyzed (r = .73 to .57, p = .001–.02). Conclusions This finding represents a new pathological marker present in AD that is therapeutically targetable through direct inhibition or by novel treatments toward oxidative/pro-apoptotic processes implicated by MAO-A overexpression. PMID:24269057

  11. Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation

    PubMed Central

    Lominac, Kevin D.; McKenna, Courtney L.; Schwartz, Lisa M.; Ruiz, Paige N.; Wroten, Melissa G.; Miller, Bailey W.; Holloway, John J.; Travis, Katherine O.; Rajasekar, Ganesh; Maliniak, Dan; Thompson, Andrew B.; Urman, Lawrence E.; Phillips, Tamara J.; Szumlinski, Karen K.

    2014-01-01

    Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5–10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction. PMID:24847220

  12. Depleted uranium management alternatives

    SciTech Connect

    Hertzler, T.J.; Nishimoto, D.D.

    1994-08-01

    This report evaluates two management alternatives for Department of Energy depleted uranium: continued storage as uranium hexafluoride, and conversion to uranium metal and fabrication to shielding for spent nuclear fuel containers. The results will be used to compare the costs with other alternatives, such as disposal. Cost estimates for the continued storage alternative are based on a life-cycle of 27 years through the year 2020. Cost estimates for the recycle alternative are based on existing conversion process costs and Capital costs for fabricating the containers. Additionally, the recycle alternative accounts for costs associated with intermediate product resale and secondary waste disposal for materials generated during the conversion process.

  13. Tank depletion flow controller

    DOEpatents

    Georgeson, Melvin A.

    1976-10-26

    A flow control system includes two bubbler tubes installed at different levels within a tank containing such as radioactive liquid. As the tank is depleted, a differential pressure transmitter monitors pressure differences imparted by the two bubbler tubes at a remote, shielded location during uniform time intervals. At the end of each uniform interval, balance pots containing a dense liquid are valved together to equalize the pressures. The resulting sawtooth-shaped signal generated by the differential pressure transmitter is compared with a second sawtooth signal representing the desired flow rate during each time interval. Variations in the two signals are employed by a control instrument to regulate flow rate.

  14. Influence of Momordica charantia on oxidative stress-induced perturbations in brain monoamines and plasma corticosterone in albino rats

    PubMed Central

    Kavitha, Naga; Babu, S. Manohar; Rao, M.E. Bhanoji

    2011-01-01

    Objectives: The objective of this study was to evaluate the antistress activity of Momordica charantia (MC) fruit extract on stress-induced changes in albino rats and also to explore attenuating effects of MC on in vitro lipid peroxidation in rat brain. Materials and Methods: In this study, Wistar albino rats (180–200 g) were used. Plasma corticosterone and monoamines—5-hydroxy tryptamine (5-HT), norepinephrine (NE), epinephrine (E) and dopamine (DA) in cortex, hypothalamus and hippocampus regions of brain were determined in animals under different stressful conditions. Ethanolic fruit extract of MC, at doses of 200 and 400 mg/kg, was used. The oxidative stress paradigms used in in vivo models were acute stress (AS) and chronic unpredictable stress (CUS). Panax quinquefolium (PQ) was used as a standard in in vivo models and ascorbic acid was used as a reference standard in the in vitro method. Results: Subjecting the animals to AS (immobilization for 150 min once only) resulted in significant elevation of plasma corticosterone levels and brain monoamine levels. Pretreatment with MC at doses of 200 and 400 mg/kg p.o. significantly countered AS-induced changes and a similar effect was exhibited by PQ at 100 mg/kg p.o. In the CUS regimen (different stressors for 7 days), plasma corticosterone levels were significantly elevated whereas the levels of 5-HT, NE, E, and DA were depleted significantly. Pretreatment with MC (200 and 400 mg/kg) attenuated the CUS-induced changes in the levels of above monoamines in cortex, hypothalamus, and hippocampus regions of brain and plasma corticosterone in a dose-dependent manner. Furthermore, MC extract (1000–5000 μg/mL) exhibited a significant quenching effect on in vitro lipid peroxidation indicating its strong antioxidant activity which was compared with ascorbic acid. Conclusions: This study reveals the antistress activity of MC as it significantly reverted the stress-induced changes, and the activity might be attributed

  15. Catalytic Amine Oxidation under Ambient Aerobic Conditions: Mimicry of Monoamine Oxidase B.

    PubMed

    Murray, Alexander T; Dowley, Myles J H; Pradaux-Caggiano, Fabienne; Baldansuren, Amgalanbaatar; Fielding, Alistair J; Tuna, Floriana; Hendon, Christopher H; Walsh, Aron; Lloyd-Jones, Guy C; John, Matthew P; Carbery, David R

    2015-07-27

    The flavoenzyme monoamine oxidase (MAO) regulates mammalian behavioral patterns by modulating neurotransmitters such as adrenaline and serotonin. The mechanistic basis which underpins this enzyme is far from agreed upon. Reported herein is that the combination of a synthetic flavin and alloxan generates a catalyst system which facilitates biomimetic amine oxidation. Mechanistic and electron paramagnetic (EPR) spectroscopic data supports the conclusion that the reaction proceeds through a radical manifold. This data provides the first example of a biorelevant synthetic model for monoamine oxidase B activity. PMID:26087676

  16. Ozone Depletion by Hydrofluorocarbons

    NASA Astrophysics Data System (ADS)

    Hurwitz, M.; Fleming, E. L.; Newman, P. A.; Li, F.; Mlawer, E. J.; Cady-Pereira, K. E.; Bailey, R.

    2015-12-01

    Hydrofluorocarbons (HFCs) are second-generation replacements for the chlorofluorocarbons (CFCs), halons and other substances that caused the 'ozone hole'. Atmospheric concentrations of HFCs are projected to increase dramatically in the coming decades. Coupled chemistry-climate simulations forced by these projections show that HFCs will impact the global atmosphere in 2050. As strong radiative forcers, HFCs modulate atmospheric temperature, thereby changing ozone-destroying catalytic cycles and enhancing the stratospheric circulation. These changes lead to a weak depletion of stratospheric ozone. Sensitivity simulations with the NASA Goddard Space Flight Center (GSFC) 2D model show that HFC-125 is the most important contributor to atmospheric change in 2050, as compared with HFC-23, HFC-32, HFC-134a and HFC-143a. Incorporating the interactions between chemistry, radiation and dynamics, for a likely 2050 climate, ozone depletion potentials (ODPs) for HFCs range from 4.3x10-4 to 3.5x10-2; previously HFCs were assumed to have negligible ODPs since these species lack chlorine or bromine atoms. The ozone impacts of HFCs are further investigated with the Goddard Earth Observing System Chemistry-Climate Model (GEOSCCM). The GEOSCCM is a three-dimensional, fully coupled ocean-atmosphere model with interactive stratospheric chemistry. Sensitivity simulations in which CO2, CFC-11 and HCFC-22 are enhanced individually are used as proxies for the atmospheric response to the HFC concentrations expected by the mid-21st century. Sensitivity simulations provide quantitative estimates of the impacts of these greenhouse gases on global total ozone, and can be used to assess their effects on the recovery of Antarctic ozone.

  17. Monoamine Oxidase a Promoter Gene Associated with Problem Behavior in Adults with Intellectual/Developmental Disabilities

    ERIC Educational Resources Information Center

    May, Michael E.; Srour, Ali; Hedges, Lora K.; Lightfoot, David A.; Phillips, John A., III; Blakely, Randy D.; Kennedy, Craig H.

    2009-01-01

    A functional polymorphism in the promoter of the gene encoding monoamine oxidase A has been associated with problem behavior in various populations. We examined the association of MAOA alleles in adult males with intellectual/developmental disabilities with and without established histories of problem behavior. These data were compared with a…

  18. INVESTIGATIONS OF AMITRAZ NEUROTOXICITY IN RATS. III. EFFECTS ON MOTOR ACTIVITY AND INHIBITION OF MONOAMINE OXIDASE

    EPA Science Inventory

    The formamidine pesticide amitraz (AMZ) produces many behavioral and physiological changes in rats. o explore possible neurochemical mechanisms for the behavioral effects of AMZ, we examined the dose effect and time course of AMZ on motor activity, monoamine oxidase (MAO) and ace...

  19. Whole brain monoamine detection and manipulation in a stalk-eyed fly.

    PubMed

    Bubak, Andrew N; Swallow, John G; Renner, Kenneth J

    2013-09-30

    Understanding the physiological mechanisms that influence conflict resolution is of great importance because the outcome of contests over limited resources such as mates, territories, and food has significant fitness consequences. Male stalk-eyed flies (Teleopsis dalmanni) compete over territory and mates and provide an excellent model system to study aggression. To investigate potential effects of serotonin (5-HT) on aggressive behavior in these flies, we developed a dissection and sample preparation method sufficiently sensitive to measure monoamine concentrations from whole brain samples of small insects. This new method allows the detection of monoamines from a single fly brain using high performance liquid chromatography with electrochemical detection. The method allows for the detection and quantification of octopamine (OA), 5-hydroxytryptophan (5-HTP), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), tyramine (TA), and serotonin (5-HT) and provides a means for assessing changes in stalk-eyed fly brain monoamine concentrations in response to drug administration in food media. We successfully elevated 5-HT levels approximately 8-fold that of control levels in stalk-eyed fly brains by oral administration of the 5-HT precursor 5-HTP. Furthermore, in size-matched competitions for a food resource, flies that had elevated 5-HT in response to 5-HTP pretreatment exhibited a high probability of winning the contests. These results suggest that 5-HT enhances aggression in the stalk-eyed fly and highlight the potential of our method for testing putative roles of monoamines in modulating self and rival assessment in conflict resolution. PMID:23891953

  20. Beyond Monoamines-Novel Targets for Treatment-Resistant Depression: A Comprehensive Review

    PubMed Central

    Rosenblat, Christian; McIntyre, Roger S.; Alves, Gilberto S.; Fountoulakis, Konstantinos N.; Carvalho, André F.

    2015-01-01

    Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown. PMID:26467412

  1. In vivo relationship between monoamine oxidase type B and alcohol dehydrogenase: effects of ethanol and phenylethylamine

    SciTech Connect

    Aliyu, S.U.; Upahi, L.

    1988-01-01

    The role of acute ethanol and phenylethylamine on the brain and platelet monoamine oxidase activities, hepatic cytosolic alcohol dehydrogenase, redox state and motor behavior were studied in male rats. Ethanol on its own decreased the redox couple ratio, as well as, alcohol dehydrogenase activity in the liver while at the same time it increased brain and platelet monoamine oxidase activity due to lower Km with no change in Vmax. The elevation in both brain and platelet MAO activity was associated with ethanol-induced hypomotility in the rats. Co-administration of phenylethylamine and ethanol to the animals, caused antagonism of the ethanol-induced effects described above. The effects of phenylethylamine alone, on the above mentioned biochemical and behavioral indices, are more complex. Phenylethylamine on its own, like ethanol, caused reduction of the cytosolic redox, ratio and elevation of monoamine oxidase activity in the brain and platelets. However, in contrast to ethanol, this monoamine produced hypermotility and activation of the hepatic cytosolic alcohol dehydrogenase activity in the animals.

  2. Alterations in central monoamine systems after postnatal lead acetate treatment in rats

    SciTech Connect

    Luthman, J. Univ. of Colorado Health Sciences Center, Denver, CO ); Lindqvist, E.; Olson, L. ); Gerhardt, G.A.; Hoffer, B.H. )

    1994-04-01

    The present study was undertaken to investigate the effect of postnatal lead exposure on central monoamine systems. Newborn male Sprague-Dawley rats were given 1 or 8 mg/kg lead acetate intraperitoneally for 20 days postnatally. Two groups of control rats received sodium acetate, or sodium acetate in oversized litters to compensate for lead-induced malnutrition in the high lead dose group, while nontreated animals also served as controls. At Day 21 or 51 regional tissue levels of monoamines were determined using HPLC techniques. No major changes were seen after the lead exposures in the levels of dopamine, noradrenaline, and serotonin, or metabolites of dopamine and serotonin, when compared to respective control groups. On the other hand, in the control group given sodium acetate in oversized litters some alterations of the monoamine levels were observed in frontal cortex and striatum at Day 21 compared to controls. At Day 51, the striatal homovanillic acid and 5-hydroxyindoleacetic acid levels were higher in the low lead dose group compared to those in the controls, No other changes in the monoamine levels were seen at Day 51. At 50-70 days postnatally, potassium-stimulated dopamine overflow was studied in striatum with in vivo chronoamperometry. In the high lead dose group the amplitudes of signals were lower in both the dorsal and ventral striatum compared to the controls, while no difference was seen in the clearance time of dopamine. The capacity of the dopamine terminals to respond to repeated stimulation was not affected by the lead exposure. Thus, the steady-state levels of monoamines were essentially unaltered after postnatal lead exposure in rats, while functional aspects of striatal dopamine transmission were affected after exposure to the higher dose of lead. These findings support the hypothesis that lead-induced changes in motor skills and exploratory behavior may be related to altered dopamine neurotransmission. 77 refs., 3 figs., 2 tabs.

  3. Resting-state functional connectivity and presynaptic monoamine signaling in Alcohol Dependence.

    PubMed

    Zhu, Xi; Dutta, Nisha; Helton, Sarah G; Schwandt, Melanie; Yan, Jia; Hodgkinson, Colin A; Cortes, Carlos R; Kerich, Mike; Hall, Samuel; Sun, Hui; Phillips, Monte; Momenan, Reza; Lohoff, Falk W

    2015-12-01

    Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls. We conducted resting-state fMRI functional connectivity (FC) analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1. Functional connectivity analyses showed a significant increase of resting-state FC in 4 networks in alcoholics compared to controls (P < 0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (P < 0.05, corrected), but not in controls. Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles. PMID:26368063

  4. 12. VIEW OF DEPLETED URANIUM INGOT AND MOLDS. DEPLETED URANIUM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    12. VIEW OF DEPLETED URANIUM INGOT AND MOLDS. DEPLETED URANIUM CASTING OPERATIONS CEASED IN 1988. (11/14/57) - Rocky Flats Plant, Non-Nuclear Production Facility, South of Cottonwood Avenue, west of Seventh Avenue & east of Building 460, Golden, Jefferson County, CO

  5. Depleted Uranium in Repositories

    SciTech Connect

    Haire, M.J.; Croff, A.G.

    1997-12-31

    For uranium to be useful in most fission nuclear reactors, it must be enriched (i.e. the concentration of the fissile isotope 235U must be increased). Therefore, depleted uranium (DU)-uranium which has less than naturally occurring concentrations of 235U-is a co-product of the enrichment process. Four to six tons of DU exist for every ton of fresh light water reactor fuel. There were 407,006 MgU 407,000 metric tons (t) of DU stored on U.S. Department of Energy (DOE) sites as of July 1993. If this DU were to be declared surplus, converted to a stable oxide form, and emplaced in a near surface disposal facility, the costs are estimated to be several billion dollars. However, the U.S. Nuclear Regulatory Commission has stated that near surface disposal of large quantities of DU tails is not appropriate. Thus, there is the possibility that disposition via disposal will be in a deep geological repository. One alternative that may significantly reduce the cost of DU disposition is to use it beneficially. In fact, DOE has begun the Beneficial Uses of DU Project to identify large scale uses of DU and to encourage its reuse. Several beneficial uses, many of which involve applications in the repository per se or in managing the wastes to go into the repository, are discussed in this report.

  6. The Toxicity of Depleted Uranium

    PubMed Central

    Briner, Wayne

    2010-01-01

    Depleted uranium (DU) is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a clear and defined set of symptoms. Chronic low-dose, or subacute, exposure to depleted uranium alters the appearance of milestones in developing organisms. Adult animals that were exposed to depleted uranium during development display persistent alterations in behavior, even after cessation of depleted uranium exposure. Adult animals exposed to depleted uranium demonstrate altered behaviors and a variety of alterations to brain chemistry. Despite its reduced level of radioactivity evidence continues to accumulate that depleted uranium, if ingested, may pose a radiologic hazard. The current state of knowledge concerning DU is discussed. PMID:20195447

  7. Stratospheric ozone depletion

    PubMed Central

    Rowland, F. Sherwood

    2006-01-01

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290–320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime—the ‘Antarctic ozone hole’. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules. PMID:16627294

  8. Stratospheric ozone depletion.

    PubMed

    Rowland, F Sherwood

    2006-05-29

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290-320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime-the 'Antarctic ozone hole'. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules. PMID:16627294

  9. Validity of urinary monoamine assay sales under the “spot baseline urinary neurotransmitter testing marketing model”

    PubMed Central

    Hinz, Marty; Stein, Alvin; Uncini, Thomas

    2011-01-01

    Spot baseline urinary monoamine assays have been used in medicine for over 50 years as a screening test for monoamine-secreting tumors, such as pheochromocytoma and carcinoid syndrome. In these disease states, when the result of a spot baseline monoamine assay is above the specific value set by the laboratory, it is an indication to obtain a 24-hour urine sample to make a definitive diagnosis. There are no defined applications where spot baseline urinary monoamine assays can be used to diagnose disease or other states directly. No peer-reviewed published original research exists which demonstrates that these assays are valid in the treatment of individual patients in the clinical setting. Since 2001, urinary monoamine assay sales have been promoted for numerous applications under the “spot baseline urinary neurotransmitter testing marketing model”. There is no published peer-reviewed original research that defines the scientific foundation upon which the claims for these assays are made. On the contrary, several articles have been published that discredit various aspects of the model. To fill the void, this manuscript is a comprehensive review of the scientific foundation and claims put forth by laboratories selling urinary monoamine assays under the spot baseline urinary neurotransmitter testing marketing model. PMID:21912487

  10. Desmodeleganine, a new alkaloid from the leaves of Desmodium elegans as a potential monoamine oxidase inhibitor.

    PubMed

    Zhi, Kang-Kang; Yang, Zhong-Duo; Shi, Dan-Feng; Yao, Xiao-Jun; Wang, Ming-Gang

    2014-10-01

    Desmodeleganine (1), a new potential monoamine oxidase inhibitor, along with three known alkaloids, bufotenin (2), hydroxy-N, N-dimethyltryptamine N(12)-oxide (3), 2-(5-methoxy-1H-indol-3-yl)-N, and N-dimethylethylamine (4) were isolated from the leaves of Desmodium elegans. Their structures were elucidated by IR, MS, 1D and 2D NMR spectra. 1 showed strong monoamine oxidase inhibitory activity with IC50 value of 13.92 ± 1.5 μM, when the IC50 value of iproniazid as a standard was 6.5 ± 0.5 μM. The molecular modeling was also performed to explore the binding mode of compounds 1, 2 at the active site of MAO-A and MAO-B. PMID:25102471

  11. Distinct effects of the serotonin-noradrenaline reuptake inhibitors milnacipran and venlafaxine on rat pineal monoamines.

    PubMed

    Muneoka, Katsumasa; Kuwagata, Makiko; Ogawa, Tetsuo; Shioda, Seiji

    2015-06-17

    Monoamine systems are involved in the pathology and therapeutic mechanism of depression. The pineal gland contains large amounts of serotonin as a precursor for melatonin, and its activity is controlled by noradrenergic sympathetic nerves. Pineal diurnal activity and its release of melatonin are relevant to aberrant states observed in depression. We investigated the effects on pineal monoamines of serotonin-noradrenaline reuptake inhibitors, which are widely used antidepressants. Four days of milnacipran treatment led to an increase in noradrenaline and serotonin levels, whereas 4 days of venlafaxine treatment reduced 5-hydroxyindoleacetic acid levels; both agents induced an increase in dopamine levels. Our data suggest that milnacipran increases levels of the precursor for melatonin synthesis by facilitating the noradrenergic regulation of pineal activity and that venlafaxine inhibits serotonin reuptake into noradrenergic terminals on the pineal gland. PMID:26016648

  12. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A

    SciTech Connect

    Brunner, H.G. ); Nelen, M.; Ropers, H.H.; van Oost, B.A. )

    1993-10-22

    Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine to a termination codon. Thus, isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.

  13. Evidence for a genetic association between alleles of monoamine oxidase A gene and bipolar affective disorder

    SciTech Connect

    Lim, L.C.C.; Sham, P.; Castle, D.

    1995-08-14

    We present evidence of a genetic association between bipolar disorder and alleles at 3 monoamine oxidase A (MAOA) markers, but not with alleles of a monoamine oxidase B (MAOB) polymorphism. The 3 MAOA markers, including one associated with low MAOA activity, show strong allelic association with each other but surprisingly not with MAOB. Our results are significantly only for females, though the number of males in our sample is too small to draw any definite conclusions. Our data is consistent with recent reports of reduced MAOA activity in patients with abnormal behavioral phenotypes. The strength of the association is weak, but significant, which suggests that alleles at the MAOA locus contribute to susceptibility to bipolar disorder rather than being a major determinant. 58 refs., 1 fig., 3 tabs.

  14. Metabolite profiling of antidepressant drug action reveals novel drug targets beyond monoamine elevation

    PubMed Central

    Webhofer, C; Gormanns, P; Tolstikov, V; Zieglgänsberger, W; Sillaber, I; Holsboer, F; Turck, C W

    2011-01-01

    Currently used antidepressants elevate monoamine levels in the synaptic cleft. There is good reason to assume that this is not the only source for antidepressant therapeutic activities and that secondary downstream effects may be relevant for alleviating symptoms of depression. We attempted to elucidate affected biochemical pathways downstream of monoamine reuptake inhibition by interrogating metabolomic profiles in DBA/2Ola mice after chronic paroxetine treatment. Metabolomic changes were investigated using gas chromatography-mass spectrometry profiling and group differences were analyzed by univariate and multivariate statistics. Pathways affected by antidepressant treatment were related to energy metabolism, amino acid metabolism and hormone signaling. The identified pathways reveal further antidepressant therapeutic action and represent targets for drug development efforts. A comparison of the central nervous system with blood plasma metabolite alterations identified GABA, galactose-6-phosphate and leucine as biomarker candidates for assessment of antidepressant treatment effects in the periphery. PMID:22832350

  15. Potent and Selective Inhibition of Plasma Membrane Monoamine Transporter by HIV Protease Inhibitors.

    PubMed

    Duan, Haichuan; Hu, Tao; Foti, Robert S; Pan, Yongmei; Swaan, Peter W; Wang, Joanne

    2015-11-01

    Plasma membrane monoamine transporter (PMAT) is a major uptake-2 monoamine transporter that shares extensive substrate and inhibitor overlap with organic cation transporters 1-3 (OCT1-3). Currently, there are no PMAT-specific inhibitors available that can be used in in vitro and in vivo studies to differentiate between PMAT and OCT activities. In this study, we showed that IDT307 (4-(4-(dimethylamino)phenyl)-1-methylpyridinium iodide), a fluorescent analog of 1-methyl-4-phenylpyridinium (MPP+), is a transportable substrate for PMAT and that IDT307-based fluorescence assay can be used to rapidly identify and characterize PMAT inhibitors. Using the fluorescent substrate-based assays, we analyzed the interactions of eight human immunodeficiency virus (HIV) protease inhibitors (PIs) with human PMAT and OCT1-3 in human embryonic kidney 293 (HEK293) cells stably transfected with individual transporters. Our data revealed that PMAT and OCTs exhibit distinct sensitivity and inhibition patterns toward HIV PIs. PMAT is most sensitive to PI inhibition whereas OCT2 and OCT3 are resistant. OCT1 showed an intermediate sensitivity and a distinct inhibition profile from PMAT. Importantly, lopinavir is a potent PMAT inhibitor and exhibited >120 fold selectivity toward PMAT (IC₅₀ = 1.4 ± 0.2 µM) over OCT1 (IC₅₀ = 174 ± 40 µM). Lopinavir has no inhibitory effect on OCT2 or OCT3 at maximal tested concentrations. Lopinavir also exhibited no or much weaker interactions with uptake-1 monoamine transporters. Together, our results reveal that PMAT and OCTs have distinct specificity exemplified by their differential interaction with HIV PIs. Further, we demonstrate that lopinavir can be used as a selective PMAT inhibitor to differentiate PMAT-mediated monoamine and organic cation transport from those mediated by OCT1-3. PMID:26285765

  16. Altered monoamine and acylcarnitine metabolites in HIV-positive and HIV-negative subjects with depression

    PubMed Central

    Cassol, Edana; Misra, Vikas; Morgello, Susan; Kirk, Gregory D.; Mehta, Shruti H.; Gabuzda, Dana

    2015-01-01

    Background Depression is a frequent comorbidity in HIV infection that has been associated with worse treatment outcomes and increased mortality. Recent studies suggest that increased innate immune activation and tryptophan catabolism are associated with higher risk of depression in HIV infection and other chronic inflammatory diseases, but the mechanisms leading to depression remain poorly understood. Methods The severity of depressive symptoms was assessed by Beck Depression Inventory or Center for Epidemiological Studies Depression Scale. Untargeted metabolomic profiling of plasma from 104 subjects (68 HIV-positive and 36 HIV-negative) across three independent cohorts was performed using liquid or gas chromatography followed by mass spectrometry. Cytokine profiling was by Bioplex array. Bioinformatic analysis was performed in Metaboanalyst and R. Results Decreased monoamine metabolites (phenylacetate, 4-hydroxyphenylacetate) and acylcarnitines (propionylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine) in plasma distinguished depressed subjects from controls in HIV-positive and HIV-negative cohorts, and these alterations correlated with the severity of depressive symptoms. In HIV-positive subjects, acylcarnitines and other markers of mitochondrial function correlated inversely with tryptophan catabolism, a marker of IFN responses, suggesting inter-relationships between inflammatory pathways, tryptophan catabolism, and metabolic alterations associated with depression. Altered metabolites mapped to pathways involved in monoamine metabolism, mitochondrial function, and inflammation, suggesting a model in which complex relationships between monoamine metabolism and mitochondrial bioenergetics contribute to biological mechanisms involved in depression that may be augmented by inflammation during HIV infection. Conclusions Integrated approaches targeting inflammation, monoamine metabolism, and mitochondrial pathways may be important for

  17. Coumarins with monoamine oxidase inhibitory activity and antioxidative coumarino-lignans from Hibiscus syriacus.

    PubMed

    Yun, B S; Lee, I K; Ryoo, I J; Yoo, I D

    2001-09-01

    A previously undescribed coumarin and a new coumarino-lignan, together with the known compounds scopoletin and cleomiscosins A, C, and D, have been isolated from the root bark of Hibiscus syriacus, and their structures were assigned on the basis of various spectral studies. The coumarin analogue and scopoletin inhibited monoamine oxidase with moderate IC(50) values. The new coumarino-lignan and cleomiscosin C showed lipid peroxidation inhibitory activity comparable to vitamin E. PMID:11575966

  18. Ego depletion impairs implicit learning.

    PubMed

    Thompson, Kelsey R; Sanchez, Daniel J; Wesley, Abigail H; Reber, Paul J

    2014-01-01

    Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing) can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL) task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent. PMID:25275517

  19. Vesicular monoamine transporter 2 (Vmat2) knockdown elicits anxiety-like behavior in zebrafish.

    PubMed

    Wang, Yali; Li, Siyue; Liu, Wenwen; Wang, Fen; Hu, Li-Fang; Zhong, Zhao-Min; Wang, Han; Liu, Chun-Feng

    2016-02-19

    Vesicular monoamine transporter 2 (Vmat2) is widely distributed in the central nervous system, and responsible for uptaking transmitters into the vesicles. However, whether Vmat2-deficiency is related to the anxiety is rarely investigated, especially in zebrafish. Here, we reported Vmat2 heterzygous mutant zebrafish displayed anxiety-like behavior. The mutants spent less time in the top area and took longer latency to the top in the novel tank test. Consistently, they showed dark avoidance in the light/dark box test, with longer duration in the light zone and increased number of crossing between the two zones. Monoamine concentration analysis showed that the levels of monoamine neurotransmitters including dopamine (DA), 5-hydroxy tryptamine (5-HT) and norepinephrine (NE), as well as their metabolites were decreased in VMAT mutants. Taken together, these findings suggest that Vmat2 heterzygous mutant zebrafish may serve as a new model of anxiety, which may be related with the low level of DA, 5-HT and NE. PMID:26801555

  20. Transcranial light affects plasma monoamine levels and expression of brain encephalopsin in the mouse.

    PubMed

    Flyktman, Antti; Mänttäri, Satu; Nissilä, Juuso; Timonen, Markku; Saarela, Seppo

    2015-05-15

    Encephalopsin (OPN3) belongs to the light-sensitive transmembrane receptor family mainly expressed in the brain and retina. It is believed that light affects mammalian circadian rhythmicity only through the retinohypothalamic tract, which transmits light information to the suprachiasmatic nucleus in the hypothalamus. However, it has been shown that light penetrates the skull. Here, we present the effect of transcranial light treatment on OPN3 expression and monoamine concentrations in mouse brain and other tissues. Mice were randomly assigned to control group, morning-light group and evening-light group, and animals were illuminated transcranially five times a week for 8 min for a total of 4 weeks. The concentrations of OPN3 and monoamines were analysed using western blotting and HPLC, respectively. We report that transcranial light treatment affects OPN3 expression in different brain areas and plasma/adrenal gland monoamine concentrations. In addition, when light was administered at a different time of the day, the response varied in different tissues. These results provide new information on the effects of light on transmitters mediating mammalian rhythmicity. PMID:25805701

  1. SDS-resistant aggregation of membrane proteins: application to the purification of the vesicular monoamine transporter.

    PubMed Central

    Sagné, C; Isambert, M F; Henry, J P; Gasnier, B

    1996-01-01

    The vesicular monoamine transporter, which catalyses a H+/ monoamine antiport in monoaminergic vesicle membrane, is a very hydrophobic intrinsic membrane protein. After solubilization, this protein was found to have a high tendency to aggregate, as shown by SDS/PAGE, especially when samples were boiled in the classical Laemmli buffer before electrophoresis. This behavior was analysed in some detail. The aggregation was promoted by high temperatures, organic solvents and acidic pH, suggesting that it resulted from the unfolding of structure remaining in SDS. The aggregates were very stable and could be dissociated only by suspension in anhydrous trifluoroacetic acid. This SDS-resistant aggregation behaviour was shared by very few intrinsic proteins of the chromaffin granule membrane. Consequently, a purification procedure was based on this property. A detergent extract of chromaffin granule membranes enriched in monoamine transporter was heated and the aggregates were isolated by size-exclusion HPLC in SDS. The aggregates, containing the transporter, were dissociated in the presence of trifluoroacetic acid and analysed on the same HPLC column. This strategy might be of general interest for the purification of membrane proteins that exhibit SDS-resistant aggregation. PMID:8670158

  2. Vesicular Monoamine and Glutamate Transporters Select Distinct Synaptic Vesicle Recycling Pathways

    PubMed Central

    Onoa, Bibiana; Li, Haiyan; Gagnon-Bartsch, Johann A.; Elias, Laura A. B.; Edwards, Robert H.

    2011-01-01

    Previous work has characterized the properties of neurotransmitter release at excitatory and inhibitory synapses, but we know remarkably little about the properties of monoamine release because these neuromodulators do not generally produce a fast ionotropic response. Since dopamine and serotonin neurons can also release glutamate in vitro and in vivo, we have used the vesicular monoamine transporter VMAT2 and the vesicular glutamate transporter VGLUT1 to compare the localization and recycling of synaptic vesicles that store, respectively, monoamines and glutamate. First, VMAT2 segregates partially from VGLUT1 in the boutons of midbrain dopamine neurons, indicating the potential for distinct release sites. Second, endocytosis after stimulation is slower for VMAT2 than VGLUT1. During the stimulus, however, the endocytosis of VMAT2 (but not VGLUT1) accelerates dramatically in midbrain dopamine but not hippocampal neurons, indicating a novel, cell-specific mechanism to sustain high rates of release. On the other hand, we find that in both midbrain dopamine and hippocampal neurons, a substantially smaller proportion of VMAT2 than VGLUT1 is available for evoked release, and VMAT2 shows considerably more dispersion along the axon after exocytosis than VGLUT1. Even when expressed in the same neuron, the two vesicular transporters thus target to distinct populations of synaptic vesicles, presumably due to their selection of distinct recycling pathways. PMID:20534840

  3. A Peroxidase-linked Spectrophotometric Assay for the Detection of Monoamine Oxidase Inhibitors.

    PubMed

    Zhi, Kangkang; Yang, Zhongduo; Sheng, Jie; Shu, Zongmei; Shi, Yin

    2016-01-01

    To develop a new more accurate spectrophotometric method for detecting monoamine oxidase inhibitors from plant extracts, a series of amine substrates were selected and their ability to be oxidized by monoamine oxidase was evaluated by the HPLC method and a new substrate was used to develop a peroxidase-linked spectrophotometric assay. 4-(Trifluoromethyl) benzylamine (11) was proved to be an excellent substrate for peroxidase-linked spectrophotometric assay. Therefore, a new peroxidase-linked spectrophotometric assay was set up. The principle of the method is that the MAO converts 11 into aldehyde, ammonia and hydrogen peroxide. In the presence of peroxidase, the hydrogen peroxide will oxidize 4-aminoantipyrine into oxidised 4-aminoantipyrine which can condense with vanillic acid to give a red quinoneimine dye. The production of the quinoneimine dye was detected at 490 nm by a microplate reader. The ⊿OD value between the blank group and blank negative control group in this new method is twice as much as that in Holt's method, which enables the procedure to be more accurate and avoids the produce of false positive results. The new method will be helpful for researchers to screening monoamine oxidase inhibitors from deep-color plant extracts. PMID:27610153

  4. Biogenic monoamine uptake by rat brain synaptosomes during aging. Effects of nootropic drugs.

    PubMed

    Stancheva, S L; Alova, L G

    1994-09-01

    1. In experiments on young (3-5-month-old), adult (10-11-month-old) and old (21-22-month-old) rats, it was found that significant age-related changes occurred in the high-affinity uptake of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) by cortical and striatal synaptosomes. 2. Changes in DA, NA and 5-HT uptake during aging are suggested to be neurochemical correlates of cognition and memory deficits that develops in senescence. 3. The in vitro effects of the nootropic drugs piracetam, aniracetam, meclofenoxate and adafenoxate on the DA, NA and 5-HT uptake by cortical and striatal synaptosomes from young rats were studied. Administered in increasing concentrations (1 x 10(-4) to 5 x 10(-3) M) these drugs inhibited monoamine uptake. 4. Adafenoxate proved to be a more potent monoamine uptake inhibitor than the other three drugs; it inhibited the uptake in the frontal cortex and striatum without selectivity for either monoaminergic system. It is suggested that adafenoxate affects cognition through the involvement of central neurotransmission and particularly through the inhibition of monoamine uptake systems. PMID:7835648

  5. Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

    PubMed Central

    Singh, Chanpreet; Bortolato, Marco; Bali, Namrata; Godar, Sean C.; Scott, Anna L.; Chen, Kevin; Thompson, Richard F.; Shih, Jean C.

    2013-01-01

    The monoamine oxidase isoenzymes (MAOs) A and B play important roles in the homeostasis of monoaminergic neurotransmitters. The combined deficiency of MAO A and B results in significantly elevated levels of serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and β-phenylethylamine; in humans and mice, these neurochemical changes are accompanied by neurodevelopmental perturbations as well as autistic-like responses. Ample evidence indicates that normal levels of monoamines in the hippocampus, amygdala, frontal cortex, and cerebellum are required for the integrity of learning and memory. Thus, in the present study, the cognitive status of MAO A/B knockout (KO) mice was examined with a wide array of behavioral tests. In comparison with male wild-type littermates, MAO A/B KO mice exhibited abnormally high and overgeneralized fear conditioning and enhanced eye-blink conditioning. These alterations were accompanied by significant increases in hippocampal long-term potentiation and alterations in the relative expression of NMDA glutamate receptor subunits. Our data suggest that chronic elevations of monoamines, because of the absence of MAO A and MAO B, cause functional alterations that are accompanied with changes in the cellular mechanisms underlying learning and memory. The characteristics exhibited by MAO A/B KO mice highlight the potential of these animals as a useful tool to provide further insight into the molecular bases of disorders associated with abnormal monoaminergic profiles. PMID:23858446

  6. Inactivation of monoamine oxidase by allylamine does not result in flavin attachment

    SciTech Connect

    Silverman, R.B.; Hiebert, C.K.; Vazquez, M.L.

    1985-11-25

    (1-TH)Allylamine was synthesized by sodium boro(TH)hydride reduction of acrolein followed by direct conversion of the (1-TH)allyl alcohol to N-allylphthalimide with triphenylphosphine, diethylazodicarboxylate, and phthalimide. The protecting group was removed with hydrazine. Inactivation of beef liver mitochondrial monoamine oxidase with (1-TH)allylamine led to incorporation of 1-6 eq of inactivator/active site depending upon the length of incubation time. Inactivation and radioactivity incorporation coincided; however, after 1 eq of tritium was incorporated and 5% enzyme activity remained, additional radioactivity continued to become incorporated into the enzyme. The optical spectrum of the FAD coenzyme changed during inactivation from that of oxidized to reduced flavin. Following dialysis of the inactivated enzyme, the spectrum remained reduced, but denaturation in urea rapidly resulted in reoxidation of the flavin. Under these same denaturing conditions, 96% of the radioactivity associated with the enzyme remained bound, therefore indicating that allylamine attachment is not to the flavin coenzyme but rather to an active site amino acid residue. The adduct also was stable to base and, to a lesser degree, acid treatment. Although allylamine and N-cyclopropylbenzylamine appear to be oxidized by monoamine oxidase to give 3-(amino acid residue) propanal adducts, two different amino acids seem to be involved because of a difference in stability of the adducts. The mechanisms for inactivation of monoamine oxidase by allylamine and reactivation by benzylamine are discussed in relation to previously reported results.

  7. A Peroxidase-linked Spectrophotometric Assay for the Detection of Monoamine Oxidase Inhibitors

    PubMed Central

    Zhi, Kangkang; Yang, Zhongduo; Sheng, Jie; Shu, Zongmei; Shi, Yin

    2016-01-01

    To develop a new more accurate spectrophotometric method for detecting monoamine oxidase inhibitors from plant extracts, a series of amine substrates were selected and their ability to be oxidized by monoamine oxidase was evaluated by the HPLC method and a new substrate was used to develop a peroxidase-linked spectrophotometric assay. 4-(Trifluoromethyl) benzylamine (11) was proved to be an excellent substrate for peroxidase-linked spectrophotometric assay. Therefore, a new peroxidase-linked spectrophotometric assay was set up. The principle of the method is that the MAO converts 11 into aldehyde, ammonia and hydrogen peroxide. In the presence of peroxidase, the hydrogen peroxide will oxidize 4-aminoantipyrine into oxidised 4-aminoantipyrine which can condense with vanillic acid to give a red quinoneimine dye. The production of the quinoneimine dye was detected at 490 nm by a microplate reader. The ⊿OD value between the blank group and blank negative control group in this new method is twice as much as that in Holt’s method, which enables the procedure to be more accurate and avoids the produce of false positive results. The new method will be helpful for researchers to screening monoamine oxidase inhibitors from deep-color plant extracts. PMID:27610153

  8. Effect of MCI-186 on ischemia-induced changes in monoamine metabolism in rat brain.

    PubMed

    Oishi, R; Itoh, Y; Nishibori, M; Watanabe, T; Nishi, H; Saeki, K

    1989-11-01

    We examined the effects of MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger and an inhibitor of ischemia-induced brain edema, on monoamine metabolism in the brains of both normal and ischemic rats. In normal rats, 3 mg/kg i.v. MCI-186, a dose that prevents ischemic brain edema, had no significant effect on brain concentrations of dopamine, norepinephrine, 5-hydroxytryptamine, or their metabolites. After the injection of 5 microliters of 3% polyvinyl acetate into the left internal carotid artery, concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid markedly increased, but that of norepinephrine decreased, in the left telencephalon of embolized rats compared with control rats injected with vehicle; the concentration of 5-hydroxyindoleacetic acid also increased slightly. These effects were maximal 2 hours after embolization. The turnover rate of dopamine between 6 and 8 hours after embolization was significantly higher but that of norepinephrine was slightly lower than that in vehicle-treated rats. When rats were treated with 3 mg/kg i.v. MCI-186 immediately after the injection of polyvinyl acetate, the embolization-induced changes in monoamine metabolism were less marked. Our results suggest that MCI-186 attenuates ischemia-induced changes in brain monoamine metabolism, probably due to its free radical scavenging action, although it has no marked effect in normal rats. PMID:2815191

  9. Behavioral expression of opiate withdrawal is altered after prefrontocortical dopamine depletion in rats: monoaminergic correlates.

    PubMed

    Espejo, E F; Serrano, M I; Caillé, S; Stinus, L

    2001-08-01

    The objective of this study was to establish the effects of prefrontocortical dopamine depletion on opiate withdrawal and prefrontocortical neurochemical changes elicited by morphine dependence and withdrawal. The dopaminergic content was also measured in the nucleus accumbens during withdrawal, in order to detect reactive changes induced by prefrontocortical lesion. Withdrawal was induced by naloxone in morphine-dependent rats. Monoamine levels were analyzed post-mortem by high performance liquid cromatography. The results showed that chronic morphine dependence did not modify basal levels of monoamines in sham rats, revealing neuroadaptation of prefrontocortical dopamine, noradrenaline and serotonin systems to chronic morphine. The neuroadaptive phenomenon remained after prefrontocortical lesion (> 79% dopamine depletion). On the other hand, a strong increase of dopamine, noradrenaline, and serotonin contents in the medial prefrontal cortex of sham rats was detected during opiate withdrawal. However, in lesioned rats, the increase of prefrontocortical dopamine and serotonin content, but not that of noradrenaline, was much lower. In the nucleus accumbens, prefrontocortical lesion reactively enhanced the dopaminergic tone and, although opiate withdrawal reduced dopaminergic activity in both sham and lesioned rats, this reduction was less intense in the latter group. At a behavioral level, some symptoms of physical opiate withdrawal were exacerbated in lesioned rats (writhing, mastication, teeth-chattering, global score) and exploration was reduced. The findings hence indicate that: (i) prefrontocortical monoaminergic changes play a role in the behavioral expression of opiate withdrawal; (ii) the severity of some withdrawal signs are related to the dopaminergic and serotonergic tone of the medial prefrontal cortex rather than to the noradrenergic one, and (iii) an inverse relationship between mesocortical and mesolimbic dopaminergic systems exists. PMID:11425504

  10. (/sup 11/C)clorgyline and (/sup 11/C)-L-deprenyl and their use in measuring functional monoamine oxidase activity in the brain using positron emission tomography

    DOEpatents

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

    1986-04-17

    This invention involves a new strategy for imaging the activity of the enzyme monoamine oxidase in the living body by using /sup 11/C-labeled enzyme inhibitors which bind irreversibly to an enzyme as a result of catalysis. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.

  11. Kinetics of Inhibition of Monoamine Oxidase Using Curcumin and Ellagic Acid

    PubMed Central

    Khatri, Dharmendra Kumar; Juvekar, Archana Ramesh

    2016-01-01

    Background: Curcumin and ellagic are the natural polyphenols having a wide range of pharmacological actions. They have been reported to have their use in various neurological disorders. Objective: This study was aimed to evaluate the effect of curcumin and ellagic acid on the activity of monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters which are pivotal for neuronal development and function. Materials and Methods: The in vitro effects of these selected polyphenols on MAO activities in mitochondria isolated from rat brains were examined. Brain mitochondria were assayed for MAO type-B (MAO-B) using benzylamine as substrates. Rat brain mitochondrial MAO preparation was used to study the kinetics of enzyme inhibition using double reciprocal Lineweaver–Burk plot. Results: MAO activity was inhibited by curcumin and ellagic acid; however, higher half maximal inhibitory concentrations of curcumin (500.46 nM) and ellagic acid (412.24 nM) were required compared to the known MAO-B inhibitor selegiline. It is observed that the curcumin and ellagic acid inhibit the MAO activity with both the competitive and noncompetitive type of inhibitions. Conclusions: Curcumin and ellagic acid can be considered a possible source of MAO inhibitor used in the treatment of Parkinson's and other neurological disorders. SUMMARY Monoamine oxidase (MAO) is involved in a variety of neurological disorders including Parkinson's disease (PD)Curcumin and ellagic acid inhibit the monoamine oxidase activityEllagic acid revealed more potent MAO type-B (MAO-B) inhibitory activity than curcuminKinetic studies of MAO inhibition using different concentrations of curcumin and ellagic acid were plotted as double reciprocal Lineweaver–Burk plotThe mode of inhibition of both compounds toward MAO-B is mixed (competitive and uncompetitive) type of inhibition with both the competitive and noncompetitive type of inhibitions. Abbreviations used: MAO: Monoamine oxidase

  12. Depleting depletion: Polymer swelling in poor solvent mixtures

    NASA Astrophysics Data System (ADS)

    Mukherji, Debashish; Marques, Carlos; Stuehn, Torsten; Kremer, Kurt

    A polymer collapses in a solvent when the solvent particles dislike monomers more than the repulsion between monomers. This leads to an effective attraction between monomers, also referred to as depletion induced attraction. This attraction is the key factor behind standard polymer collapse in poor solvents. Strikingly, even if a polymer exhibits poor solvent condition in two different solvents, it can also swell in mixtures of these two poor solvents. This collapse-swelling-collapse scenario is displayed by poly(methyl methacrylate) (PMMA) in aqueous alcohol. Using molecular dynamics simulations of a thermodynamically consistent generic model and theoretical arguments, we unveil the microscopic origin of this phenomenon. Our analysis suggests that a subtle interplay of the bulk solution properties and the local depletion forces reduces depletion effects, thus dictating polymer swelling in poor solvent mixtures.

  13. Fully depleted back illuminated CCD

    DOEpatents

    Holland, Stephen Edward

    2001-01-01

    A backside illuminated charge coupled device (CCD) is formed of a relatively thick high resistivity photon sensitive silicon substrate, with frontside electronic circuitry, and an optically transparent backside ohmic contact for applying a backside voltage which is at least sufficient to substantially fully deplete the substrate. A greater bias voltage which overdepletes the substrate may also be applied. One way of applying the bias voltage to the substrate is by physically connecting the voltage source to the ohmic contact. An alternate way of applying the bias voltage to the substrate is to physically connect the voltage source to the frontside of the substrate, at a point outside the depletion region. Thus both frontside and backside contacts can be used for backside biasing to fully deplete the substrate. Also, high resistivity gaps around the CCD channels and electrically floating channel stop regions can be provided in the CCD array around the CCD channels. The CCD array forms an imaging sensor useful in astronomy.

  14. Depletable externalities and Pigouvian taxation

    SciTech Connect

    Freeman, A.M. III

    1984-06-01

    In their book Baumol and Oates (The Theory of Environmental Policy: Externalities, Public Outlays, and the Quality of Life; Prentice-Hall, Englewood Cliffs, NJ (1975).) argue that whether an externality is depletable (private) or undepletable (public) is the key characteristic in determining the optimal pricing pattern. They argue that unlike the undepletable case a negative depletable externality requires not only a charge or tax on the generator of the externality but a payment or compensation to the victim in order to achieve Pareto optimality. It is shown that the key characteristic determining whether compensation of victims is required for efficiency is not the depletability of the externality but whether the victim can costlessly control or limit the amount of the damaging substance received. 6 references.

  15. Effect of mealing on plasma and brain amino acid, and brain monoamine in rats after oral aspartame.

    PubMed

    Torii, K; Mimura, T; Takasaki, Y; Ichimura, M

    1986-01-01

    Aspartame (APM; L-aspartyl-L-phenylalanine methyl ester) was investigated for its ability to alter brain amino acids and monoamines in overnight fasted rats allowed to consume commercial diets for 60 minutes. In addition, the effects of mealing on the changes in plasma and brain amino acids and brain monoamines induced by glucose and/or insulin, and known pharmacologically active compounds, were studied. The consumption of the commercial chow largely prevented changes in blood glucose and amino acids, and brain amino acids and the monoamines dopamine, norepinephrine and serotonin that might be expected to occur following glucose with or without insulin. Feeding failed to prevent changes in the above parameters when 5-hydroxy-tryptophan, p-chlorophenylalanine and reserpine were administered. The oral administration of up to 250 mg/kg BW APM with water or glucose followed by free feeding failed to alter brain monoamines. These studies demonstrate the potent ability of food to normalize biochemical parameters in blood and brain that otherwise might occur, and clearly show the lack of effect on brain monoamine levels of abuse doses of APM when administered with food. PMID:2940610

  16. Ginsenoside rb1 modulates level of monoamine neurotransmitters in mice frontal cortex and cerebellum in response to immobilization stress.

    PubMed

    Lee, Sang Hee; Hur, Jinyoung; Lee, Eunjoo H; Kim, Sun Yeou

    2012-09-01

    Cerebral monoamines play important roles as neurotransmitters that are associated with various stressful stimuli. Some components such as ginsenosides (triterpenoidal glycosides derived from the Ginseng Radix) may interact with monoamine systems. The aim of this study was to determine whether ginsenoside Rb1 can modulate levels of the monoamines such as dihydroxyphenylalanine (DOPA), dopamine (DA), norepinephrine (NE), epinephrine (EP), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydorxytryptamine (5-HT), 5-hydroxindole-3-acetic acid (5-HIAA), and 5-hydroxytryptophan (5-HTP) in mice frontal cortex and cerebellum in response to immobilization stress. Mice were treated with ginsenoside Rb1 (10 mg/kg, oral) before a single 30 min immobilization stress. Acute immobilization stress resulted in elevation of monoamine levels in frontal cortex and cerebellum. Pretreatment with ginsenoside Rb1 attenuated the stress-induced changes in the levels of monoamines in each region. The present findings showed the anti-stress potential of ginsenoside Rb1 in relation to regulation effects on the cerebral monoaminergic systems. Therefore, the ginsenoside Rb1 may be a useful candidate for treating several brain symptoms related with stress. PMID:24009838

  17. DOPAMINE DEPLETION SLOWS RETINAL TRANSMISSION

    EPA Science Inventory

    In male hooded rats, depletion of norepinephrine and dopamine by a-methyl-paratyrosine (AMT) significantly increased the latencies of early peaks in flash-evoked potentials recorded from the visual cortex, lateral geniculate nucleus, and optic tract. These effects were not produc...

  18. High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU).

    PubMed

    Winn, Shelley R; Scherer, Tanja; Thöny, Beat; Harding, Cary O

    2016-01-01

    Central nervous system (CNS) deficiencies of the monoamine neurotransmitters, dopamine and serotonin, have been implicated in the pathophysiology of neuropsychiatric dysfunction in phenylketonuria (PKU). Increased brain phenylalanine concentration likely competitively inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), the rate limiting steps in dopamine and serotonin synthesis respectively. Tetrahydrobiopterin (BH4) is a required cofactor for TH and TPH activity. Our hypothesis was that treatment of hyperphenylalaninemic Pah(enu2/enu2) mice, a model of human PKU, with sapropterin dihydrochloride, a synthetic form of BH4, would stimulate TH and TPH activities leading to improved dopamine and serotonin synthesis despite persistently elevated brain phenylalanine. Sapropterin (20, 40, or 100mg/kg body weight in 1% ascorbic acid) was administered daily for 4 days by oral gavage to Pah(enu2/enu2) mice followed by measurement of brain biopterin, phenylalanine, tyrosine, tryptophan and monoamine neurotransmitter content. A significant increase in brain biopterin content was detected only in mice that had received the highest sapropterin dose, 100mg/kg. Blood and brain phenylalanine concentrations were unchanged by sapropterin therapy. Sapropterin therapy also did not alter the absolute amounts of dopamine and serotonin in brain but was associated with increased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), dopamine and serotonin metabolites respectively, in both wild type and Pah(enu2/enu2) mice. Oral sapropterin therapy likely does not directly affect central nervous system monoamine synthesis in either wild type or hyperphenylalaninemic mice but may stimulate synaptic neurotransmitter release and subsequent metabolism. PMID:26653793

  19. Changes of brain monoamine levels and physiological indexes during heat acclimation in rats.

    PubMed

    Nakagawa, Hikaru; Matsumura, Takeru; Suzuki, Kota; Ninomiya, Chisa; Ishiwata, Takayuki

    2016-05-01

    Brain monoamines, such as noradrenaline (NA), dopamine (DA), and serotonin (5-HT), regulate many important physiological functions including thermoregulation. The purpose of this study was to clarify changes in NA, DA, and 5-HT levels in several brain regions in response to heat acclimation while also recording body temperature (Tb), heart rate (HR), and locomotor activity (Act). Rats were exposed to a heated environment (32°C) for 3h (3H), 1 day (1D), 7 days, 14 days (14D), 21 days, or 28 days (28D). After heat exposure, each of the following brain regions were immediately extracted and homogenized: the caudate putamen (CPu), preoptic area (PO), dorsomedial hypothalamus (DMH), frontal cortex (FC), and hippocampus (Hip). NA, DA, and 5-HT levels in the extract were measured by high performance liquid chromatography. Although Tb increased immediately after heat exposure, it decreased about 14D later. HR was maintained at a low level throughout heat exposure, and Act tended to increase near the end of heat exposure. After 3H, we observed a marked increase in NA level in the CPu. Although this response vanished after 1D, the level increased again after 28D. DA level in the CPu decreased significantly from 1D to 28D. 5-HT level in the PO and DMH decreased from 1D to 14D. It returned to control levels after 28D with increment of DA level. 5-HT level in the FC decreased at the start of heat exposure, but recovered after 28D; a time point at which DA level also increased. Monoamine levels in the Hip were unchanged after early heat exposure, but both 5-HT and DA levels increased after 28D. These results provide definitive evidence of changes in monoamines in individual brain regions involved in thermoregulation and behavioral, cognitive, and memory function during both acute and chronic heat exposure. PMID:27157329

  20. Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters

    PubMed Central

    Sandtner, Walter; Stockner, Thomas; Hasenhuetl, Peter S.; Partilla, John S.; Seddik, Amir; Zhang, Yuan-Wei; Cao, Jianjing; Holy, Marion; Steinkellner, Thomas; Rudnick, Gary; Baumann, Michael H.; Ecker, Gerhard F.; Newman, Amy Hauck

    2016-01-01

    Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating the mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted 3,4-methylenedioxyamphetamine analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-N-methylamphetamine, 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) were prepared. We evaluated the functional activities of the compounds at all three monoamine transporters in native brain tissue and cells expressing the transporters. In addition, we used ligand docking to generate models of the respective protein-ligand complexes, which allowed us to relate the experimental findings to available structural information. Our results suggest that the 3,4-methylenedioxyamphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes. 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy-N-methylamphetamine adopt a high-affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a low-affinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes, whereas MDTMA exclusively binds to the low-affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation. PMID:26519222

  1. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics.

    PubMed

    Riba, Jordi; Valle, Marta; Urbano, Gloria; Yritia, Mercedes; Morte, Adelaida; Barbanoj, Manel J

    2003-07-01

    The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug's pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting beta-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system. PMID:12660312

  2. Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters.

    PubMed

    Sandtner, Walter; Stockner, Thomas; Hasenhuetl, Peter S; Partilla, John S; Seddik, Amir; Zhang, Yuan-Wei; Cao, Jianjing; Holy, Marion; Steinkellner, Thomas; Rudnick, Gary; Baumann, Michael H; Ecker, Gerhard F; Newman, Amy Hauck; Sitte, Harald H

    2016-01-01

    Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating the mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted 3,4-methylenedioxyamphetamine analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-N-methylamphetamine, 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) were prepared. We evaluated the functional activities of the compounds at all three monoamine transporters in native brain tissue and cells expressing the transporters. In addition, we used ligand docking to generate models of the respective protein-ligand complexes, which allowed us to relate the experimental findings to available structural information. Our results suggest that the 3,4-methylenedioxyamphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes. 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy-N-methylamphetamine adopt a high-affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a low-affinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes, whereas MDTMA exclusively binds to the low-affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation. PMID:26519222

  3. X-linked borderline mental retardation with prominent behavioral disturbance: Phenotype, genetic localization, and evidence for disturbed monoamine metabolism

    SciTech Connect

    Brunner, H.G.; Nelen, M.R.; Zandvoort, P. van; Abeling, N.G.G.M.; Gennip, A.H. van; Ropers, H.H.; Oost, B.A. van ); Wolters, E.C.; Kuiper, M.A. )

    1993-06-01

    The authors have identified a large Dutch kindred with a new form of X-linked nondysmorphic mild mental retardation. All affected males in this family show very characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior include arson, attempted rape, and exhibitionism. Attempted suicide has been reported in a single case. The locus for this disorder could be assigned to the Xp11-21 interval between DXS7 and DXS77 by linkage analysis using markers spanning the X chromosome. A maximal multipoint lod score of 3.69 was obtained at the monoamine oxidase type A (MAOA) monoamine metabolism. These data are compatible with a primary defect in the structural gene for MAOA and/or monoamine oxidase type B (MAOB). Normal platelet MAOB activity suggests that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency. 34 refs., 4 figs., 4 tabs.

  4. Noncovalent Complexation of Monoamine Neurotransmitters and Related Ammonium Ions by Tetramethoxy Tetraglucosylcalix[4]arene

    NASA Astrophysics Data System (ADS)

    Torvinen, Mika; Kalenius, Elina; Sansone, Francesco; Casnati, Alessandro; Jänis, Janne

    2012-02-01

    The noncovalent complexation of monoamine neurotransmitters and related ammonium and quaternary ammonium ions by a conformationally flexible tetramethoxy glucosylcalix[4]arene was studied by electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry. The glucosylcalixarene exhibited highest binding affinity towards serotonin, norepinephrine, epinephrine, and dopamine. Structural properties of the guests, such as the number, location, and type of hydrogen bonding groups, length of the alkyl spacer between the ammonium head-group and the aromatic ring structure, and the degree of nitrogen substitution affected the complexation. Competition experiments and guest-exchange reactions indicated that the hydroxyl groups of guests participate in intermolecular hydrogen bonding with the glucocalixarene.

  5. An antifungal gamma-pyrone and xanthones with monoamine oxidase inhibitory activity from Hypericum brasiliense.

    PubMed

    Rocha, L; Marston, A; Kaplan, M A; Stoeckli-Evans, H; Thull, U; Testa, B; Hostettmann, K

    1994-08-01

    A new gamma-pyrone (hyperbrasilone), three known xanthones (1,5-dihydroxyxanthone, 5-hydroxy-1-methoxyxanthone and 6-deoxyjacareubin) and betulinic acid have been isolated from a dichloromethane extract of stems and roots of Hypericum brasiliense. Their structures were established by spectroscopic methods (UV, EI-MS, 1H and 13C NMR) and that of the gamma-pyrone was confirmed by X-ray crystallography. Hyperbrasilone and the xanthones were all antifungal against Cladosporium cucumerinum, while the three xanthones showed differing degrees of inhibition of monoamine oxidase A and B. PMID:7765428

  6. Sex-dependent effects of maternal separation on plasma corticosterone and brain monoamines in response to chronic ethanol administration.

    PubMed

    Kawakami, S E; Quadros, I M H; Machado, R B; Suchecki, D

    2013-12-01

    Prolonged and repeated periods of maternal separation produce behavioral phenotype of increased vulnerability to neuropsychiatric disorders and drug abuse. Most of the changes in behavior, corticosterone (CORT) and monoamine levels induced by long maternal separation (LMS) are observed after a challenge, but not in basal conditions. LMS increases ethanol-induced locomotor response and self-administration, possibly due to changes in CORT release and/or monoamine concentrations. This study examined the effects of LMS in association with chronic ethanol treatment on plasma CORT and brain monoamine concentrations in male and female Swiss mice, which were kept undisturbed (animal facility rearing - AFR) or separated from their mothers for 3h/day, from 2 to 14 days of age (LMS). As adults, one set of male and female mice received no drug treatment to assess the effect of LMS per se. Another set of animals received saline injections for 20 days and one ethanol injection (2.2g/kg, i.p.) on day 21 (acute) or ethanol for 21 days (chronic). Locomotor activity, plasma CORT levels and monoamines in the frontal cortex, striatum and hippocampus of AFR and LMS mice were evaluated in non-treated, acute and chronic ethanol-treated animals. In non-treated mice, no differences were found in CORT or locomotor activity, with small changes in monoamines content. In LMS females, chronic ethanol increased dopamine and serotonin concentrations in the frontal cortex, relative to acute ethanol LMS and to chronic ethanol-treated AFR groups (p<0.05). In LMS males, chronic ethanol increased hippocampal noradrenaline, dopamine, serotonin and metabolites when compared to respective AFR controls, as well as acute LMS. Moreover, chronic ethanol treatment resulted in higher CORT concentrations in LMS than in AFR males. Overall, these results indicate that LMS mice were more susceptible to the effects of chronic ethanol administration on CORT and brain monoamine concentrations, and that these effects

  7. Effect of dichloromethane fraction of Areca catechu nut on monoamines associated behaviors and tyramine pressor sensitivity in rodents.

    PubMed

    Khan, Shagufta; Abbas, Ghulam; Ahmed, Fahad Shabbir; Rahman, Attaur; Dar, Ahsana

    2014-03-01

    The current study was aimed at investigating the effect of Areca catechu nut dichloromethane fraction (7 mg/kg) on monoamines (serotonin and dopamine) modulation (5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypes) and its interaction with tyramine (cheese effect). The dichloromethane fraction caused pronounced increase in 5-HTP-induced tremors (50%) with negligible PEA-induced stereotypes (20%). Additionally, it did not produce a significant increase in the tyramine pressor effects. These results suggest that the dichloromethane fraction of A. catechu nut primarily elevates serotonin levels (probably via monoamine oxidase A inhibition) and does not induce cheese effect. PMID:24577919

  8. Elevated Levels of the Vesicular Monoamine Transporter and a Novel Repetitive Behavior in the Drosophila Model of Fragile X Syndrome

    PubMed Central

    Tauber, John M.; Vanlandingham, Phillip A.; Zhang, Bing

    2011-01-01

    Fragile X Syndrome (FXS) is characterized by mental impairment and autism in humans, and it often features hyperactivity and repetitive behaviors. The mechanisms for the disease, however, remain poorly understood. Here we report that the dfmr1 mutant in the Drosophila model of FXS grooms excessively, which may be regulated differentially by two signaling pathways. Blocking metabotropic glutamate receptor signaling enhances grooming in dfmr1 mutant flies, whereas blocking the vesicular monoamine transporter (VMAT) suppresses excessive grooming. dfmr1 mutant flies also exhibit elevated levels of VMAT mRNA and protein. These results suggest that enhanced monoamine signaling correlates with repetitive behaviors and hyperactivity associated with FXS. PMID:22087250

  9. Dietary aspartame with protein on plasma and brain amino acids, brain monoamines and behavior in rats.

    PubMed

    Torii, K; Mimura, T; Takasaki, Y; Ichimura, M

    1986-01-01

    Aspartame (APM; L-aspartyl-L-phenylalanine methyl ester), was investigated for its ability to alter levels of the large neutral amino acids and monoamines in overnight fasted rats allowed to consume meals with or without protein for two hours. Additionally, the possible long term behavioral consequences of APM in 25% casein diets with or without 10% sucrose were determined. Acute APM ingestion increased both plasma and brain phenylalanine and tyrosine levels, but brain tryptophan levels were not altered regardless of dietary protein. Brain norepinephrine and dopamine levels were unaltered by any of the diet while serotonin levels were slightly increased when a protein-free diet was consumed. But APM and/or protein ingestion minimized this increase of brain serotonin levels as much as controls. Chronic APM ingestion failed to influence diurnal feeding patterns, meal size distributions, or diurnal patterns of spontaneous motor activity. The chronic ingestion of abuse doses of APM produced no significant chemical changes in brain capable of altering behavioral parameters believed to be controlled by monoamines in rats. PMID:3714850

  10. An HPLC-ECD method for monoamines and metabolites quantification in cuttlefish (cephalopod) brain tissue.

    PubMed

    Bidel, Flavie; Corvaisier, Sophie; Jozet-Alves, Christelle; Pottier, Ivannah; Dauphin, François; Naud, Nadège; Bellanger, Cécile

    2016-08-01

    The cuttlefish belongs to the mollusk class Cephalopoda, considered as the most advanced marine invertebrates and thus widely used as models to study the biology of complex behaviors and cognition, as well as their related neurochemical mechanisms. Surprisingly, methods to quantify the biogenic monoamines and their metabolites in cuttlefish brain remain sparse and measure a limited number of analytes. This work aims to validate an HPLC-ECD method for the simultaneous quantification of dopamine, serotonin, norepinephrine and their main metabolites in cuttlefish brain. In comparison and in order to develop a method suitable to answer both ecological and biomedical questions, the validation was also carried out on a phylogenetically remote species: mouse (mammals). The method was shown to be accurate, precise, selective, repeatable and sensitive over a wide range of concentrations for 5-hydroxyindole-3-acetic acid, serotonin, dopamine, 3,4-dihydroxyphenylacetic acid and norepinephrine in the both extracts of cuttlefish and mouse brain, though with low precision and recovery for 4-hydroxy-3-methoxyphenylethylene glycol. Homovanillic acid, accurately studied in rodents, was not detectable in the brain of cuttlefish. Overall, we described here the first fully validated HPLC method for the routine measurement of both monoamines and metabolites in cuttlefish brain. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26613377

  11. Parasite manipulation of brain monoamines in California killifish (Fundulus parvipinnis) by the trematode Euhaplorchis californiensis

    USGS Publications Warehouse

    Shaw, J.C.; Korzan, W.J.; Carpenter, R.E.; Kuris, A.M.; Lafferty, K.D.; Summers, C.H.; Overli, O.

    2009-01-01

    California killifish (Fundulus parvipinnis) infected with the brain-encysting trematode Euhaplorchis californiensis display conspicuous swimming behaviours rendering them more susceptible to predation by avian final hosts. Heavily infected killifish grow and reproduce normally, despite having thousands of cysts inside their braincases. This suggests that E. californiensis affects only specific locomotory behaviours. We hypothesised that changes in the serotonin and dopamine metabolism, essential for controlling locomotion and arousal may underlie this behaviour modification. We employed micropunch dissection and HPLC to analyse monoamine and monoamine metabolite concentrations in the brain regions of uninfected and experimentally infected fish. The parasites exerted density-dependent changes in monoaminergic activity distinct from those exhibited by fish subjected to stress. Specifically, E. californiensis inhibited a normally occurring, stress-induced elevation of serotonergic metabolism in the raphae nuclei. This effect was particularly evident in the experimentally infected fish, whose low-density infections were concentrated on the brainstem. Furthermore, high E. californiensis density was associated with increased dopaminergic activity in the hypothalamus and decreased serotonergic activity in the hippocampus. In conclusion, the altered monoaminergic metabolism may explain behavioural differences leading to increased predation of the infected killifish by their final host predators. ?? 2008 The Royal Society.

  12. Parasite manipulation of brain monoamines in California killifish (Fundulus parvipinnis) by the trematode Euhaplorchis californiensis

    PubMed Central

    Shaw, J.C.; Korzan, W.J.; Carpenter, R.E.; Kuris, A.M.; Lafferty, K.D.; Summers, C.H.; Øverli, Ø.

    2008-01-01

    California killifish (Fundulus parvipinnis) infected with the brain-encysting trematode Euhaplorchis californiensis display conspicuous swimming behaviours rendering them more susceptible to predation by avian final hosts. Heavily infected killifish grow and reproduce normally, despite having thousands of cysts inside their braincases. This suggests that E. californiensis affects only specific locomotory behaviours. We hypothesised that changes in the serotonin and dopamine metabolism, essential for controlling locomotion and arousal may underlie this behaviour modification. We employed micropunch dissection and HPLC to analyse monoamine and monoamine metabolite concentrations in the brain regions of uninfected and experimentally infected fish. The parasites exerted density-dependent changes in monoaminergic activity distinct from those exhibited by fish subjected to stress. Specifically, E. californiensis inhibited a normally occurring, stress-induced elevation of serotonergic metabolism in the raphae nuclei. This effect was particularly evident in the experimentally infected fish, whose low-density infections were concentrated on the brainstem. Furthermore, high E. californiensis density was associated with increased dopaminergic activity in the hypothalamus and decreased serotonergic activity in the hippocampus. In conclusion, the altered monoaminergic metabolism may explain behavioural differences leading to increased predation of the infected killifish by their final host predators. PMID:19129105

  13. (+)-Methamphetamine-induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia.

    PubMed

    Herring, Nicole R; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T

    2010-10-01

    Methamphetamine (MA) is widely abused and implicated in residual cognitive deficits. In rats, increases in plasma corticosterone and egocentric learning deficits are observed after a 1-day binge regimen of MA (10 mg/kg x 4 at 2-h intervals). The purpose of this experiment was to determine if adrenal inactivation during and following MA exposure would attenuate the egocentric learning deficits in the Cincinnati water maze (CWM). In the first experiment, the effects of adrenalectomy (ADX) or sham surgery (SHAM) on MA-induced neurotoxicity at 72 h were determined. SHAM-MA animals showed typical patterns of hyperthermia, whereas ADX-MA animals were normothermic. Both SHAM-MA- and ADX-MA-treated animals showed increased neostriatal glial fibrillary acidic protein and decreased monoamines in the neostriatum, hippocampus, and entorhinal cortex. In the second experiment, SHAM-MA- and ADX-MA-treated groups showed equivalently impaired CWM performance 2 weeks post-treatment (increased latencies, errors, and start returns) compared to SHAM-saline (SAL) and ADX-SAL groups with no effects on novel object recognition, elevated zero maze, or acoustic startle/prepulse inhibition. Post-testing, monoamine levels remained decreased in both MA-treated groups in all three brain regions, but were not as large as those observed at 72-h post-treatment. The data demonstrate that MA-induced learning deficits can be dissociated from drug-induced increases in plasma corticosterone or hyperthermia, but co-occur with dopamine and serotonin reductions. PMID:20698032

  14. Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis.

    PubMed

    Andreou, Dimitrios; Söderman, Erik; Axelsson, Tomas; Sedvall, Göran C; Terenius, Lars; Agartz, Ingrid; Jönsson, Erik G

    2015-09-30

    Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis. PMID:26142836

  15. Behavioral and neurochemical effects of amphetamine analogs that release monoamines in the squirrel monkey.

    PubMed

    Kimmel, Heather L; Manvich, Daniel F; Blough, Bruce E; Negus, S Stevens; Howell, Leonard L

    2009-12-01

    To date, there are no effective pharmacotherapies for treating psychostimulant abuse. Previous preclinical and clinical studies have shown that continuous treatment with the monoamine releaser amphetamine reduces cocaine self-administration, but amphetamine selectively targets the dopamine system and is reinforcing. In the present study, we examined the consequences of administration of amphetamine and three structurally related analogs that vary in their potencies for releasing dopamine and serotonin on behavioral-stimulant effects and nucleus accumbens dopamine levels in squirrel monkeys. Amphetamine and PAL-353, which have relatively high selectivity for releasing dopamine vs. serotonin, increased accumbens dopamine levels and induced stimulant effects on behavior maintained by a fixed-interval schedule of reinforcement. PAL-313, which has a relatively low selectivity for releasing dopamine vs. serotonin, increased dopamine levels, but did not induce behavioral-stimulant effects. PAL-287, which is relatively nonselective in releasing dopamine and serotonin, did not increase dopamine levels or induce behavioral-stimulant effects. These results demonstrate that increasing serotonergic activity attenuates dopamine release and dopamine-mediated behavioral effects of monoamine releasers. In addition, these results support further investigation of PAL-313 and similar compounds as a potential medication for treating psychostimulant abuse. PMID:19766133

  16. Cough and cold remedies: a potential danger to patients on monoamine oxidase inhibitors.

    PubMed

    Cuthbert, M F; Greenberg, M P; Morley, S W

    1969-02-15

    Experiments have been carried out in healthy volunteers to study the effects of phenylpropanolamine on the blood pressure and possible interactions with monamine oxidase inhibitors.In three subjects 50 mg. of phenylpropanolamine taken orally produced a modest rise of systolic pressure. Two proprietary preparations containing this dose in a slow-release form had no significant effect on the blood pressure. In all three subjects 100 mg. of phenylpropanolamine taken orally caused a more pronounced rise of systolic pressure and a rise of diastolic pressure.In contrast, 50 mg. of phenylpropanolamine orally caused a rapid and potentially dangerous rise of blood pressure in a subject taking the monamine oxidase inhibitor tranylcypromine, and a similar acute rise of blood pressure occurred in this subject when given a proprietary cough linctus containing the same dose of phenylpropanolamine. These and other results suggest that severe hypertensive episodes are more likely to occur when preparations containing phenylpropanolamine in a free form, rather than in slow-release form, are taken by patients being treated with monoamine oxidase inhibitors.The acute rise of blood pressure due to the interaction of phenylpropanolamine and monoamine oxidase inhibitors was reversed by intramuscular injection of phentolamine. PMID:5763957

  17. Monoamine oxidase B and free radical scavenging activities of natural flavonoids in Melastoma candidum D. Don.

    PubMed

    Lee, M H; Lin, R D; Shen, L Y; Yang, L L; Yen, K Y; Hou, W C

    2001-11-01

    Monoamine oxidase type B (MAO-B) activity and free radicals are elevated in certain neurological diseases. Four natural flavonoids, quercitrin, isoquercitrin, rutin, and quercetin, were isolated for the first time from the leaves of Melastoma candidum D. Don. They exhibited an inhibitory effect on MAO-B. These potent flavonoids were purified using bioassay-guided fractionation and were separated by Diaion, Sephadex LH-20, and MCI CHP20P columns. The IC(50) values of the four potent flavonoids, quercitrin, isoquercitrin, rutin, and quercetin on monoamine oxidase were 19.06, 11.64, 3.89, and 10.89 microM and enzyme kinetics analysis revealed apparent inhibition constants (K(i)) of 21.01, 2.72, 1.83, and 7.95 microM, respectively, on the substrate, benzylamine. The four potent compounds also exhibited hydroxyl radical scavenging activity as determined using a spin trapping electron spin resonance method. This suggests that the four flavonoids from M. candidum possess both MAO-B inhibitory and free radical scavenging activities. These important properties may be used for preventing some neurodegenerative diseases in the future. PMID:11714358

  18. SCISAT to study ozone depletion

    NASA Astrophysics Data System (ADS)

    Showstack, Randy

    The Canadian Space Agency's SCISAT satellite began its mission to study the depletion of the ozone layer, following a successful launch on 12 August.The goal for the atmospheric chemistry experiment, which is SCISAT's mission, is to improve the scientific understanding of the complex chemical changes occurring in the upper atmosphere, particularly in the far north, according to Canada's Minister of Industry, Allan Rock.

  19. Ozone depletion, paradigms, and politics

    SciTech Connect

    Iman, R.L.

    1993-10-01

    The destruction of the Earth`s protective ozone layer is a prime environmental concern. Industry has responded to this environmental problem by: implementing conservation techniques to reduce the emission of ozone-depleting chemicals (ODCs); using alternative cleaning solvents that have lower ozone depletion potentials (ODPs); developing new, non-ozone-depleting solvents, such as terpenes; and developing low-residue soldering processes. This paper presents an overview of a joint testing program at Sandia and Motorola to evaluate a low-residue (no-clean) soldering process for printed wiring boards (PWBs). Such processes are in widespread use in commercial applications because they eliminate the cleaning operation. The goal of this testing program was to develop a data base that could be used to support changes in the mil-specs. In addition, a joint task force involving industry and the military has been formed to conduct a follow-up evaluation of low-residue processes that encompass the concerns of the tri-services. The goal of the task force is to gain final approval of the low-residue technology for use in military applications.

  20. Ozone Depletion from Nearby Supernovae

    NASA Technical Reports Server (NTRS)

    Gehrels, Neil; Laird, Claude M.; Jackman, Charles H.; Cannizzo, John K.; Mattson, Barbara J.; Chen, Wan; Bhartia, P. K. (Technical Monitor)

    2002-01-01

    Estimates made in the 1970's indicated that a supernova occurring within tens of parsecs of Earth could have significant effects on the ozone layer. Since that time improved tools for detailed modeling of atmospheric chemistry have been developed to calculate ozone depletion, and advances have been made also in theoretical modeling of supernovae and of the resultant gamma ray spectra. In addition, one now has better knowledge of the occurrence rate of supernovae in the galaxy, and of the spatial distribution of progenitors to core-collapse supernovae. We report here the results of two-dimensional atmospheric model calculations that take as input the spectral energy distribution of a supernova, adopting various distances from Earth and various latitude impact angles. In separate simulations we calculate the ozone depletion due to both gamma rays and cosmic rays. We find that for the combined ozone depletion from these effects roughly to double the 'biologically active' UV flux received at the surface of the Earth, the supernova must occur at approximately or less than 8 parsecs.

  1. Issues in Stratospheric Ozone Depletion.

    NASA Astrophysics Data System (ADS)

    Lloyd, Steven Andrew

    Following the announcement of the discovery of the Antarctic ozone hole in 1985 there have arisen a multitude of questions pertaining to the nature and consequences of polar ozone depletion. This thesis addresses several of these specific questions, using both computer models of chemical kinetics and the Earth's radiation field as well as laboratory kinetic experiments. A coupled chemical kinetic-radiative numerical model was developed to assist in the analysis of in situ field measurements of several radical and neutral species in the polar and mid-latitude lower stratosphere. Modeling was used in the analysis of enhanced polar ClO, mid-latitude diurnal variation of ClO, and simultaneous measurements of OH, HO_2, H_2 O and O_3. Most importantly, such modeling was instrumental in establishing the link between the observed ClO and BrO concentrations in the Antarctic polar vortex and the observed rate of ozone depletion. The principal medical concern of stratospheric ozone depletion is that ozone loss will lead to the enhancement of ground-level UV-B radiation. Global ozone climatology (40^circS to 50^ circN latitude) was incorporated into a radiation field model to calculate the biologically accumulated dosage (BAD) of UV-B radiation, integrated over days, months, and years. The slope of the annual BAD as a function of latitude was found to correspond to epidemiological data for non-melanoma skin cancers for 30^circ -50^circN. Various ozone loss scenarios were investigated. It was found that a small ozone loss in the tropics can provide as much additional biologically effective UV-B as a much larger ozone loss at higher latitudes. Also, for ozone depletions of > 5%, the BAD of UV-B increases exponentially with decreasing ozone levels. An important key player in determining whether polar ozone depletion can propagate into the populated mid-latitudes is chlorine nitrate, ClONO_2 . As yet this molecule is only indirectly accounted for in computer models and field

  2. Effects of ractopamine feeding, gender and social rank on aggressiveness and monoamine concentrations in different brain areas of finishing pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study evaluated the effects of the feed additive ractopamine (RAC), gender and social rank on aggressiveness and brain monoamines levels of serotonin (5HT), dopamine (DA), their metabolites, norepinephrine (NE) and epinephrine (EP) in finishing pigs. Thirty-two pigs (16 barrows/16 gilts) were a...

  3. Monoamine content during the reproductive cycle of Perna perna depends on site of origin on the Atlantic Coast of Morocco

    PubMed Central

    Klouche, Mounia S.; De Deurwaerdère, Philippe; Dellu-Hagedorn, Françoise; Lakhdar-Ghazal, Nouria; Benomar, Soumaya

    2015-01-01

    Bivalve molluscs such as Perna perna display temporal cycles of reproduction that result from the complex interplay between endogenous and exogenous signals. The monoamines serotonin, dopamine and noradrenaline represent possible endocrine and neuronal links between these signals allowing the molluscs to modulate reproductive functions in conjunction with environmental constraints. Here, we report a disruption of the reproductive cycle of mussels collected from two of three sites along the Moroccan atlantic coast soiled by industrial or domestic waste. Using high pressure liquid chromatography, we show that the temporal pattern of monoamine content in the gonads, pedal and cerebroid ganglia varied throughout the reproductive cycle (resting, developing, maturing, egg-laying) of mussels from the unpolluted site. Marked modification of monoamine tissue content was found between sites, notably in noradrenaline content of the gonads. Discriminant statistics revealed a specific impact of mussel location on the temporal variations of noradrenaline and serotonin levels in gonads and cerebroid ganglia. Correlation analyses showed profound and temporal changes in the monoamine content between organs and ganglia, at the two sites where the reproduction was disrupted. We suggest that environmental constraints lead to profound changes of monoaminergic systems, which thereby compromises the entry of mussels into their reproductive cycle. PMID:26349428

  4. Combining Stimulants and Monoamine Oxidase Inhibitors: A Reexamination of the Literature and a Report of a New Treatment Combination

    PubMed Central

    Israel, Joshua A.

    2015-01-01

    This report reviews the medical literature on combining stimulants with monoamine oxidase inhibitors. A case is also presented documenting successful treatment of major depressive disorder and comorbid attention-deficit/hyperactivity disorder using the previously undocumented combination of transdermal selegiline and lisdexamfetamine. This combination should be used cautiously and with ongoing monitoring of heart rate and blood pressure. PMID:27057401

  5. Identification of conformationally sensitive residues essential for inhibition of vesicular monoamine transport by the noncompetitive inhibitor tetrabenazine.

    PubMed

    Ugolev, Yelena; Segal, Tali; Yaffe, Dana; Gros, Yael; Schuldiner, Shimon

    2013-11-01

    Vesicular monoamine transporter 2 (VMAT2) transports monoamines into storage vesicles in a process that involves exchange of the charged monoamine with two protons. VMAT2 is a member of the DHA12 family of multidrug transporters that belongs to the major facilitator superfamily of secondary transporters. Tetrabenazine (TBZ) is a non-competitive inhibitor of VMAT2 that is used in the treatment of hyperkinetic disorders associated with Huntington disease and Tourette syndrome. Previous biochemical studies suggested that the recognition site for TBZ and monoamines is different. However, the precise mechanism of TBZ interaction with VMAT2 remains unknown. Here we used a random mutagenesis approach and selected TBZ-resistant mutants. The mutations clustered around the lumenal opening of the transporter and mapped to either conserved proline or glycine, or to residues immediately adjacent to conserved proline and glycine. Directed mutagenesis provides further support for the essential role of the latter residues. Our data strongly suggest that the conserved α-helix breaking residues identified in this work play an important role in conformational rearrangements required for TBZ binding and substrate transport. Our results provide a novel insight into the mechanism of transport and TBZ binding by VMAT2. PMID:24062308

  6. Combining Stimulants and Monoamine Oxidase Inhibitors: A Reexamination of the Literature and a Report of a New Treatment Combination.

    PubMed

    Israel, Joshua A

    2015-01-01

    This report reviews the medical literature on combining stimulants with monoamine oxidase inhibitors. A case is also presented documenting successful treatment of major depressive disorder and comorbid attention-deficit/hyperactivity disorder using the previously undocumented combination of transdermal selegiline and lisdexamfetamine. This combination should be used cautiously and with ongoing monitoring of heart rate and blood pressure. PMID:27057401

  7. Effects of delayed treatment with nafronyl oxalate on microsphere embolism-induced changes in monoamine levels of rat brain regions.

    PubMed Central

    Takagi, N.; Miyake, K.; Ohiwa, A.; Nukaga, R.; Takeo, S.

    1996-01-01

    1. The present study was undertaken to examine the effects of delayed treatment with nafronyl oxalate (nafronyl), a cerebral vasodilator, on monoamine neurotransmitters of brain regions in the microsphere-embolized rat. 2. Microsphere embolism was induced by injecting 900 microspheres with a diameter of 48 microns into the right internal carotid artery of rats. Microsphere-embolized rats were treated with nafronyl, 15 mg kg-1, i.p., twice daily from the first to the 5th day. Levels of monoamines and their metabolites in the cerebral cortex, striatum, and hippocampus were measured on days 3 and 5 after the operation by a high-performance liquid chromatograph with electrochemical detection. In vivo tyrosine or tryptophan hydroxylation was estimated by measurement of the accumulation of 3, 4-dihydroxyphenylalanine or 5-hydroxy-1-tryptophan after administration of 3-hydroxybenzylhydrazine dihydrochloride, an inhibitor of aromatic L-amino acid decarboxylase. 3. Microsphere embolism induced decreases in dopamine, noradrenaline and 5-hydroxytryptamine in three brain regions of the right hemisphere on days 3 and 5. In the left hemisphere, the monoamines were reduced, but to a lesser degree than in the right hemisphere. On days 3 and 5, the decrease in the monoamines of the right hemisphere was attenuated by nafronyl treatment except for noradrenaline on day 3. The decrease in the monoamines levels in the left hemisphere was almost completely prevented by nafronyl treatment. 4. On day 3 after microsphere embolism, in vivo tyrosine and tryptophan hydroxylation was lower than the pre-embolic value in all three brain regions. Treatment of the embolized rats with nafronyl significantly attenuated the decrease in in vivo tyrosine and tryptophan hydroxylation in the ipsilateral hemisphere, but not hippocampal tryptophan hydroxylation. 5. The results suggested that treatment with nafronyl improves or attenuates changes in monoamine neurotransmitter metabolism of the brain regions

  8. The Case of Ozone Depletion

    NASA Technical Reports Server (NTRS)

    Lambright, W. Henry

    2005-01-01

    While the National Aeronautics and Space Administration (NASA) is widely perceived as a space agency, since its inception NASA has had a mission dedicated to the home planet. Initially, this mission involved using space to better observe and predict weather and to enable worldwide communication. Meteorological and communication satellites showed the value of space for earthly endeavors in the 1960s. In 1972, NASA launched Landsat, and the era of earth-resource monitoring began. At the same time, in the late 1960s and early 1970s, the environmental movement swept throughout the United States and most industrialized countries. The first Earth Day event took place in 1970, and the government generally began to pay much more attention to issues of environmental quality. Mitigating pollution became an overriding objective for many agencies. NASA's existing mission to observe planet Earth was augmented in these years and directed more toward environmental quality. In the 1980s, NASA sought to plan and establish a new environmental effort that eventuated in the 1990s with the Earth Observing System (EOS). The Agency was able to make its initial mark via atmospheric monitoring, specifically ozone depletion. An important policy stimulus in many respects, ozone depletion spawned the Montreal Protocol of 1987 (the most significant international environmental treaty then in existence). It also was an issue critical to NASA's history that served as a bridge linking NASA's weather and land-resource satellites to NASA s concern for the global changes affecting the home planet. Significantly, as a global environmental problem, ozone depletion underscored the importance of NASA's ability to observe Earth from space. Moreover, the NASA management team's ability to apply large-scale research efforts and mobilize the talents of other agencies and the private sector illuminated its role as a lead agency capable of crossing organizational boundaries as well as the science-policy divide.

  9. Effects of developmental methylphenidate (MPH) treatment on monoamine neurochemistry of male and female rats.

    PubMed

    Panos, John J; O'Callaghan, James P; Miller, Diane B; Ferguson, Sherry A

    2014-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is estimated to affect 4-5% of the adult human population (Kessler et al., 2006; Willcutt, 2012). Often prescribed to attenuate ADHD symptoms (Nair and Moss, 2009), methylphenidate hydrochloride (MPH) can have substantial positive effects. However, there is a paucity of literature regarding its use during pregnancy. Thus, adult women with ADHD face a difficult decision when contemplating pregnancy. In this study, pregnant Sprague-Dawley rats were orally treated a total of 0 (water), 6 (low), 18 (medium), or 42 (high) mg MPH/kg body weight/day (divided into three doses) on gestational days 6-21 (i.e., the low dose received 2 mg MPH/kg body weight 3×/day). Offspring were orally treated with the same daily dose as their dam (divided into two doses) on postnatal days (PNDs) 1-21. One offspring/sex/litter was sacrificed at PND 22 or PND 104 (n=6-7/age/sex/treatment group) and the striatum was quickly dissected and frozen. High Performance Liquid Chromatography (HPLC) coupled to a Photo Diode Array detector (PDA) was used to analyze monoamine content in the striatum of one side while a sandwich ELISA was used to analyze tyrosine hydroxylase (TH) from the other side. Age significantly affected monoamine and metabolite content as well as turnover ratios (i.e., DA, DOPAC, HVA, DOPAC/DA, HVA/DA, 5-HT and 5-HIAA); however, there were no significant effects of sex. Adult rats of the low MPH group had higher DA levels than control adults (p<0.05). At both ages, subjects of the low MPH group had higher TH levels than controls (p<0.05), although neither effect (i.e., higher DA or TH levels) exhibited an apparent dose-response. PND 22 subjects of the high MPH treatment group had higher ratios of HVA/DA and DOPAC/DA than same-age control subjects (p<0.05). The increased TH levels of the low MPH group may be related to the increased DA levels of adult rats. While developmental MPH treatment appears to have some effects on monoamine

  10. "When the going gets tough, who keeps going?" Depletion sensitivity moderates the ego-depletion effect.

    PubMed

    Salmon, Stefanie J; Adriaanse, Marieke A; De Vet, Emely; Fennis, Bob M; De Ridder, Denise T D

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In three studies, we assessed individual differences in depletion sensitivity, and demonstrate that depletion sensitivity moderates ego-depletion effects. The Depletion Sensitivity Scale (DSS) was employed to assess depletion sensitivity. Study 1 employs the DSS to demonstrate that individual differences in sensitivity to ego-depletion exist. Study 2 shows moderate correlations of depletion sensitivity with related self-control concepts, indicating that these scales measure conceptually distinct constructs. Study 3 demonstrates that depletion sensitivity moderates the ego-depletion effect. Specifically, participants who are sensitive to depletion performed worse on a second self-control task, indicating a stronger ego-depletion effect, compared to participants less sensitive to depletion. PMID:25009523

  11. Biomedical consequences of ozone depletion

    NASA Astrophysics Data System (ADS)

    Coohill, Thomas P.

    1994-07-01

    It is widely agreed that a portion of the earth's protective stratospheric ozone layer is being depleted. The major effect of this ozone loss will be an increase in the amount of ultraviolet radiation (UV reaching the biosphere. This increase will be completely contained within the UVB (290nm - 320nm). It is imperative that assessments be made of the effects of this additional UVB on living organisms. This requires a detailed knowledge of the UVB photobiology of these life forms. One analytical technique to aid in the approximations is the construction of UV action spectra for such important biological end-points as human skin cancer, cataracts, immune suppression; plant photosynthesis and crop yields; and aquatic organism responses to UVB, especially the phytoplankton. Combining these action spectra with the known solar spectrum (and estimates for various ozone depletion scenarios) can give rise to a series of effectiveness spectra for these parameters. This manuscript gives a first approximation, rough estimate, for the effectiveness spectra for some of these bioresponses, and a series of crude temporary values for how a 10% ozone loss would affect the above end-points. These are not intended to masquerade as final answers, but rather, to serve as beginning attempts for a process which should be continually refined. It is hoped that these estimates will be of some limited use to agencies, such as government and industry, that have to plan now for changes in human activities that might alter future atmospheric chemistry in a beneficial manner.

  12. The 1988 Antarctic ozone depletion: Comparison with previous year depletions

    SciTech Connect

    Schoeberl, M.R.; Stolarski, R.S.; Krueger, A.J. )

    1989-05-01

    The 1988 spring Antarctic ozone depletion was observed by TOMS to be substantially smaller than in recent years. The minimum polar total ozone values declined only 15% during September 1988 compared to nearly 50% during September 1987. At southern midlatitudes, exceptionally high total ozone values were recorded beginning in July 1988. The total integrated southern hemispheric ozone increased rapidly during the Austral spring, approaching 1980 levels during October. The high midlatitude total ozone values were associated with a substantial increase in eddy activity as indicated by the standard deviation in total ozone in the zonal band 30{degree}-60{degree}S. The standard deviation also correlates with the QBO cycling of the tropical winds. Mechanisms through which the increased midlatitude eddy activity could disrupt the formation of the Antarctic ozone hole are briefly discussed.

  13. The 1988 Antarctic ozone depletion - Comparison with previous year depletions

    NASA Technical Reports Server (NTRS)

    Schoeberl, Mark R.; Stolarski, Richard S.; Krueger, Arlin J.

    1989-01-01

    The 1988 spring Antarctic ozone depletion was observed by TOMS to be substantially smaller than in recent years. The minimum polar total ozone values declined only 15 percent during September 1988, compared to nearly 50 percent during September 1987. At southern midlatitudes, exceptionally high total ozone values were recorded beginning in July 1988. The total integrated southern hemispheric ozone increased rapidly during the Austral spring, approaching 1980 levels during October. The high midlatitude total ozone values were associated with a substantial increase in eddy activity as indicated by the standard deviation in total ozone in the zonal band 30-60 deg S. Mechanisms through which the increased midlatitude eddy activity could disrupt the formation of the Antarctic ozone hole are briefly discussed.

  14. The reaction pathway of membrane-bound rat liver mitochondrial monoamine oxidase

    PubMed Central

    Houslay, Miles D.; Tipton, Keith F.

    1973-01-01

    1. A preparation of a partly purified mitochondrial outer-membrane fraction suitable for kinetic investigations of monoamine oxidase is described. 2. An apparatus suitable for varying the O2 concentration in a spectrophotometer cuvette is described. 3. The reaction catalysed by the membrane-bound enzyme is shown to proceed by a double-displacement (Ping Pong) mechanism, and a formal mechanism is proposed. 4. KCN, NaN3, benzyl cyanide and 4-cyanophenol are shown to be reversible inhibitors of the enzyme. 5. The non-linear reciprocal plot obtained with impure preparations of benzylamine, which is typical of high substrate inhibition, is shown to be due to aldehyde contamination of the substrate. PMID:4778271

  15. A mutation in the enzyme monoamine oxidase explains part of the Astyanax cavefish behavioural syndrome.

    PubMed

    Elipot, Yannick; Hinaux, Hélène; Callebert, Jacques; Launay, Jean-Marie; Blin, Maryline; Rétaux, Sylvie

    2014-01-01

    We use Astyanax mexicanus, a single species with surface-dwelling forms (SF) and blind de-pigmented cave forms (CF), to study mechanisms underlying the evolution of brain and behaviour. In CF, the origin of changes in complex motivated behaviours (social, feeding, sleeping, exploratory) is unknown. Here we find a hyper-aminergic phenotype in CF brains, including high levels and neurotransmission indexes for serotonin, dopamine and noradrenaline, and low monoamine oxidase (MAO) activity. Although MAO expression is unchanged in CF, a pro106leu mutation is identified in the MAO coding sequence. This mutation is responsible for low MAO activity and high serotonin neurotransmission index in CF brains. We find the same mutated allele in several natural CF populations, some being independently evolved. Such occurrence of the same allele in several caves may suggest that low MAO activity is advantageous for cave life. These results provide a genetic basis for several aspects of the cavefish 'behavioural syndrome'. PMID:24717983

  16. “Ping-pong gaze” secondary to monoamine oxidase inhibitor overdose

    PubMed Central

    Attaway, Amy; Sroujieh, Laila; Mersfelder, Tracey L.; Butler, Christopher; Ouellette, Daniel

    2016-01-01

    An infrequent manifestation of monoamine oxidase inhibitor (MAOI) toxicity is “ping-pong gaze” (PPG). We describe the case of a 26-year-old female who was found unresponsive after taking 40 tablets of phenelzine. On presentation to the hospital, her eyes were moving in characteristic “ping pong” fashion. After 6 hours her gaze terminated. The following day her neurologic exam was benign and she had no long-term sequelae. While the etiology of PPG is unknown, it is most often seen with irreversible structural brain damage. However, a detailed literature review revealed that previous cases of MAOI toxicity where the patient survived have all had complete neurologic recovery. PMID:27127395

  17. Improved method for HPLC analysis of polyamines, agmatine and aromatic monoamines in plant tissue

    NASA Technical Reports Server (NTRS)

    Slocum, R. D.; Flores, H. E.; Galston, A. W.; Weinstein, L. H.

    1989-01-01

    The high performance liquid chromatographic (HPLC) method of Flores and Galston (1982 Plant Physiol 69: 701) for the separation and quantitation of benzoylated polyamines in plant tissues has been widely adopted by other workers. However, due to previously unrecognized problems associated with the derivatization of agmatine, this important intermediate in plant polyamine metabolism cannot be quantitated using this method. Also, two polyamines, putrescine and diaminopropane, also are not well resolved using this method. A simple modification of the original HPLC procedure greatly improves the separation and quantitation of these amines, and further allows the simulation analysis of phenethylamine and tyramine, which are major monoamine constituents of tobacco and other plant tissues. We have used this modified HPLC method to characterize amine titers in suspension cultured carrot (Daucas carota L.) cells and tobacco (Nicotiana tabacum L.) leaf tissues.

  18. Capillary electrochromatography using monoamine- and triamine-bonded silica nanoparticles as pseudostationary phases.

    PubMed

    Takeda, Yuto; Hayashi, Yuka; Utamura, Naonori; Takamoto, Chise; Kinoshita, Mitsuhiro; Yamamoto, Sachio; Hayakawa, Takao; Suzuki, Shigeo

    2016-01-01

    Monoamine- and triamine-bonded silica nanoparticles were prepared using 3-aminopropyltrimethoxysilane and N(1)-(3-trimethoxysilylpropyl)diethylenetriamine, respectively, and used as pseudostationary phases for capillary electrochromatography. The amine-bonded silica nanoparticles were tightly adsorbed on the inner wall of a capillary and generated fast electro-osmotic flow (2.59 × 10(-4) cm(2) V(-1) s(-1)) toward the anode in an electric field. The electro-osmotic velocities obtained with 20 nm triamine-bonded silica were three to five times larger than those generated by a fused silica capillary and two times faster than those for the commercial cationic polymer-modified capillary. Fast electro-osmotic flow enables rapid analysis. This method was applied to hydrophilic interaction chromatography (HILIC) mode separation of various samples including the size separation of glucose oligomer derivatives and the resolution of four nucleic acid bases. PMID:26700155

  19. Exclusion of close linkage between the synaptic vesicular monoamine transporter locus and schizophrenia spectrum disorders

    SciTech Connect

    Persico, A.M.; Uhl, G.R.; Wang, Zhe Wu

    1995-12-18

    The principal brain synaptic vesicular monoamine transporter (VMAT2) is responsible for the reuptake of serotonin, dopamine, norepinephrine, epinephrine, and histamine from the cytoplasm into synaptic vesicles, thus contributing to determination of the size of releasable neurotransmitter vesicular pools. Potential involvement of VMAT2 gene variants in the etiology of schizophrenia and related disorders was tested using polymorphic VMAT2 gene markers in 156 subjects from 16 multiplex pedigrees with schizophrenia, schizophreniform, schizoaffective, and schizotypal disorders and mood incongruent psychotic depression. Assuming genetic homogeneity, complete ({theta} = 0.0) linkage to the schizophrenia spectrum was excluded under both dominant and recessive models. Allelic variants at the VMAT2 locus do not appear to provide major genetic contributions to the etiology of schizophrenia spectrum disorders in these pedigrees. 16 refs.

  20. A cerium method for the ultracytochemical localization of monoamine oxidase activity.

    PubMed

    Fujimoto, T; Inomata, K; Ogawa, K

    1982-01-01

    A cytochemical method based on the complex formation between cerous ions and hydrogen peroxide is described for the ultrastructural localization of monoamine oxidase (MAO). First, the residual MAO activity after fixation was measured by a radiochemical assay technique and was found to be sufficiently retained for cytochemical detection. Although the Tris buffer used in the present method was found to be inhibitory to MAO, considerable activity was still retained after fixation and incubation in Tris. MAO activity, detected as precipitates of cerium perhydroxide, was observed in the mitochondrial outer compartment, mitochondrial cristae and perinuclear space of myocardial cells and endothelial cells of rat heart. MAO activity was also found along the plasma membrane of capillary endothelia. Omission of substrate from the incubation medium or pre-incubation with pargyline, a specific MAO inhibitor, drastically reduced the amount of deposits. The present cerium method seems promising because of its reproducibility and the high electron density of the reaction products. PMID:6174485

  1. Parkin degrades estrogen-related receptors to limit the expression of monoamine oxidases.

    PubMed

    Ren, Yong; Jiang, Houbo; Ma, Dingyuan; Nakaso, Kazuhiro; Feng, Jian

    2011-03-15

    Parkin, whose mutations cause Parkinson disease (PD), controls oxidative stress by limiting the expression of monoamine oxidases (MAO)--mitochondrial enzymes responsible for the oxidative de-amination of dopamine. Here, we show that parkin performed this function by increasing the ubiquitination and degradation of estrogen-related receptors (ERR), orphan nuclear receptors that play critical roles in the transcription regulation of many nuclear-encoded mitochondrial proteins. All three ERRs (α, β and γ) increased the transcription of MAOs A and B; the effects were abolished by parkin, but not by its PD-linked mutants. Parkin bound to ERRs and increased their ubiquitination and degradation. In fibroblasts from PD patients with parkin mutations or brain slices from parkin knockout mice, degradation of ERRs was significantly attenuated. The results reveal the molecular mechanism by which parkin suppresses the transcription of MAOs to control oxidative stress induced by dopamine oxidation. PMID:21177257

  2. Parkin degrades estrogen-related receptors to limit the expression of monoamine oxidases

    PubMed Central

    Ren, Yong; Jiang, Houbo; Ma, Dingyuan; Nakaso, Kazuhiro; Feng, Jian

    2011-01-01

    Parkin, whose mutations cause Parkinson disease (PD), controls oxidative stress by limiting the expression of monoamine oxidases (MAO)—mitochondrial enzymes responsible for the oxidative de-amination of dopamine. Here, we show that parkin performed this function by increasing the ubiquitination and degradation of estrogen-related receptors (ERR), orphan nuclear receptors that play critical roles in the transcription regulation of many nuclear-encoded mitochondrial proteins. All three ERRs (α, β and γ) increased the transcription of MAOs A and B; the effects were abolished by parkin, but not by its PD-linked mutants. Parkin bound to ERRs and increased their ubiquitination and degradation. In fibroblasts from PD patients with parkin mutations or brain slices from parkin knockout mice, degradation of ERRs was significantly attenuated. The results reveal the molecular mechanism by which parkin suppresses the transcription of MAOs to control oxidative stress induced by dopamine oxidation. PMID:21177257

  3. Monoamine oxidase: an important intracellular regulator of gastrin release in the rat.

    PubMed

    Dial, E J; Huang, J; Delansorne, R; Lichtenberger, L M

    1986-04-01

    The role of monoamine oxidase (MAO) in the meal-induced or amino acid-induced release of gastrin was investigated. Rats that were pretreated with the nonspecific MAO inhibitor nialamide (200 mg/kg) showed a greater rise in meal-induced serum gastrin than did untreated controls. In vitro experiments demonstrated that gastrin secretion from dispersed antral G cells in response to a stimulatory dose of phenylalanine or methylbenzylamine (10 mM) was markedly enhanced if the cells were treated with nialamide. Studies with the more specific MAO inhibitors clorgyline and deprenyl indicated that antral mucosa contained predominantly type A activity. Inhibition of MAO type A with clorgyline, both in vivo and in vitro, resulted in a greater release of gastrin after stimulation by a meal or phenylalanine. It is concluded that MAO may play an important role in the regulation of gastrin release from the G cell by partially controlling the level of amines within the cell. PMID:3081396

  4. [Effects of Kaixin San formulas on behavioristics and central monoamine neurotransmitters of chronic stress rats].

    PubMed

    Liu, Wan-wan; Xu, Lu; Dong, Xian-zhe; Tan, Xiao; Wang, Shi; Zhu, Wei-yu; Liu, Ping

    2015-06-01

    The efficacy of Chinese herbal formula in treating depression has been proved in many studies. In this study, six different Kaixin San formulas were compared to investigate their effects on central monoamine neurotransmitters of chronic stress rats and against depression based on their different components in plasma, in order to discuss the efficacy-comparability relationship and the possible efficacy mechanism. The classic isolation method and the chronic unpredictable mild stress (CUMS) depression model were combined to investigate the changes in contents in hippocampus and monoamine neurotransmitters (NE, DA, 5-HT) and the components of some formulas in plasma with HPLC and UPLC-Q-TOF-MSE methods. As a result, Dingzhi Xiaowan recorded in Essential Recipes for Emergent Use Worth A Thousand significantly increased the behavioral scores, NE and 5-HT contents in hippocampus and NE, DA and 5-HT contents in cortex, with the best anti-depressant effect. Dingzhi Xiaowan recorded in Complete Records of Ancient and Modern Medical Works showed a notable increase in sucrose preference and open field score in model rats, NE content in hippocampus and NE, DA and 5-HT contents in cortex, with a certain anti anti-depressant effect. Kaixin San recorded in Ishinpo showed remarkable rise in weight of model rats. NE content in hippocampus and DA content in cortex. Puxin Decoction recorded in A Supplement to Recipes Worth A Thousand Gold showed 5-HT content in hippocampus and DA content in cortex. Kaixin San recorded in Yimenfang only showed DA content in cortex. Kaixin Wan recorded in Essential Recipes for Emergent Use Worth A Thousand did not mention the antidepressant effect. According to the results, the formulas' different anti-depressant effects may be related to the different plasma components. PMID:26552177

  5. DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls

    SciTech Connect

    Adamson, M.D.; Dean, M.; Goldman, D.

    1995-06-19

    The DRD4 dopamine receptor is thus far unique among neurotransmitter receptors in having a highly polymorphic gene structure that has been reported to produce altered receptor functioning. These allelic variations are caused by a 48-bp segment in exon III of the coding region which may be repeated from 2-10 times. Varying the numbers of repeated segments changes the length, structure, and, possibly, the functional efficiency of the receptor, which makes this gene an intriguing candidate for variations in dopamine-related behaviors, such as alcoholism and drug abuse. Thus far, these DRD4 alleles have been investigated for association with schizophrenia, bipolar disorder, Parkinson`s disease, and chronic alcoholism, and all have been largely negative for a direct association. We evaluated the DRD4 genotype in 226 Finish adult males, 113 of whom were alcoholics, many of the early onset type with features of impulsivity and antisocial traits. Genotype frequencies were compared to 113 Finnish controls who were free of alcohol abuse, substance abuse, and major mental illness. In 70 alcoholics and 20 controls, we measured CSF homovanillic acid (HVA), the major metabolite of dopamine, and 5-hydroxyindoleacetic acid (5-HIAA). No association was found between a particular DRD4 dopamine receptor allele and alcoholism. CSF concentrations of the monoamine metabolites showed no significant difference among the DRD4 genotypes. This study of the DRD4 dopamine receptor in alcoholics is the first to be conducted in a clinically and ethnically homogeneous population and to relate the DRD4 genotype to CSF monoamine concentrations. The results indicate that there is no association of the DRD4 receptor with alcoholism. 52 refs., 3 figs., 1 tab.

  6. Corticotropin releasing factor influences aggression and monoamines: Modulation of attacks and retreats

    PubMed Central

    Carpenter, Russ E.; Korzan, Wayne J.; Bockholt, Craig; Watt, Michael J.; Forster, Gina L.; Renner, Kenneth J.; Summers, Cliff H.

    2009-01-01

    Salmonids establish social hierarchies as a result of aggressive social interactions. The establishment of dominant or subordinate status is strongly linked to neuroendocrine responses mediated through the stress axis. In this study, we tested the effects of icv CRF on the behavioral outcome, plasma cortisol and monoamine function in trout subjected to a socially aggressive encounter. Rainbow trout were treated with an icv injection of artificial cerebrospinal fluid (aCSF), 500 or 2000 ng ovine CRF, or not injected. Fish were allowed to interact with a similarly sized conspecific for 15 minutes. Following the behavioral interaction, plasma cortisol and central monoamine concentrations were analyzed. Trout treated with CRF were victorious in approximately 60% of the aggressive encounters against aCSF treated opponents. Trout injected with CRF exhibited a reduction in the total number of attacks and decreased latency to attack. When trout were divided winners and losers, only victorious CRF-treated fish exhibited a reduced latency to attack and fewer retreats. Social stress increased cortisol levels in both winners and losers of aggressive interaction. This effect was enhanced with the additional stress incurred from icv injection of aCSF. However, icv CRF in addition to social stress decreased plasma cortisol in both winners and losers. While aggression stimulated significant changes in serotonergic and dopaminergic activity, the magnitude and direction were dependent on limbic brain region, CRF dose, and outcome of social aggression. With broad effects on aggressive behavior, anxiety, stress responsiveness, and central monoaminergic activity, CRF plays an important role modulating the behavioral components of social interaction. PMID:18992791

  7. A brief history of the development of antidepressant drugs: From monoamines to glutamate

    PubMed Central

    Hillhouse, Todd M.; Porter, Joseph H.

    2015-01-01

    Major depressive disorder (MDD) is a chronic, recurring, and debilitating mental illness that is the most common mood disorder in the United States. It has been almost 50 years since the monoamine hypothesis of depression was articulated, and just over 50 years since the first pharmacological treatment for MDD was discovered. Several monoamine-based pharmacological drug classes have been developed and approved for the treatment of MDD; however, remission rates are low (often less than 60%) and there is a delayed onset before remission of depressive symptoms is achieved. As a result of a “proof-of-concept” study in 2000 with the noncompetitive NMDA antagonist ketamine, a number of studies have examined the glutamatergic systems as viable targets for the treatment of MDD. This review will provide a brief history on the development of clinically available antidepressant drugs, and then review the possible role of glutamatergic systems in the pathophysiology of MDD. Specifically, the glutamatergic review will focus on the N-methyl-D-aspartate (NMDA) receptor and the efficacy of drugs that target the NMDA receptor for the treatment of MDD. The noncompetitive NMDA receptor antagonist ketamine, which has consistently produced rapid and sustained antidepressant effects in MDD patients in a number of clinical studies, has shown the most promise as a novel glutamatergic-based treatment for MDD. However, compounds that target other glutamatergic mechanisms, such as GLYX-13 (a glycine-site partial agonist at NMDA receptors) appear promising in early clinical trials. Thus, the clinical findings to date are encouraging and support the continued search for and the development of novel compounds that target glutamatergic mechanisms. PMID:25643025

  8. Reduced vesicular monoamine transport disrupts serotonin signaling but does not cause serotonergic degeneration

    PubMed Central

    Alter, Shawn P.; Stout, Kristen A.; Lohr, Kelly M.; Taylor, Tonya N.; Shepherd, Kennie R.; Wang, Minzheng; Guillot, Thomas S.; Miller, Gary W.

    2016-01-01

    We previously demonstrated that mice with reduced expression of the vesicular monoamine transporter 2 (VMAT2 LO) undergo age-related degeneration of the catecholamine-producing neurons of the substantia nigra pars compacta and locus ceruleus and exhibit motor disturbances and depressive-like behavior. In this work, we investigated the effects of reduced vesicular transport on the function and viability of serotonin neurons in these mice. Adult (4–6 months of age), VMAT2 LO mice exhibit dramatically reduced (90%) serotonin release capacity, as measured by fast scan cyclic voltammetry. We observed changes in serotonin receptor responsivity in in vivo pharmacological assays. Aged (months) VMAT2 LO mice exhibited abolished 5-HT1A autoreceptor sensitivity, as determined by 8-OH-DPAT (0.1 mg/kg) induction of hypothermia. When challenged with the 5HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (1 mg/kg), VMAT2 LO mice exhibited a marked increase (50%) in head twitch responses. We observed sparing of serotonergic terminals in aged mice (18–24 months) throughout the forebrain by SERT immunohistochemistry and [3H]-paroxetine binding in striatal homogenates of aged VMAT2 LO mice. In contrast to their loss of catecholamine neurons of the substantia nigra and locus ceruleus, aged VMAT2 LO mice do not exhibit a change in the number of serotonergic (TPH2 +) neurons within the dorsal raphe, as measured by unbiased stereology at 26–30 months. Collectively, these data indicate that reduced vesicular monoamine transport significantly disrupts serotonergic signaling, but does not drive degeneration of serotonin neurons. PMID:26428905

  9. Depleted Argon from Underground Sources

    SciTech Connect

    Back, H. O.; Galbiati, C.; Goretti, A.; Loer, B.; Montanari, D.; Mosteiro, P.; Alexander, T.; Alton, A.; Rogers, H.; Kendziora, C.; Pordes, S.

    2011-04-27

    Argon is a strong scintillator and an ideal target for Dark Matter detection; however {sup 39}Ar contamination in atmospheric argon from cosmic ray interactions limits the size of liquid argon dark matter detectors due to pile-up. Argon from deep underground is depleted in {sup 39}Ar due to the cosmic ray shielding of the earth. In Cortez, Colorado, a CO{sub 2} well has been discovered to contain approximately 600 ppm of argon as a contamination in the CO{sub 2}. We first concentrate the argon locally to 3% in an Ar, N{sub 2}, and He mixture, from the CO{sub 2} through chromatographic gas separation, and then the N{sub 2} and He will be removed by continuous distillation to purify the argon. We have collected 26 kg of argon from the CO{sub 2} facility and a cryogenic distillation column is under construction at Fermilab to further purify the argon.

  10. Forebrain-specific Expression of Monoamine Oxidase A Reduces Neurotransmitter Levels, Restores the Brain Structure, and Rescues Aggressive Behavior in Monoamine Oxidase A-deficient Mice*

    PubMed Central

    Chen, Kevin; Cases, Olivier; Rebrin, Igor; Wu, Weihua; Gallaher, Timothy K.; Seif, Isabelle; Shih, Jean Chen

    2010-01-01

    Previous studies have established that abrogation of monoamine oxidase (MAO) A expression leads to a neurochemical, morphological, and behavioral specific phenotype with increased levels of serotonin (5-HT), norepinephrine, and dopamine, loss of barrel field structure in mouse somatosensory cortex, and an association with increased aggression in adults. Forebrain-specific MAO A transgenic mice were generated from MAO A knock-out (KO) mice by using the promoter of calcium-dependent kinase IIα (CaMKIIα). The presence of human MAO A transgene and its expression were verified by PCR of genomic DNA and reverse transcription-PCR of mRNA and Western blot, respectively. Significant MAO A catalytic activity, autoradiographic labeling of 5-HT, and immunocytochemistry of MAO A were found in the frontal cortex, striatum, and hippocampus but not in the cerebellum of the forebrain transgenic mice. Also, compared with MAO A KO mice, lower levels of 5-HT, norepinephrine, and DA and higher levels of MAO A metabolite 5-hydroxyin-doleacetic acid were found in the forebrain regions but not in the cerebellum of the transgenic mice. These results suggest that MAO A is specifically expressed in the forebrain regions of transgenic mice. This forebrain-specific differential expression resulted in abrogation of the aggressive phenotype. Furthermore, the disorganization of the somatosensory cortex barrel field structure associated with MAO A KO mice was restored and became morphologically similar to wild type. Thus, the lack of MAO A in the forebrain of MAO A KO mice may underlie their phenotypes. PMID:17090537

  11. CO depletion in the Gould Belt clouds

    NASA Astrophysics Data System (ADS)

    Christie, H.; Viti, S.; Yates, J.; Hatchell, J.; Fuller, G. A.; Duarte-Cabral, A.; Sadavoy, S.; Buckle, J. V.; Graves, S.; Roberts, J.; Nutter, D.; Davis, C.; White, G. J.; Hogerheijde, M.; Ward-Thompson, D.; Butner, H.; Richer, J.; Di Francesco, J.

    2012-05-01

    We present a statistical comparison of CO depletion in a set of local molecular clouds within the Gould Belt using Sub-millimetre Common User Bolometer Array (SCUBA) and Heterodyne Array Receiver Programme (HARP) data. This is the most wide-ranging study of depletion thus far within the Gould Belt. We estimate CO column densities assuming local thermodynamic equilibrium and, for a selection of sources, using the radiative transfer code RADEX in order to compare the two column density estimation methods. High levels of depletion are seen in the centres of several dust cores in all the clouds. We find that in the gas surrounding protostars, levels of depletion are somewhat lower than for starless cores with the exception of a few highly depleted protostellar cores in Serpens and NGC 2024. There is a tentative correlation between core mass and core depletion, particularly in Taurus and Serpens. Taurus has, on average, the highest levels of depletion. Ophiuchus has low average levels of depletion which could perhaps be related to the anomalous dust grain size distribution observed in this cloud. High levels of depletion are often seen around the edges of regions of optical emission (Orion) or in more evolved or less dynamic regions such as the bowl of L1495 in Taurus and the north-western region of Serpens.

  12. The state of the art of pyrazole derivatives as monoamine oxidase inhibitors and antidepressant/anticonvulsant agents.

    PubMed

    Secci, D; Bolasco, A; Chimenti, P; Carradori, S

    2011-01-01

    Monoamine oxidase plays a significant role in the control of intracellular concentration of monoaminergic neurotransmitters or neuromodulators and dietary amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional and other brain functions. The development of human MAO inhibitors led to important breakthroughs in the therapy of several neuropsychiatric disorders. Different families of heterocycles containing 2 or 4 nitrogen atoms have been used as scaffolds for synthesizing selective monoamine oxidase inhibitors, but the early period of the MAO-inhibitors started with hydrazine derivatives. Pyrazole, pyrazoline, and pyrazolidine derivatives can be considered as a cyclic hydrazine moiety. This scaffold also displayed promising antidepressant and anticonvulsant properties as demonstrated by different and established animal models. Diversely substituted pyrazoles, embedded with a variety of functional groups, are important biological agents and a significant amount of research activity has been directed towards this chemical class. PMID:22050759

  13. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.

    PubMed Central

    Erickson, J D; Schafer, M K; Bonner, T I; Eiden, L E; Weihe, E

    1996-01-01

    A second isoform of the human vesicular monoamine transporter (hVMAT) has been cloned from a pheochromocytoma cDNA library. The contribution of the two transporter isoforms to monoamine storage in human neuroendocrine tissues was examined with isoform-specific polyclonal antibodies against hVMAT1 and hVMAT2. Central, peripheral, and enteric neurons express only VMAT2. VMAT1 is expressed exclusively in neuroendocrine, including chromaffin and enterochromaffin, cells. VMAT1 and VMAT2 are coexpressed in all chromaffin cells of the adrenal medulla. VMAT2 alone is expressed in histamine-storing enterochromaffin-like cells of the oxyntic mucosa of the stomach. The transport characteristics and pharmacology of each VMAT isoform have been directly compared after expression in digitonin-permeabilized fibroblastic (CV-1) cells, providing information about substrate feature recognition by each transporter and the role of vesicular monoamine storage in the mechanism of action of psychopharmacologic and neurotoxic agents in human. Serotonin has a similar affinity for both transporters. Catecholamines exhibit a 3-fold higher affinity, and histamine exhibits a 30-fold higher affinity, for VMAT2. Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. N-methyl-4-phenylpyridinium, phenylethylamine, amphetamine, and methylenedioxymethamphetamine are all more potent inhibitors of VMAT2 than of VMAT1, whereas fenfluramine is a more potent inhibitor of VMAT1-mediated monamine transport than of VMAT2-mediated monoamine transport. The unique distributions of hVMAT1 and hVMAT2 provide new markers for multiple neuroendocrine lineages, and examination of their transport properties provides mechanistic insights into the pharmacology and physiology of amine storage in cardiovascular, endocrine, and central nervous system function. Images Fig. 3 Fig. 4 PMID:8643547

  14. Linezolid-induced serotonin toxicity in a patient not taking monoamine oxidase inhibitors or serotonin receptor antagonists

    PubMed Central

    Sutton, Jacob; Stroup, Jeff

    2016-01-01

    Linezolid is an oxazolidinone antibiotic with weak monoamine oxidase (MAO) type A and MAO type B inhibitory effects. Linezolid has been associated with serotonin toxicity when used concomitantly with multiple medications that are known to increase serotonin concentrations. We report the case of a 65-year-old woman with signs and symptoms of serotonin toxicity following administration of linezolid for treatment of methicillin-resistant Staphylococcus aureus pneumonia. PMID:27034576

  15. Comparison of time-dependent effects of (+)-methamphetamine or forced swim on monoamines, corticosterone, glucose, creatine, and creatinine in rats

    PubMed Central

    Herring, Nicole R; Schaefer, Tori L; Tang, Peter H; Skelton, Matthew R; Lucot, James P; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T

    2008-01-01

    Background Methamphetamine (MA) use is a worldwide problem. Abusers can have cognitive deficits, monoamine reductions, and altered magnetic resonance spectroscopy findings. Animal models have been used to investigate some of these effects, however many of these experiments have not examined the impact of MA on the stress response. For example, numerous studies have demonstrated (+)-MA-induced neurotoxicity and monoamine reductions, however the effects of MA on other markers that may play a role in neurotoxicity or cell energetics such as glucose, corticosterone, and/or creatine have received less attention. In this experiment, the effects of a neurotoxic regimen of (+)-MA (4 doses at 2 h intervals) on brain monoamines, neostriatal GFAP, plasma corticosterone, creatinine, and glucose, and brain and muscle creatine were evaluated 1, 7, 24, and 72 h after the first dose. In order to compare MA's effects with stress, animals were subjected to a forced swim test in a temporal pattern similar to MA administration [i.e., (30 min/session) 4 times at 2 h intervals]. Results MA increased corticosterone from 1–72 h with a peak 1 h after the first treatment, whereas glucose was only increased 1 h post-treatment. Neostriatal and hippocampal monoamines were decreased at 7, 24, and 72 h, with a concurrent increase in GFAP at 72 h. There was no effect of MA on regional brain creatine, however plasma creatinine was increased during the first 24 h and decreased by 72 h. As with MA treatment, forced swim increased corticosterone more than MA initially. Unlike MA, forced swim reduced creatine in the cerebellum with no change in other brain regions while plasma creatinine was decreased at 1 and 7 h. Glucose in plasma was decreased at 7 h. Conclusion Both MA and forced swim increase demand on energy substrates but in different ways, and MA has persistent effects on corticosterone that are not attributable to stress alone. PMID:18513404

  16. Discriminative stimulus effects of magnesium chloride: substitution studies with monoamine uptake inhibitors and N-methyl-D-aspartate antagonists.

    PubMed

    Kantak, K M; Edwards, M A; Wilcox, K M; Kitchel, E

    1997-10-01

    Previous studies suggest that magnesium chloride may have discriminative stimulus effects that partially overlap with those of noncompetitive N-methyl-D-aspartate antagonists as well as certain monoamine uptake inhibitors. In our study, rats were trained to discriminate 100 mg/kg magnesium chloride from saline and its discriminative stimulus effects were characterized with respect to N-methyl-D-aspartate receptor and monoamine transporter functions in substitution tests. The discriminative stimulus effects of magnesium chloride were acquired within a moderate number of training sessions and showed dose-related substitution after either subcutaneous (3-300 mg/kg) or intracerebroventricular (0.3-300 microg) administration. The intracerebroventricular administration of magnesium chloride was over 4000 times more potent than its s.c. administration. The monoamine uptake inhibitors cocaine, GBR 12909, talsupram and citalopram fully substituted (> or =90% magnesium-appropriate responses) for magnesium chloride in the majority of subjects tested and the group averages reached a maximum of 72 to 82% responses on the magnesium-appropriate lever. Based on relative potency analysis, the rank order of potency of these four drugs for producing magnesium-appropriate responses was talsupram = cocaine > citalopram = GBR 12909. The N-methyl-D-aspartate receptor antagonists dizocilpine, phencyclidine and NPC 17742 engendered maximum group averages of 49 to 65% responses on the magnesium-appropriate lever. The results suggest that the centrally mediated discriminative stimulus effects of magnesium chloride may be more directly related to interactions with monoamine neurotransmitter functions than to N-methyl-D-aspartate receptor blockade. PMID:9336325

  17. Depleted argon from underground sources

    SciTech Connect

    Back, H.O.; Alton, A.; Calaprice, F.; Galbiati, C.; Goretti, A.; Kendziora, C.; Loer, B.; Montanari, D.; Mosteiro, P.; Pordes, S.; /Fermilab

    2011-09-01

    Argon is a powerful scintillator and an excellent medium for detection of ionization. Its high discrimination power against minimum ionization tracks, in favor of selection of nuclear recoils, makes it an attractive medium for direct detection of WIMP dark matter. However, cosmogenic {sup 39}Ar contamination in atmospheric argon limits the size of liquid argon dark matter detectors due to pile-up. The cosmic ray shielding by the earth means that Argon from deep underground is depleted in {sup 39}Ar. In Cortez Colorado a CO{sub 2} well has been discovered to contain approximately 500ppm of argon as a contamination in the CO{sub 2}. In order to produce argon for dark matter detectors we first concentrate the argon locally to 3-5% in an Ar, N{sub 2}, and He mixture, from the CO{sub 2} through chromatographic gas separation. The N{sub 2} and He will be removed by continuous cryogenic distillation in the Cryogenic Distillation Column recently built at Fermilab. In this talk we will discuss the entire extraction and purification process; with emphasis on the recent commissioning and initial performance of the cryogenic distillation column purification.

  18. Beneficial Uses of Depleted Uranium

    SciTech Connect

    Brown, C.; Croff, A.G.; Haire, M. J.

    1997-08-01

    Naturally occurring uranium contains 0.71 wt% {sup 235}U. In order for the uranium to be useful in most fission reactors, it must be enriched the concentration of the fissile isotope {sup 235}U must be increased. Depleted uranium (DU) is a co-product of the processing of natural uranium to produce enriched uranium, and DU has a {sup 235}U concentration of less than 0.71 wt%. In the United States, essentially all of the DU inventory is in the chemical form of uranium hexafluoride (UF{sub 6}) and is stored in large cylinders above ground. If this co-product material were to be declared surplus, converted to a stable oxide form, and disposed, the costs are estimated to be several billion dollars. Only small amounts of DU have at this time been beneficially reused. The U.S. Department of Energy (DOE) has begun the Beneficial Uses of DU Project to identify large-scale uses of DU and encourage its reuse for the primary purpose of potentially reducing the cost and expediting the disposition of the DU inventory. This paper discusses the inventory of DU and its rate of increase; DU disposition options; beneficial use options; a preliminary cost analysis; and major technical, institutional, and regulatory issues to be resolved.

  19. Mild Traumatic Brain Injury with Social Defeat Stress Alters Anxiety, Contextual Fear Extinction, and Limbic Monoamines in Adult Rats

    PubMed Central

    Davies, Daniel R.; Olson, Dawne; Meyer, Danielle L.; Scholl, Jamie L.; Watt, Michael J.; Manzerra, Pasquale; Renner, Kenneth J.; Forster, Gina L.

    2016-01-01

    Mild traumatic brain injury (mTBI) produces symptoms similar to those typifying posttraumatic stress disorder (PTSD) in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM), or for contextual fear conditioning and extinction. Brains were collected 24 h after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes. PMID:27147992

  20. CSF monoamine metabolites, cholinesterases and lactate in the adult hydrocephalus syndrome (normal pressure hydrocephalus) related to CSF hydrodynamic parameters.

    PubMed Central

    Malm, J; Kristensen, B; Ekstedt, J; Adolfsson, R; Wester, P

    1991-01-01

    Monoamine metabolites, cholinesterases and lactic acid in lumbar cerebrospinal fluid (CSF) were investigated on patients with the adult hydrocephalus syndrome (idiopathic normal pressure syndrome; AHS, n = 15), Alzheimer's disease (AD, n = 14), multi-infarct dementia (MID, n = 13) and controls (n = 21). Patients had clinical and CSF hydrodynamic investigations. Monoamine concentrations were determined by reversed-phase liquid chromatography, cholinesterases and lactate were determined photometrically. In the AHS patients, CSF monoamine concentrations were not significantly different compared with controls, AD or MID patients. AHS and AD patients showed a similar reduction of CSF acetylcholinesterase activity compared with controls. Positive correlations were found in concentrations of CSF homovanillic acid, CSF 5-hydroxyindoleacetic acid and CSF lactic acid versus CSF outflow conductance (that is, resistance against CSF outflow) in the AHS patients. A similar pattern was observed in a subgroup of MID patients characterised by dilated ventricles and disturbed CSF hydrodynamics. These data suggest that a low CSF outflow conductance may facilitate the clearance of acidic substances from the arachnoid space at the probenecid sensitive active transport site. Alternative explanations would be that a pathologically low CSF outflow conductance is accompanied by an inverse caudorostral flow of CSF or a compromised trans-ependymal diffusion. PMID:1709421

  1. Analysis of microdialysate monoamines, including noradrenaline, dopamine and serotonin, using capillary ultra-high performance liquid chromatography and electrochemical detection.

    PubMed

    Ferry, Barbara; Gifu, Elena-Patricia; Sandu, Ioana; Denoroy, Luc; Parrot, Sandrine

    2014-03-01

    Electrochemical methods are very often used to detect catecholamine and indolamine neurotransmitters separated by conventional reverse-phase high performance liquid chromatography (HPLC). The present paper presents the development of a chromatographic method to detect monoamines present in low-volume brain dialysis samples using a capillary column filled with sub-2μm particles. Several parameters (repeatability, linearity, accuracy, limit of detection) for this new ultrahigh performance liquid chromatography (UHPLC) method with electrochemical detection were examined after optimization of the analytical conditions. Noradrenaline, adrenaline, serotonin, dopamine and its metabolite 3-methoxytyramine were separated in 1μL of injected sample volume; they were detected above concentrations of 0.5-1nmol/L, with 2.1-9.5% accuracy and intra-assay repeatability equal to or less than 6%. The final method was applied to very low volume dialysates from rat brain containing monoamine traces. The study demonstrates that capillary UHPLC with electrochemical detection is suitable for monitoring dialysate monoamines collected at high sampling rate. PMID:24508677

  2. Mild Traumatic Brain Injury with Social Defeat Stress Alters Anxiety, Contextual Fear Extinction, and Limbic Monoamines in Adult Rats.

    PubMed

    Davies, Daniel R; Olson, Dawne; Meyer, Danielle L; Scholl, Jamie L; Watt, Michael J; Manzerra, Pasquale; Renner, Kenneth J; Forster, Gina L

    2016-01-01

    Mild traumatic brain injury (mTBI) produces symptoms similar to those typifying posttraumatic stress disorder (PTSD) in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM), or for contextual fear conditioning and extinction. Brains were collected 24 h after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes. PMID:27147992

  3. Chronic α-Tocopherol Increases Central Monoamines Synthesis and Improves Cognitive and Motor Abilities in Old Rats.

    PubMed

    Ramis, Margarita R; Sarubbo, Fiorella; Terrasa, Juan L; Moranta, David; Aparicio, Sara; Miralles, Antonio; Esteban, Susana

    2016-04-01

    Limiting enzymes in the synthesis of brain monoamines seems to be susceptible to oxidative damage, one of the most important factors in aging. It has been suggested that the use of anti-oxidants can reduce the rate of free radical production related with aging and the associated damage. Therefore, this study aims to analyze the effects of the chronic treatments with the anti-oxidant α-tocopherol (vitamin E) on central monoamines (high-performance liquid chromatography [HPLC] analysis) mediating cognitive functions, as well as on the evaluation of memory and motor abilities in old rats measured by radial maze, Barnes maze, novel object recognition test, and rotarod test. Results show that α-tocopherol significantly increased in a dose- and/or time-dependent manner the synthesis rate and the levels of monoaminergic neurotransmitters (serotonin, dopamine, and noradrenaline) in the hippocampus and striatum, brain regions involved in memory processing and motor coordination. These positive neurochemical effects, largely due to an increased activity of the limiting enzymes in monoamines synthesis, tryptophan hydroxylase and tyrosine hydroxylase, were accompanied by an improvement in cognitive and motor abilities in old rats. Altogether these findings suggest that α-tocopherol exhibits neuroprotective actions in old rats; thus, diets with α-tocopherol might represent a promising strategy to mitigate or delay the cognitive and motor decline associate with aging and related-diseases. PMID:26414867

  4. Monoamine Oxidase and Dopamine β-Hydroxylase Inhibitors from the Fruits of Gardenia jasminoides

    PubMed Central

    Kim, Ji Ho; Kim, Gun Hee; Hwang, Keum Hee

    2012-01-01

    This research was designed to determine what components of Gardenia jasminoides play a major role in inhibiting the enzymes related antidepressant activity of this plant. In our previous research, the ethyl acetate fraction of G. jasminosides fruits inhibited the activities of both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B), and oral administration of the ethanolic extract slightly increased serotonin concentrations in the brain tissues of rats and decreased MAO-B activity. In addition, we found through in vitro screening test that the ethyl acetate fraction showed modest inhibitory activity on dopamine-β hydroxylase (DBH). The bioassay-guided fractionation led to the isolation of five bio-active compounds, protocatechuic acid (1), geniposide (2), 6'-O-trans-p-coumaroylgeniposide (3), 3,5-d-ihydroxy-1,7-bis (4-hydroxyphenyl) heptanes (4), and ursolic acid (5), from the ethyl acetate fraction of G. jasminoides fruits. The isolated compounds showed different inhibitory potentials against MAO-A, -B, and DBH. Protocatechuic acid showed potent inhibition against MAO-B (IC50 300 μmol/L) and DBH (334 μmol/L), exhibiting weak MAO-A inhibition (2.41 mmol/L). Two iridoid glycosides, geniposide (223 μmol/L) and 6'-O-trans-p-coumaroylgeniposide (127μmol/L), were selective MAO-B inhibitor. Especially, 6'-O-trans-p-coumaroylgeniposide exhibited more selective MAO-B inhibition than deprenyl, well-known MAO-B inhibitor for the treatment of early-stage Parkinson’s disease. The inhibitory activity of 3,5-di-hydroxy-1,7-bis (4-hydroxyphenyl) heptane was strong for MAO-B (196 μmol/L), modest for MAO-A (400 μmol/L), and weak for DBH (941 μmol/L). Ursolic acid exhibited significant inhibition of DBH (214 μmol/L), weak inhibition of MAO-B (780 μmol/L), and no inhibition against MAO-A. Consequently, G. jasminoides fruits are considerable for development of biofunctional food materials for the combination treatment of depression and neurodegenerative disorders

  5. Blood Levels of Monoamine Precursors and Smoking in Patients with Schizophrenia.

    PubMed

    Mathai, Ashwin Jacob; Kanwar, Jyoti; Okusaga, Olaoluwa; Fuchs, Dietmar; Lowry, Christopher A; Peng, Xiaoqing; Giegling, Ina; Hartmann, Annette M; Konte, Bettina; Friedl, Marion; Gragnoli, Claudia; Reeves, Gloria M; Groer, Maureen W; Rosenthal, Richard N; Rujescu, Dan; Postolache, Teodor T

    2016-01-01

    Smoking is highly prevalent in patients with schizophrenia and exerts a negative impact on cardiovascular mortality in these patients. Smoking has complex interactions with monoamine metabolism through the ability of cigarette smoke to suppress Type 1 T helper cell (Th1) type immunity, the immunophenotype that is implicated in phenylalanine hydroxylase (PAH) dysfunction and tryptophan (Trp) breakdown to kynurenine (Kyn) via indoleamine 2,3-dioxygenase. Nicotine also induces tyrosine hydroxylase (TH) gene expression, leading to increased synthesis of catecholamines. Furthermore, there is evidence for PAH dysfunction in schizophrenia. This study aimed to compare the plasma levels of selected monoamine precursors and their metabolites in smokers vs. non-smokers in a large sample of patients with schizophrenia. We measured plasma phenylalanine (Phe), tyrosine (Tyr), Trp, and Kyn levels using high-performance liquid chromatography and calculated Phe:Tyr and Kyn:Trp ratios in 920 patients with schizophrenia. Analysis of variance and linear regression analyses were used to compare these endpoints between three groups of patients with schizophrenia: (1) current smokers, (2) past smokers, and (3) non-smokers. There were significant differences among the three groups with regards to Tyr levels [F (2,789) = 3.77, p = 0.02], with current smokers having lower Tyr levels when compared with non-smokers (p = 0.02). Kyn levels and Kyn:Trp ratio were different among the three groups [F (2,738) = 3.17, p = 0.04, F (2,738) = 3.61, p = 0.03] with current smokers having lower Kyn levels (p = 0.04) and higher Kyn:Trp ratio (p = 0.02) when compared with past smokers. These findings need to be replicated with protocols that include healthy controls to further elucidate the neurobiological underpinnings of altered Tyr and Kyn levels in smokers. Results do suggest potential molecular links between schizophrenia and smoking that may represent biomarkers and

  6. [18F]CFT synthesis and binding to monoamine transporters in rats

    PubMed Central

    2012-01-01

    Background We present the electrophilic synthesis of [18F]2β-carbomethoxy-3β-(4-fluoro)tropane [[18F]CFT] and the pharmacological specificity and selectivity of [18F]CFT for monoamine transporters in the brain and peripheral organs of rats. The human radiation dose is extrapolated from the animal data. Methods [18F]CFT was synthesized by electrophilic fluorination of a stannylated precursor by using post-target-produced [18F]F2 as a fluorinating agent. The ex vivo 18F-activity biodistribution of [18F]CFT in the brain of rats was studied by autoradiography. The binding of [18F]CFT to the monoamine transporters was studied using in vivo blocking experiments with dopamine transporter [DAT], norepinephrine transporter [NET], or serotonin transporter [SERT] inhibitors. In vivo animal positron emission tomography was used as a comparative method to determine tracer kinetics. Human radiation dose was assessed using OLINDA software. Results The radiochemical yield of [18F]CFT from the initial [18F]F-, decay corrected to the end of bombardment, was 3.2 ± 1.0%. The specific activity [SA] was 14.5 ± 3.4 GBq/μmol, decay corrected to the end of synthesis. Radiochemical purity exceeded 99%. DAT-specific binding was found in the striatum, locus coeruleus, and pancreas. NET-specific binding was found in the locus coeruleus. SERT-specific binding was not found in any of the studied organs. Effective dose equivalent [EDE] estimated for the standard human model was 12.8 μSv/MBq. Effective dose [ED] was 9.17 μSv/MBq. Conclusions Post-target-produced high-SA [18F]F2 was used to incorporate18F directly into the phenyl ring of [18F]CFT. The final product had high radiochemical and chemical purities and a high SA for DAT and NET studies in vivo. In periphery, [18F]CFT showed a specific uptake in the pancreas. EDE and ED corresponded well with other18F-radioligands. PMID:22277306

  7. Blood Levels of Monoamine Precursors and Smoking in Patients with Schizophrenia

    PubMed Central

    Mathai, Ashwin Jacob; Kanwar, Jyoti; Okusaga, Olaoluwa; Fuchs, Dietmar; Lowry, Christopher A.; Peng, Xiaoqing; Giegling, Ina; Hartmann, Annette M.; Konte, Bettina; Friedl, Marion; Gragnoli, Claudia; Reeves, Gloria M.; Groer, Maureen W.; Rosenthal, Richard N.; Rujescu, Dan; Postolache, Teodor T.

    2016-01-01

    Smoking is highly prevalent in patients with schizophrenia and exerts a negative impact on cardiovascular mortality in these patients. Smoking has complex interactions with monoamine metabolism through the ability of cigarette smoke to suppress Type 1 T helper cell (Th1) type immunity, the immunophenotype that is implicated in phenylalanine hydroxylase (PAH) dysfunction and tryptophan (Trp) breakdown to kynurenine (Kyn) via indoleamine 2,3-dioxygenase. Nicotine also induces tyrosine hydroxylase (TH) gene expression, leading to increased synthesis of catecholamines. Furthermore, there is evidence for PAH dysfunction in schizophrenia. This study aimed to compare the plasma levels of selected monoamine precursors and their metabolites in smokers vs. non-smokers in a large sample of patients with schizophrenia. We measured plasma phenylalanine (Phe), tyrosine (Tyr), Trp, and Kyn levels using high-performance liquid chromatography and calculated Phe:Tyr and Kyn:Trp ratios in 920 patients with schizophrenia. Analysis of variance and linear regression analyses were used to compare these endpoints between three groups of patients with schizophrenia: (1) current smokers, (2) past smokers, and (3) non-smokers. There were significant differences among the three groups with regards to Tyr levels [F(2,789) = 3.77, p = 0.02], with current smokers having lower Tyr levels when compared with non-smokers (p = 0.02). Kyn levels and Kyn:Trp ratio were different among the three groups [F(2,738) = 3.17, p = 0.04, F(2,738) = 3.61, p = 0.03] with current smokers having lower Kyn levels (p = 0.04) and higher Kyn:Trp ratio (p = 0.02) when compared with past smokers. These findings need to be replicated with protocols that include healthy controls to further elucidate the neurobiological underpinnings of altered Tyr and Kyn levels in smokers. Results do suggest potential molecular links between schizophrenia and smoking that may represent biomarkers and

  8. Genetic KCa3.1-Deficiency Produces Locomotor Hyperactivity and Alterations in Cerebral Monoamine Levels

    PubMed Central

    Sivasaravanaparan, Mithula; Ditzel, Nicholas; Sevelsted-Møller, Linda Maria; Oliván-Viguera, Aida; Rabjerg, Maj; Wulff, Heike; Köhler, Ralf

    2012-01-01

    Background The calmodulin/calcium-activated K+ channel KCa3.1 is expressed in red and white blood cells, epithelia and endothelia, and possibly central and peripheral neurons. However, our knowledge about its contribution to neurological functions and behavior is incomplete. Here, we investigated whether genetic deficiency or pharmacological activation of KCa3.1 change behavior and cerebral monoamine levels in mice. Methodology/Principal Findings In the open field test, KCa3.1-deficiency increased horizontal activity, as KCa3.1−/− mice travelled longer distances (≈145% of KCa3.1+/+) and at higher speed (≈1.5-fold of KCa3.1+/+). Working memory in the Y-maze was reduced by KCa3.1-deficiency. Motor coordination on the rotarod and neuromuscular functions were unchanged. In KCa3.1−/− mice, HPLC analysis revealed that turn-over rates of serotonin were reduced in frontal cortex, striatum and brain stem, while noradrenalin turn-over rates were increased in the frontal cortex. Dopamine turn-over rates were unaltered. Plasma catecholamine and corticosterone levels were unaltered. Intraperitoneal injections of 10 mg/kg of the KCa3.1/KCa2-activator SKA-31 reduced rearing and turning behavior in KCa3.1+/+ but not in KCa3.1−/− mice, while 30 mg/kg SKA-31 caused strong sedation in 50% of the animals of either genotypes. KCa3.1−/− mice were hyperactive (≈+60%) in their home cage and SKA-31-administration reduced nocturnal physical activity in KCa3.1+/+ but not in KCa3.1−/− mice. Conclusions/Significance KCa3.1-deficiency causes locomotor hyperactivity and altered monoamine levels in selected brain regions, suggesting a so far unknown functional link of KCa3.1 channels to behavior and monoaminergic neurotransmission in mice. The tranquilizing effects of low-dose SKA-31 raise the possibility to use KCa3.1/KCa2 channels as novel pharmacological targets for the treatment of neuropsychiatric hyperactivity disorders. PMID:23077667

  9. Concentrations of Ozone-Depleting Substances

    EPA Science Inventory

    This indicator presents trends in global concentrations of ozone-depleting substances (ODSs) from 1992 to 2009. This trend is an important environmental issue, because ODSs can deplete the atmosphere's ability to shield the Earth from harmful ultraviolet rays.

  10. Tritium transport vessel using depleted uranium

    SciTech Connect

    Heung, L.K.

    1995-01-01

    A tritium transport vessel using depleted uranium was tested in the laboratory using deuterium and protium. The vessel contains 0.5 kg of depleted uranium and can hold up to 18 grams of tritium. The conditions for activation, tritium loading and tritium unloading were defined. The safety aspects that included air-ingress, tritium diffusion, temperature and pressure potentials were evaluated.

  11. Specification for the VERA Depletion Benchmark Suite

    SciTech Connect

    Kim, Kang Seog

    2015-12-17

    CASL-X-2015-1014-000 iii Consortium for Advanced Simulation of LWRs EXECUTIVE SUMMARY The CASL neutronics simulator MPACT is under development for the neutronics and T-H coupled simulation for the pressurized water reactor. MPACT includes the ORIGEN-API and internal depletion module to perform depletion calculations based upon neutron-material reaction and radioactive decay. It is a challenge to validate the depletion capability because of the insufficient measured data. One of the detoured methods to validate it is to perform a code-to-code comparison for benchmark problems. In this study a depletion benchmark suite has been developed and a detailed guideline has been provided to obtain meaningful computational outcomes which can be used in the validation of the MPACT depletion capability.

  12. High homocysteine induces betaine depletion

    PubMed Central

    Imbard, Apolline; Benoist, Jean-François; Esse, Ruben; Gupta, Sapna; Lebon, Sophie; de Vriese, An S; de Baulny, Helene Ogier; Kruger, Warren; Schiff, Manuel; Blom, Henk J.

    2015-01-01

    Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI—LC–MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte. PMID:26182429

  13. Naproxen, a Nonsteroidal Anti-Inflammatory Drug, Can Affect Daily Hypobaric Hypoxia-Induced Alterations of Monoamine Levels in Different Areas of the Brain in Male Rats.

    PubMed

    Goswami, Ananda Raj; Dutta, Goutam; Ghosh, Tusharkanti

    2016-06-01

    Goswami, Ananda Raj, Goutam Dutta, and Tusharkanti Ghosh. Naproxen, a nonsteroidal anti-inflammatory drug can affect daily hypobaric hypoxia-induced alterations of monoamine levels in different areas of the brain in male rats. High Alt Med Biol. 17:133-140, 2016.-The oxidative stress (OS)-induced prostaglandin (PG) release, in hypobaric hypoxic (HHc) condition, may be linked with the changes of brain monoamines. The present study intends to explore the changes of monoamines in hypothalamus (H), cerebral cortex (CC), and cerebellum (CB) along with the motor activity in rats after exposing them to simulated hypobaric condition and the role of PGs on the daily hypobaric hypoxia (DHH)-induced alteration of brain monoamines by administering, an inhibitor of PG synthesis, naproxen. The rats were exposed to a decompression chamber at 18,000 ft for 8 hours per day for 6 days after administration of vehicle or naproxen (18 mg/kg body wt.). The monoamine levels (epinephrine, E; norepinephrine, NE; dopamine, DA; and 5-hydroxytryptamine, 5-HT) in CC, CB, and H were assayed by high-performance liquid chromatography (HPLC) with electrochemical detection, and the locomotor behavior was measured by open field test. The NE and DA levels were decreased in CC, CB, and H of the rat brain in HHc condition. The E and 5-HT levels were decreased in CC, but in H and CB, they remained unaltered in HHc condition. These DHH-induced changes of monoamines in brain areas were prevented after administration of naproxen in HHc condition. The locomotor behavior remained unaltered in HHc condition and after administration of naproxen in HHc condition. The DHH-induced changes of monoamines in the brain in HHc condition are probably linked with PGs that may be induced by OS. PMID:26894935

  14. POLYCHLORINATED BIPHENYL-INDUCED OXIDATIVE STRESS IN ORGANOTYPIC CO-CULTURES: EXPERIMENTAL DOPAMINE DEPLETION PREVENTS REDUCTIONS IN GABA

    PubMed Central

    Lyng, Gregory D.; Seegal, Richard F.

    2008-01-01

    Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been demonstrated to be toxic to the dopamine (DA) systems of the central nervous system. One proposed mechanism for PCB-induced DA neurotoxicity is inhibition of the vesicular monoamine transporter (VMAT); such inhibition results in increased levels of unsequestered DA and DA metabolism leading to oxidative stress. We have used an organotypic co-culture system of developing rat striatum and ventral mesencephalon (VM) to determine whether alterations in the vesicular storage of DA, resulting from PCB exposure and consequent induction of oxidative stress, leads to GABA and DA neuronal dysfunction. 24 hr exposure to an environmentally relevant mixture of PCBs reduced tissue DA and GABA concentrations, increased medium levels of DA and measures of oxidative stress in both the striatum and VM. Alterations in neurochemistry and increases in measures of oxidative stress were blocked in the presence of n-acetylcysteine (NAC). Although NAC treatment did not alter PCB-induced changes in DA neurochemistry, it did protect against reductions in GABA concentration. To determine whether alterations in the vesicular storage of DA were responsible for PCB-induced oxidative stress and consequent reductions in GABA levels, we depleted DA from the co-cultures using α-methyl-p-tyrosine (AMPT). AMPT reduced striatal and VM DA levels by 90% and 70%, respectively. PCB exposure, following DA depletion, neither increased levels of oxidative stress nor resulted in GABA depletion. These results suggest that PCB-induced alterations in the vesicular storage of DA, resulting in increased levels of unsequestered DA, leads to increased oxidative stress, depletion of tissue glutathione, and consequent reductions in tissue GABA concentrations. PMID:18262273

  15. The MAO-B inhibitor deprenyl reduces the oral tremor and the dopamine depletion induced by the VMAT-2 inhibitor tetrabenazine.

    PubMed

    Podurgiel, Samantha J; Yohn, Samantha E; Dortche, Kristina; Correa, Merce; Salamone, John D

    2016-02-01

    Tetrabenazine (TBZ) is prescribed for the treatment of chorea associated with Huntington's disease. Via inhibition of the vesicular monoamine transporter (VMAT-2), TBZ blocks dopamine (DA) storage and depletes striatal DA; this drug also has been shown to induce Parkinsonian motor side effects in patients. Recently, TBZ was shown to induce tremulous jaw movements (TJMs) in rats and mice. TJMs are an oral tremor that has many of the characteristics of Parkinsonian tremor in humans. The present study focused upon the ability of the well-established antiparkinsonian agent deprenyl to attenuate the behavioral and neurochemical effects of 2.0mg/kg TBZ. Deprenyl is a selective and irreversible inhibitor of monoamine oxidase-B, and administration of deprenyl produced a dose-related suppression of TBZ-induced TJMs. A second experiment employed in vivo microdialysis to examine extracellular DA levels in the ventrolateral striatum, the neostriatal region most closely associated with the production of TJMs, after administration of TBZ and deprenyl. Consistent with the behavioral data, TBZ alone produced a biphasic effect on extracellular DA, with an initial increases followed by a prolonged decrease during the period in which TJMs are displayed. Co-administration of deprenyl with TBZ increased DA levels compared to rats treated with TBZ alone. These results provide support for use of TBZ as a rodent model of Parkinsonism, and future studies should utilize this model to evaluate putative anti-Parkinsonian agents. PMID:26590367

  16. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo.

    PubMed

    Lohr, Kelly M; Bernstein, Alison I; Stout, Kristen A; Dunn, Amy R; Lazo, Carlos R; Alter, Shawn P; Wang, Minzheng; Li, Yingjie; Fan, Xueliang; Hess, Ellen J; Yi, Hong; Vecchio, Laura M; Goldstein, David S; Guillot, Thomas S; Salahpour, Ali; Miller, Gary W

    2014-07-01

    Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease. PMID:24979780

  17. Functional variation in promoter region of monoamine oxidase A and subtypes of alcoholism: haplotype analysis.

    PubMed

    Parsian, Abbas; Cloninger, C Robert; Sinha, Rashmi; Zhang, Zhen Hua

    2003-02-01

    Monoamine oxidase (MAO) is a mitochondrial enzyme involved in the degradation of certain neurotransmitter amines. MAO-A, due to its function in central nervous system, has been one of the important candidate genes involved in the development of neuropsychiatric disorders. A functional polymorphism in the promoter region of the MAO-A gene has been identified. This variation affects the transcriptional efficiency of the gene. To determine the role of this MAO-A functional polymorphism in the development of subtypes of alcoholism, a sample of alcoholics and normal controls were screened with this marker. The allele frequency differences between total alcoholics, Types I and II alcoholics, and normal controls was not significant. Comparison of male alcoholics to male normal controls for the frequencies of two-loci and three-loci haplotypes was statistically significant. After Bonferroni's correction for multiple tests none of the results remained significant at P < 0.05. Our results indicate that MAO-A may play a role in the development of alcoholism but the gene effect is very small. PMID:12555234

  18. Release of (/sup 3/H)-monoamines from superfused rat striatal slices by methylenedioxymethamphetamine (MDMA)

    SciTech Connect

    Levin, J.A.; Schmidt, C.J.; Lovenberg, W.

    1986-03-05

    MDMA is a phenylisopropylamine which is reported to have unique behavioral effects in man. Because of its structural similarities to the amphetamines the authors have compared the effects of MDMA and two related amphetamines on the spontaneous release of tritiated dopamine (DA) and serotonin (5HT) from superfused rat striatal slices. At concentrations of 10/sup -7/ - 10/sup -5/M MDMA and the serotonergic neurotoxin, p-chloroamphetamine, were equipotent releasers of (/sup 3/H)5HT being approximately 10x more potent than methamphetamine. However, methamphetamine was the more potent releaser of (/sup 3/H)DA by a factor of approximately 10x. MDMA-induced release of both (/sup 5/H)5HT and (/sup 3/H)DA was Ca/sup 2 +/-independent and inhibited by selective monoamine uptake blockers suggesting a carrier-dependent release mechanism. Synaptosomal uptake experiments with (+)(/sup 3/H)MDMA indicated no specific uptake of the drug further suggesting the effect of uptake blockers may be to inhibit the carrier-mediated export of amines displaced by MDMA.

  19. Assessment of Mitochondrial Dysfunction and Monoamine Oxidase Contribution to Oxidative Stress in Human Diabetic Hearts

    PubMed Central

    Duicu, O. M.; Lighezan, R.; Sturza, A.; Balica, R.; Vaduva, A.; Feier, H.; Gaspar, M.; Ionac, A.; Noveanu, L.; Borza, C.; Muntean, D. M.; Mornos, C.

    2016-01-01

    Mitochondria-related oxidative stress is a pathomechanism causally linked to coronary heart disease (CHD) and diabetes mellitus (DM). Recently, mitochondrial monoamine oxidases (MAOs) have emerged as novel sources of oxidative stress in the cardiovascular system and experimental diabetes. The present study was purported to assess the mitochondrial impairment and the contribution of MAOs-related oxidative stress to the cardiovascular dysfunction in coronary patients with/without DM. Right atrial appendages were obtained from 75 patients randomized into 3 groups: (1) Control (CTRL), valvular patients without CHD; (2) CHD, patients with confirmed CHD; and (3) CHD-DM, patients with CHD and DM. Mitochondrial respiration was measured by high-resolution respirometry and MAOs expression was evaluated by RT-PCR and immunohistochemistry. Hydrogen peroxide (H2O2) emission was assessed by confocal microscopy and spectrophotometrically. The impairment of mitochondrial respiration was substrate-independent in CHD-DM group. MAOs expression was comparable among the groups, with the predominance of MAO-B isoform but no significant differences regarding oxidative stress were detected by either method. Incubation of atrial samples with MAOs inhibitors significantly reduced the H2O2 in all groups. In conclusion, abnormal mitochondrial respiration occurs in CHD and is more severe in DM and MAOs contribute to oxidative stress in human diseased hearts with/without DM. PMID:27190576

  20. An evaluation of synthetic indole derivatives as inhibitors of monoamine oxidase.

    PubMed

    Chirkova, Zhanna V; Kabanova, Mariya V; Filimonov, Sergey I; Abramov, Igor G; Petzer, Anél; Petzer, Jacobus P; Suponitsky, Kyrill Yu

    2016-05-01

    In a recent study we have shown that several indole-5,6-dicarbonitrile derivatives are potent inhibitors of human monoamine oxidase (MAO) A and B. To expand on these results and to further determine structure-activity relationships (SARs) for MAO inhibition by this chemical class, the present study investigates the MAO inhibition properties of additional indole-5,6-dicarbonitriles and related indole-5,6-dicarboxylic acid and pyrrolo[3,4-f]indole-5,7-dione derivatives. Among the active compounds two pyrrolo[3,4-f]indole-5,7-dione derivatives inhibited MAO-A (4g) and MAO-B (4d) with IC50 values of 0.250 and 0.581μM, respectively. In general indole-5,6-dicarbonitriles, however, exhibit higher MAO inhibition potencies while indole-5,6-dicarboxylic acids are weak MAO inhibitors. Active MAO inhibitors such as 4g and 4d may be used as leads for the development of drugs for the treatment of disease states such as Parkinson's disease and depression. MAO inhibitors are also under investigation as potential agents for the treatment of prostate cancer, certain types of cardiomyopathies and Alzheimer's disease. PMID:27020523

  1. Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies

    PubMed Central

    Sorato, E.; Menazza, S.; Zulian, A.; Sabatelli, P.; Gualandi, F.; Merlini, L.; Bonaldo, P.; Canton, M.; Bernardi, P.; Di Lisa, F.

    2014-01-01

    Although mitochondrial dysfunction and oxidative stress have been proposed to play a crucial role in several types of muscular dystrophy (MD), whether a causal link between these two alterations exists remains an open question. We have documented that mitochondrial dysfunction through opening of the permeability transition pore plays a key role in myoblasts from patients as well as in mouse models of MD, and that oxidative stress caused by monoamine oxidases (MAO) is involved in myofiber damage. In the present study we have tested whether MAO-dependent oxidative stress is a causal determinant of mitochondrial dysfunction and apoptosis in myoblasts from patients affected by collagen VI myopathies. We find that upon incubation with hydrogen peroxide or the MAO substrate tyramine myoblasts from patients upregulate MAO-B expression and display a significant rise in reactive oxygen species (ROS) levels, with concomitant mitochondrial depolarization. MAO inhibition by pargyline significantly reduced both ROS accumulation and mitochondrial dysfunction, and normalized the increased incidence of apoptosis in myoblasts from patients. Thus, MAO-dependent oxidative stress is causally related to mitochondrial dysfunction and cell death in myoblasts from patients affected by collagen VI myopathies, and inhibition of MAO should be explored as a potential treatment for these diseases. PMID:25017965

  2. Methadone, monoamine oxidase, and depression: opioid distribution and acute effects on enzyme activity

    SciTech Connect

    Kaufmann, C.A.; Kreek, M.J.; Raghunath, J.; Arns, P.

    1983-09-01

    Narcotic withdrawal is often accompanied by an atypical depression which responds to resumption of narcotics. It was hypothesized that methadone might exert its antidepressant effects through monoamine oxidase (MAO) inhibition. The current study examined /sub 3/H-methadone distribution in rat brain and effects on regional MAO activity with acute doses (2.5 mg/kg) which approximate those found during chronic methadone maintenance in man. Limbic areas (amygdala, basomedial hypothalamus, caudate-putamen, hippocampus, preoptic nucleus), as well as pituitary and liver were assayed for MAO activity and methadone concentration. MAO activities did not differ significantly in acute methadone or saline-treated cage-mates at 1 or 24 hr. The concentrations of methadone at 1 hr ranged between 17 and 223 ng/100 mg wet wt tissue in the preoptic nucleus and pituitary, respectively. No significant correlation was found between change in MAO activity (MAO methadone/MAO saline) and methadone concentration in any region at 1 or 24 hr. This study does not support the hypothesis that methadone acts as an antidepressant through MAO inhibition, at least not following acute administration of this exogenous opioid.

  3. Red emission fluorescent probes for visualization of monoamine oxidase in living cells.

    PubMed

    Li, Ling-Ling; Li, Kun; Liu, Yan-Hong; Xu, Hao-Ran; Yu, Xiao-Qi

    2016-01-01

    Here we report two novel red emission fluorescent probes for the highly sensitive and selective detection of monoamine oxidase (MAO) with large Stokes shift (227 nm). Both of the probes possess solid state fluorescence and can accomplish the identification of MAO on test papers. The probe MAO-Red-1 exhibited a detection limit down to 1.2 μg mL(-1) towards MAO-B. Moreover, the cleavage product was unequivocally conformedby HPLC and LCMS and the result was in accordance with the proposed oxidative deamination mechanism. The excellent photostability of MAO-Red-1 was proved both in vitro and in vivo through fluorescent kinetic experiment and laser exposure experiment of confocal microscopy, respectively. Intracellular experiments also confirmed the low cytotoxity and exceptional cell imaging abilities of MAO-Red-1. It was validated both in HeLa and HepG2 cells that MAO-Red-1 was capable of reporting MAO activity through the variation of fluorescence intensity. PMID:27499031

  4. Determination of the rate constant for neuronal and extra-neuronal monoamine oxidase

    SciTech Connect

    Cassis, L.; Ludwig, J.; Trendelenburg, U.

    1986-03-01

    In the rat vas deferens, neuronal deamination of /sup 3/H-(-) noradrenaline (/sup 3/H-NA) to /sup 3/H-dihydroxyphenethylglycol (/sup 3/HDOPEG) cannot be inhibited by pretreatment with a monoamine oxidase (MAO) inhibitor. However, in the extraneuronal compartment of the rat heart, inhibition of MAO abolishes the formation of /sup 3/HDOPEG. To clarify this discrepancy, the authors determined the rate constant for MAO (/sup k/mao/) neuronally (rat vas deferens) and extraneuronally (rat heart). For neuronal /sup k/mao, vasa deferentia were incubated with /sup 3/HNA for 300 minutes, and the cumulative formation of /sup 3/HDOPEG measured. The delay in time before /sup 3/HDOPEG achieves steady state (/sup tau/system), is inversely proportional to /sup k/mao. Because /sup tau/system is very short for neuronal MAO, an appreciable delay was only achieved after partial inhibition of MAO with various parglyline concentrations. To relate to the uninhibited enzyme, the percentage inhibition by pargyline was then determined in homogenate preparations. For extraneuronal MAO, a similar procedure was performed in perfused rat hearts. Results show a significantly greater /sup k/mao of neuronal origin, (/sup k/mao = .57min/sup -/1) which when related to the fractional size of the neuronal compartment suggests a very high activity of neuronal MAO.

  5. Social challenge increases cortisol and hypothalamic monoamine levels in matrinxã (Brycon amazonicus).

    PubMed

    Wolkers, Carla Patrícia Bejo; Serra, Mônica; Urbinati, Elisabeth Criscuolo

    2015-12-01

    The neural circuitry for social behavior and aggression appears to be evolutionarily conserved across the vertebrate subphylum and involves a complex neural network that includes the hypothalamus as a key structure. In the present study, we evaluated the changes in monoamine levels in the hypothalamus and on serum cortisol and plasma glucose of resident matrinxã (Brycon amazonicus) submitted to a social challenge (introduction of an intruder in their territory). The fight promoted a significant increase in hypothalamic 5-HT, NA and DA levels and on the metabolites 5-HIAA and DOPAC, and decreased 5-HIAA/5-HT and DOPAC/DA ratios in resident fish. Furthermore, an increase in serum cortisol and plasma glucose was also observed after the fight. Resident fish presented a high aggressiveness even with increased 5-HT levels in the hypothalamus. The alteration in hypothalamic monoaminergic activity of matrinxã suggests that this diencephalic region is involved in aggression and stress modulation in fish; however, it does not exclude the participation of other brain areas not tested here. PMID:26205527

  6. A Novel Potential Positron Emission Tomography Imaging Agent for Vesicular Monoamine Transporter Type 2.

    PubMed

    Huang, Zih-Rou; Tsai, Chia-Ling; Huang, Ya-Yao; Shiue, Chyng-Yann; Tzen, Kai-Yuan; Yen, Ruoh-Fang; Hsin, Ling-Wei

    2016-01-01

    In the early 1990s, 9-(+)-11C-dihydrotetrabenazine (9-(+)-11C-DTBZ) was shown to be a useful positron emission tomography (PET) imaging agent for various neurodegenerative disorders. Here, we described the radiosynthesis and evaluation of the 9-(+)-11C-DTBZ analog, 10-(+)-11C-DTBZ, as a vesicular monoamine transporter 2 (VMAT2) imaging agent and compare it with 9-(+)-11C-DTBZ. 10-(+)-11C-DTBZ was obtained by 11C-MeI methylation with its 10 hydroxy precursor in the presence of 5 M NaOH. It had a slightly better average radiochemical yield of 35.3 ± 3.6% (decay-corrected to end of synthesis (EOS)) than did 9-(+)-11C-DTBZ (30.5 ± 2.3%). MicroPET studies showed that 10-(+)-11C-DTBZ had a striatum-to-cerebellum ratio of 3.74 ± 0.21 at 40 min post-injection, while the ratio of 9-(+)-11C-DTBZ was 2.50 ± 0.33. This indicated that 10-(+)-11C-DTBZ has a higher specific uptake in VMAT2-rich brain regions, and 10-(+)-11C-DTBZ may be a potential VMAT2 radioligand. Our experiment is the first study of 10-(+)-11C-DTBZ to include dynamic brain distribution in rat brains. PMID:27612194

  7. Modulation of monoamine neurotransmitters in fighting fish Betta splendens exposed to waterborne phytoestrogens.

    PubMed

    Clotfelter, Ethan D; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H

    2010-12-01

    Endogenous estrogens are known to affect the activity of monoamine neurotransmitters in vertebrate animals, but the effects of exogenous estrogens on neurotransmitters are relatively poorly understood. We exposed sexually mature male fighting fish Betta splendens to environmentally relevant and pharmacological doses of three phytoestrogens that are potential endocrine disruptors in wild fish populations: genistein, equol, and β-sitosterol. We also exposed fish to two doses of the endogenous estrogen 17β-estradiol, which we selected as a positive control because phytoestrogens are putative estrogen mimics. Our results were variable, but the effects were generally modest. Genistein increased dopamine levels in the forebrains of B. splendens at both environmentally relevant and pharmacological doses. The environmentally relevant dose of equol increased dopamine levels in B. splendens forebrains, and the pharmacological dose decreased norepinephrine (forebrain), dopamine (hindbrain), and serotonin (forebrain) levels. The environmentally relevant dose of β-sitosterol decreased norepinephrine and dopamine in the forebrain and hindbrain, respectively. Our results suggest that sources of environmental phytoestrogens, such as runoff or effluent from agricultural fields, wood pulp mills, and sewage treatment plants, have the potential to modulate neurotransmitter activity in free-living fishes in a way that could interfere with normal behavioral processes. PMID:20012186

  8. Simultaneous determination of cadaverine and putrescine using a disposable monoamine oxidase based biosensor.

    PubMed

    Henao-Escobar, Wilder; Domínguez-Renedo, Olga; Asunción Alonso-Lomillo, M; Julia Arcos-Martínez, M

    2013-12-15

    The selective and simultaneous amperometric determination of putrescine (Put) and cadaverine (Cad) has been carried out using a novel design of screen-printed carbon electrode (SPCE) with two working electrodes connected in array mode. A mixture of 3% of tetrathiafulvalene (TTF), as mediator, and carbon ink was used for the construction of the screen-printed working electrode. The employment of different amounts of monoamine oxidase (MAO) enzyme on these modified TTF/SPCEs and the use of gold nanoparticles (AuNPs) allowed performing the simultaneous determination of both analytes. The amperometric detection has been performed by measuring the oxidation current of the mediator at a potential of+250 mV vs. screen-printed Ag/AgCl reference electrode. A linear response in the Cad concentration range from 19.6 till 107.1 µM and from 9.9 till 74.1 μM for Put was obtained at the MAO/AuNPs/TTF/SPCE biosensor. This device showed a capability of detection of 9.9 and 19.9±0.9 µM (n=4 α=β=0.05) and a precision of 4.9% and 10.3% in terms of relative standard deviation for Put and Cad, respectively. The developed biosensor was successfully applied to the simultaneous determination of Put and Cad in octopus samples. PMID:24209360

  9. An Adrenal Mass and Increased Catecholamines: Monoamine Oxidase or Pheochromocytoma Effect?

    PubMed Central

    Bosscher, Marianne R. F.; Wentholt, Iris M.; Ackermans, Mariette T.; Nieveen van Dijkum, Els J. M.

    2015-01-01

    Hormonal evaluation in patients with an adrenal incidentaloma can be difficult in patients with comorbidities or in patients using interfering drugs. We present a case of a 54-year-old man who was evaluated for an adrenal mass. The medical history reported treatment with a monoamine oxidase (MAO) inhibitor for recurrent psychoses. Hormonal screening showed elevated levels of normetanephrine and metanephrine in plasma and urine, suggesting a diagnosis of pheochromocytoma (PHEO), and an adrenalectomy was performed. Histologic examination showed that the tumor had an origin of the adrenal cortex. MAO inhibitors are also known to cause elevated levels of catecholamines. In this case, a PHEO seemed more likely the cause due to repeatedly elevated levels of metanephrines and normal levels of catecholamines. Since the tumor had an origin of the adrenal cortex, the use of MAO inhibitors was the most likely explanation for the elevated levels of metanephrines. This case illustrated the difficulties in diagnosing PHEO, especially in patients with comorbidities and interfering drugs. PMID:25584109

  10. Assessment of Mitochondrial Dysfunction and Monoamine Oxidase Contribution to Oxidative Stress in Human Diabetic Hearts.

    PubMed

    Duicu, O M; Lighezan, R; Sturza, A; Balica, R; Vaduva, A; Feier, H; Gaspar, M; Ionac, A; Noveanu, L; Borza, C; Muntean, D M; Mornos, C

    2016-01-01

    Mitochondria-related oxidative stress is a pathomechanism causally linked to coronary heart disease (CHD) and diabetes mellitus (DM). Recently, mitochondrial monoamine oxidases (MAOs) have emerged as novel sources of oxidative stress in the cardiovascular system and experimental diabetes. The present study was purported to assess the mitochondrial impairment and the contribution of MAOs-related oxidative stress to the cardiovascular dysfunction in coronary patients with/without DM. Right atrial appendages were obtained from 75 patients randomized into 3 groups: (1) Control (CTRL), valvular patients without CHD; (2) CHD, patients with confirmed CHD; and (3) CHD-DM, patients with CHD and DM. Mitochondrial respiration was measured by high-resolution respirometry and MAOs expression was evaluated by RT-PCR and immunohistochemistry. Hydrogen peroxide (H2O2) emission was assessed by confocal microscopy and spectrophotometrically. The impairment of mitochondrial respiration was substrate-independent in CHD-DM group. MAOs expression was comparable among the groups, with the predominance of MAO-B isoform but no significant differences regarding oxidative stress were detected by either method. Incubation of atrial samples with MAOs inhibitors significantly reduced the H2O2 in all groups. In conclusion, abnormal mitochondrial respiration occurs in CHD and is more severe in DM and MAOs contribute to oxidative stress in human diseased hearts with/without DM. PMID:27190576

  11. New Water Vapor Barrier Film Based on Lamellar Aliphatic-Monoamine-Bridged Polysilsesquioxane.

    PubMed

    Zhang, Cong; Zhang, Ce; Ding, Ruimin; Cui, Xinmin; Wang, Jing; Zhang, Qinghua; Xu, Yao

    2016-06-15

    Siloxane-based hybrid lamellar materials with ordered nanostructure units paralleling to the substrate have been widely used for water vapor barrier. However, it is very difficult to control the orientation of the lamellar units at molecular level. In this Research Article, a new lamellar bridged polysilsesquioxane (BPSQ) film, whose voids between lamellae were filled by pendant alkyl chains in the organic bridge, was prepared via the stoichiometric reaction between 3-glycidoxypropyltrimethoxysilane and aliphatic monoamine at 60 °C without catalyst. Experimental evidence obtained from FT-IR, MS, NMR, and GIXRD techniques suggested that the as-prepared BPSQ films were constructed by lamellar units with disordered orientation. Nonetheless, they possessed satisfactory water vapor barrier performance for potassium dihydrogen phosphate (KDP) and deuterated potassium dihydrogen phosphate (DKDP) optical crystals, and the water vapor transmission rate through BPSQ film with thickness of 25 μm was as low as 20.3 g·m(-2)·d(-1). Those results proved that filling the voids between molecular lamellae with alkyl chains greatly weakened the effect of lamellar unit orientation on the vapor barrier property of BPSQ film. PMID:27224032

  12. Effect of PCB and DES on rat monoamine oxidase, acetylcholinesterase, testosterone, and estradiol ontogeny

    SciTech Connect

    Vincent, D.R.; Bradshaw, W.S.; Booth, G.M.; Seegmiller, R.E.; Allen, S.D.

    1992-06-01

    Diethylstilbestrol (DES) and polychlorinated biphenyl (PCB) have been documented as potentially hazardous environmental agents. In utero exposure to DES produces human vaginal adenocarcinoma, male reproductive tract lesions in mice, and has been correlated with personality changes in human males. PCB (Kanechlor) was found to be the major toxin in the {open_quotes}Yusho{close_quotes} rice oil poisoning in Japan in 1968. Other investigators have shown in rats that PCB (Arochlor) causes liver adenofibrosis, thyroid dysfunction, atypical mitochondria, and dilation of both smooth and rough endoplasmic reticulum. Matthews et al. (1978) also reported that 4, 4{prime} chlorinated biphenyl was the most potent inducer of monooxygenases, irrespective of chlorination at other sites. Although these compounds have been studied extensively in mammals, there is a paucity of data examining their effects when non-fetotoxic amounts are administered chronically and orally during gestation. The present study is part of a larger effort designed to establish a protocol for testing the developmental effects of xenobiotics such as DES and PCB. Levels of acetylcholinesterase (AChE) were measured as an indicator of the integrity of nerve transmission in the central nervous system. Monoamine oxidase (MAO) is a marker for the outer mitochondrial membrane and is an important amine metabolizing enzyme. Testosterone and estradiol are important sex steroids in mammals, and effects upon levels of the two hormones may signal anomalies in development of sex characteristics. 35 refs., 3 figs., 1 tab.

  13. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

    PubMed Central

    Lohr, Kelly M.; Bernstein, Alison I.; Stout, Kristen A.; Dunn, Amy R.; Lazo, Carlos R.; Alter, Shawn P.; Wang, Minzheng; Li, Yingjie; Fan, Xueliang; Hess, Ellen J.; Yi, Hong; Vecchio, Laura M.; Goldstein, David S.; Guillot, Thomas S.; Salahpour, Ali; Miller, Gary W.

    2014-01-01

    Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease. PMID:24979780

  14. Evaluation of Natural and Synthetic 1,4-naphthoquinones as Inhibitors of Monoamine Oxidase.

    PubMed

    Mostert, Samantha; Petzer, Anél; Petzer, Jacobus P

    2016-05-01

    Previous reports have documented that 1,4-naphthoquinones act as inhibitors of the monoamine oxidase (MAO) enzymes. In particular, fractionation of the extracts of cured tobacco leafs has led to the characterization of 2,3,6-trimethyl-1,4-naphthoquinone, a non-selective MAO inhibitor. To derive structure-activity relationships for MAO inhibition by the 1,4-naphthoquinone class of compounds, this study investigates the human MAO inhibitory activities of fourteen structurally diverse 1,4-naphthoquinones of natural and synthetic origin. Of these, 5,8-dihydroxy-1,4-naphthoquinone was found to be the most potent inhibitor with an IC50 value of 0.860 μm for the inhibition of MAO-B. A related compound, shikonin, inhibits both the MAO-A and MAO-B isoforms with IC50 values of 1.50 and 1.01 μm, respectively. It is further shown that MAO-A and MAO-B inhibition by these compounds is reversible by dialysis. In this respect, kinetic analysis suggests that the modes of MAO inhibition are competitive. This study contributes to the discovery of novel MAO inhibitors, which may be useful in the treatment for disorders such as Parkinson's disease, depressive illness, congestive heart failure and cancer. PMID:26684482

  15. Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes.

    PubMed

    Sturza, Adrian; Duicu, Oana M; Vaduva, Adrian; Dănilă, Maria D; Noveanu, Lavinia; Varró, András; Muntean, Danina M

    2015-07-01

    Diabetes mellitus (DM) is widely recognized as the most severe metabolic disease associated with increased cardiovascular morbidity and mortality. The generation of reactive oxygen species (ROS) is a major event causally linked to the development of cardiovascular complications throughout the evolution of DM. Recently, monoamine oxidases (MAOs) at the outer mitochondrial membrane, with 2 isoforms, MAO-A and MAO-B, have emerged as novel sources of constant hydrogen peroxide (H2O2) production in the cardiovascular system via the oxidative deamination of biogenic amines and neurotransmitters. Whether MAOs are mediators of endothelial dysfunction in DM is unknown, and so we studied this in a streptozotocin-induced rat model of diabetes. MAO expression (mRNA and protein) was increased in both arterial samples and hearts isolated from the diabetic animals. Also, H2O2 production (ferrous oxidation - xylenol orange assay) in aortic samples was significantly increased, together with an impairment of endothelium-dependent relaxation (organ-bath studies). MAO inhibitors (clorgyline and selegiline) attenuated ROS production by 50% and partially normalized the endothelium-dependent relaxation in diseased vessels. In conclusion, MAOs, in particular the MAO-B isoform, are induced in aortas and hearts in the streptozotocin-induced diabetic rat model and contribute, via the generation of H2O2, to the endothelial dysfunction associated with experimental diabetes. PMID:25996256

  16. Monoamine Oxidase Inhibitory Activity of Ferulic Acid Amides: Curcumin-Based Design and Synthesis.

    PubMed

    Badavath, Vishnu N; Baysal, İpek; Uçar, Gülberk; Mondal, Susanta K; Sinha, Barij N; Jayaprakash, Venkatesan

    2016-01-01

    Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, we designed a series of ferulic acid amides 6a-m and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or non-selectively. Nine compounds (6a, 6b, 6g-m) were found to inhibit hMAO-B selectively, whereas the other four (6c-f) were found to be non-selective. There is a gradual shift from hMAO-B selectivity (6a,b) to non-selectivity (6c-f) as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Compounds 6f, 6j, and 6k were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a better pharmacokinetic profile than curcumin, ferulic acid, and selegiline. In order to understand the structural features responsible for the potency and selectivity of 6k, we carried out a molecular docking simulation study. PMID:26592858

  17. (E)-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors.

    PubMed

    Desideri, Nicoletta; Proietti Monaco, Luca; Fioravanti, Rossella; Biava, Mariangela; Yáñez, Matilde; Alcaro, Stefano; Ortuso, Francesco

    2016-07-19

    A series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino)pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC50 = 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC50 = 19.60 nM, IC50 > 3431). Molecular modelling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent. PMID:27135371

  18. Defining the Role of the Monoamine Oxidase-B Inhibitors for Parkinson's Disease.

    PubMed

    Robakis, Daphne; Fahn, Stanley

    2015-06-01

    Inhibitors of monoamine oxidase-B (MAO-B) occupy an important place in the treatment of Parkinson's disease. Selegiline was the first MAO-B to be used therapeutically, while rasagiline is a second-generation drug with higher potency and selectivity. Safinamide is an investigational MAO-B inhibitor with non-dopaminergic properties that may provide advantages over its predecessors. As a class, MAO-B inhibitors are safe and well tolerated and provide symptomatic benefit both as monotherapy and in combination with other antiparkinsonian medications from early to late stages of disease. In combination with levodopa, MAO-B inhibitors may improve motor fluctuations and allow for lower total doses of levodopa. Patient characteristics and preferences can be important factors in deciding between agents. As a class, MAO-B inhibitors have shown promise as disease-modifying agents, but the clinical trial evidence to date has not been strong enough to afford them such a label. Future research may help further elucidate their relative merits and clarify their role in altering disease progression. PMID:26164425

  19. Acute effects of a bicyclophosphate neuroconvulsant on monoamine neurotransmitter and metabolite levels in the rat brain.

    PubMed

    Lindsey, J W; Jung, A E; Narayanan, T K; Ritchie, G D

    1998-07-10

    Naive male Sprague-Dawley rats were injected intraperitoneally (i.p.) with the bicyclophosphate convulsant trimethylolpropane phosphate (TMPP) at dose levels from 0.2 to 0.6 mg/kg. Rats were observed for convulsive activity, and were sacrificed 15 min posttreatment. Levels of the monoamine neurotransmitters norepinephrine (NE), epinephrine (EPI), dopamine (DA), and serotonin (5-HT) and the major metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were assayed in forebrain, midbrain, hindbrain, cerebellum and brainstem regions. Neurotransmitter and metabolite levels were compared between control rats and rats that did and did not experience seizures. TMPP administration induced significant decreases in levels of measured neurotransmitters that varied as a function of brain region, dose, and expression of the seizure activity. These results show that tonic or tonic-clonic seizures induced by TMPP administration (0.6 mg/kg) are reliably associated with regional decreases in serotonin, dopamine, and norepinephrine. Convulsive activity resulting from lower dose administrations (0.2-0.4 mg/kg) of TMPP result only in decreased regional levels of serotonin. PMID:9650574

  20. Red emission fluorescent probes for visualization of monoamine oxidase in living cells

    PubMed Central

    Li, Ling-Ling; Li, Kun; Liu, Yan-Hong; Xu, Hao-Ran; Yu, Xiao-Qi

    2016-01-01

    Here we report two novel red emission fluorescent probes for the highly sensitive and selective detection of monoamine oxidase (MAO) with large Stokes shift (227 nm). Both of the probes possess solid state fluorescence and can accomplish the identification of MAO on test papers. The probe MAO-Red-1 exhibited a detection limit down to 1.2 μg mL−1 towards MAO-B. Moreover, the cleavage product was unequivocally conformedby HPLC and LCMS and the result was in accordance with the proposed oxidative deamination mechanism. The excellent photostability of MAO-Red-1 was proved both in vitro and in vivo through fluorescent kinetic experiment and laser exposure experiment of confocal microscopy, respectively. Intracellular experiments also confirmed the low cytotoxity and exceptional cell imaging abilities of MAO-Red-1. It was validated both in HeLa and HepG2 cells that MAO-Red-1 was capable of reporting MAO activity through the variation of fluorescence intensity. PMID:27499031

  1. beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO).

    PubMed

    Herraiz, T; González, D; Ancín-Azpilicueta, C; Arán, V J; Guillén, H

    2010-03-01

    Peganum harmala L. is a multipurpose medicinal plant increasingly used for psychoactive recreational purposes (Ayahuasca analog). Harmaline, harmine, harmalol, harmol and tetrahydroharmine were identified and quantified as the main beta-carboline alkaloids in P. harmala extracts. Seeds and roots contained the highest levels of alkaloids with low levels in stems and leaves, and absence in flowers. Harmine and harmaline accumulated in dry seeds at 4.3% and 5.6% (w/w), respectively, harmalol at 0.6%, and tetrahydroharmine at 0.1% (w/w). Roots contained harmine and harmol with 2.0% and 1.4% (w/w), respectively. Seed extracts were potent reversible and competitive inhibitors of human monoamine oxidase (MAO-A) with an IC(50) of 27 microg/l whereas root extracts strongly inhibited MAO-A with an IC(50) of 159 microg/l. In contrast, they were poor inhibitors of MAO-B. Inhibition of MAO-A by seed extracts was quantitatively attributed to harmaline and harmine whereas inhibition by root extracts came from harmine with no additional interferences. Stems and leaves extracts were poor inhibitors of MAO. The potent inhibition of MAO-A by seed and root extracts of P. harmala containing beta-carbolines should contribute to the psychopharmacological and toxicological effects of this plant and could be the basis for its purported antidepressant actions. PMID:20036304

  2. Discovery of 3-Hydroxy-3-phenacyloxindole Analogues of Isatin as Potential Monoamine Oxidase Inhibitors.

    PubMed

    Tripathi, Rati K P; Krishnamurthy, Sairam; Ayyannan, Senthil R

    2016-01-01

    A series of 3-hydroxy-3-phenacyloxindole analogues of isatin were designed, synthesized, and evaluated in vitro for their inhibitory activity toward monoamine oxidase (MAO) A and B. Most of the synthesized compounds proved to be potent and selective inhibitors of MAO-A rather than MAO-B. 1-Benzyl-3-hydroxy-3-(4'-hydroxyphenacyl)oxindole (compound 18) showed the highest MAO-A inhibitory activity (IC50 : 0.009 ± 0.001 μM, Ki : 3.69 ± 0.003 nM) and good selectivity (selectivity index: 60.44). Kinetic studies revealed that compounds 18 and 16 (1-benzyl-3-hydroxy-3-(4'-bromophenacyl)oxindole) exhibit competitive inhibition against MAO-A and MAO-B, respectively. Structure-activity relationship studies suggested that the 3-hydroxy group is an essential feature for these analogues to exhibit potent MAO-A inhibitory activity. Computational studies revealed the possible molecular interactions between the inhibitors and MAO isozymes. The computational data obtained are congruent with experimental results. Further studies on the lead inhibitors, including co-crystallization of inhibitor-MAO complexes and in vivo evaluations, are essential for their development as potential therapeutic agents for the treatment of MAO-associated neurological disorders. PMID:26592797

  3. The role of monoamine oxidase A in aggression: Current translational developments and future challenges.

    PubMed

    Godar, Sean C; Fite, Paula J; McFarlin, Kenneth M; Bortolato, Marco

    2016-08-01

    Drawing upon the recent resurgence of biological criminology, several studies have highlighted a critical role for genetic factors in the ontogeny of antisocial and violent conduct. In particular, converging lines of evidence have documented that these maladaptive manifestations of aggression are influenced by monoamine oxidase A (MAOA), the enzyme that catalyzes the degradation of brain serotonin, norepinephrine and dopamine. The interest on the link between MAOA and aggression was originally sparked by Han Brunner's discovery of a syndrome characterized by marked antisocial behaviors in male carriers of a nonsense mutation of this gene. Subsequent studies showed that MAOA allelic variants associated with low enzyme activity moderate the impact of early-life maltreatment on aggression propensity. In spite of overwhelming evidence pointing to the relationship between MAOA and aggression, the neurobiological substrates of this link remain surprisingly elusive; very little is also known about the interventions that may reduce the severity of pathological aggression in genetically predisposed subjects. Animal models offer a unique experimental tool to investigate these issues; in particular, several lines of transgenic mice harboring total or partial loss-of-function Maoa mutations have been shown to recapitulate numerous psychological and neurofunctional endophenotypes observed in humans. This review summarizes the current knowledge on the link between MAOA and aggression; in particular, we will emphasize how an integrated translational strategy coordinating clinical and preclinical research may prove critical to elucidate important aspects of the pathophysiology of aggression, and identify potential targets for its diagnosis, prevention and treatment. PMID:26776902

  4. Memory impairment induced by sodium fluoride is associated with changes in brain monoamine levels.

    PubMed

    Pereira, Marcela; Dombrowski, Patrícia A; Losso, Estela M; Chioca, Lea R; Da Cunha, Cláudio; Andreatini, Roberto

    2011-01-01

    Previous studies suggest that sodium fluoride (NaF) can impair performance in some memory tasks, such as open-field habituation and two-way active avoidance. In the present study, we evaluated the effect of NaF intake (100 ppm in drinking water for 30 days) and its short-term (15 days) withdrawal on open-field habituation and brain monoamine level. Adult male rats were allocated to three groups: tap water (NaF 1.54 ppm) for 45 days (control group); 15 days of tap water followed by NaF for 30 days; and NaF for 30 days followed by 15 days of tap water. The results showed that NaF impairs open-field habituation and increases noradrenaline (NA) and serotonin (5-HT) in the striatum, hippocampus and neocortex. Dopamine (DA) increase was restricted to the striatum. Short-term NaF withdrawal did not reverse these NaF-induced changes, and both NaF treatments led to a mild fluorosis in rat incisors. No treatment effect was seen in body weight or fluid/water consumption. These results indicate that sodium fluoride induces memory impairment that outlasts short-term NaF withdrawal (2 weeks) and may be associated with NA and 5-HT increases in discrete brain regions. PMID:19957215

  5. Microspectrofluorometric study of monoamines in the auricle of the heart of Protopterus aethiopicus.

    PubMed

    Scheuermann, D W; Stilman, C; Reinhold, C; De Groodt-Lasseel, M H

    1981-01-01

    The auricle of the heart of Protopterus aethiopicus contains large numbers of chromaffin cells, often lying immediately adjacent to the endothelium and displaying a bright blue-white fluorescence characteristic for catecholamines after formaldehyde treatment (Falck and Owman 1965). These results combined with X-ray microanalysis after initial fixation with glutaraldehyde and subsequent treatment with dichromate established that these chromaffin cells are the storage site of primary catecholamines (Scheuermann 1978, 1979, 1980; Scheuermann et al. 1980). The aim of the present pilot study was to demonstrate in these cells noradrenaline (NA) or dopamine (DA), or a mixture of both. The evaluation of the excitation spectra of the catecholamine fluorophore transformed by treatment with HCl vapour (excitation maxima at 320 and 370 nm) and the excitation-peak ratio analysis (peak ratio 370/320 nm = 1.05-1.5; and 320/280 nm greater than 1.5) identify DA as the primary catecholamine stored in these chromaffin cells. The low fading rate of the monoamine fluorescence after acidification confirms the presence of DA. These microspectrofluorometric findings demonstrate that chromaffin cells in the auricle of the Protopterus heart, which are a part of the medullary homologue of the adrenal gland of higher vertebrates, contain a primary catecholamine, namely DA. PMID:7237540

  6. Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

    PubMed Central

    Suri, Deepika; Teixeira, Cátia M; Cagliostro, Martha K Caffrey; Mahadevia, Darshini; Ansorge, Mark S

    2015-01-01

    Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system development, such sensitive periods shape the formation of neurocircuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint as well as the environmental context. While allowing for adaptation, such sensitive periods are also vulnerability windows during which external and internal factors can confer risk to disorders by derailing otherwise resilient developmental programs. Here we review developmental periods that are sensitive to monoamine signaling and impact adult behaviors of relevance to psychiatry. Specifically, we review (1) a serotonin-sensitive period that impacts sensory system development, (2) a serotonin-sensitive period that impacts cognition, anxiety- and depression-related behaviors, and (3) a dopamine- and serotonin-sensitive period affecting aggression, impulsivity and behavioral response to psychostimulants. We discuss preclinical data to provide mechanistic insight, as well as epidemiological and clinical data to point out translational relevance. The field of translational developmental neuroscience has progressed exponentially providing solid conceptual advances and unprecedented mechanistic insight. With such knowledge at hand and important methodological innovation ongoing, the field is poised for breakthroughs elucidating the developmental origins of neuropsychiatric disorders, and thus understanding pathophysiology. Such knowledge of sensitive periods that determine the developmental trajectory of complex behaviors is a necessary step towards improving prevention and treatment approaches for neuropsychiatric disorders. PMID:25178408

  7. Plant observation report and evaluation, Pennwalt Corporation, secondary and tertiary aliphatic monoamines

    SciTech Connect

    Not Available

    1980-08-27

    A site visit was made to the amine manufacturing facility of the Pennwalt Corporation, Wyandotte, Michigan, to evaluate the facility in regard to the Secondary and Tertiary Aliphatic Monoamines Criteria Document. A total of 21 people were directly in contact with the amine production process. Two to four of the maintenance personnel may also come in contact with the process. Maintenance workers ran the risk of exposure not only to primary, secondary and tertiary amine compounds, but also to several other chemicals being used in the process. The processes used to unload raw materials are described, along with reactor operations, decanter and recycling operations, distillation operations, product storage and shipping. Medical monitoring at the facility included chest x-ray, respiratory function tests, sight screening, urinalysis, and back x-rays. Restricted and potentially hazardous area signs were clearly posted. Employees wore hard hats and safety glasses on the job as well as gloves, rubber boots, face shields, goggles, and respirators as necessary. Emergency procedures are described, including fire protection. Sanitation and personal hygiene are discussed, along with monitoring of the workplace conditions.

  8. Transformation of heterocyclic reversible monoamine oxidase-B inactivators into irreversible inactivators by N-methylation.

    PubMed

    Ding, C Z; Silverman, R B

    1993-11-12

    3-[4-[(3-Chlorophenyl)methoxy]phenyl]-5-[(methylamino)methyl]- 2-oxazolidinone (1) is a secondary amine known to be a potent time-dependent irreversible inactivator of monoamine oxidase B (MAO-B). The primary amine analogues of derivatives of 1, as well as of the corresponding dihydrofuranone and pyrrolidinone, had been shown to be time-dependent, but reversible, inhibitors of MAO-B. Here it is shown that the primary amine analogue of 1 is a time-dependent reversible inhibitor of MAO-B and that the secondary and tertiary amine analogues of the corresponding oxazolidinone, dihydrofuranone, and pyrrolidinone are time-dependent irreversible inhibitors of MAO-B. The reaction leading to the irreversible enzyme adduct formation with 1 can be reversed by increasing the temperature. These results are consistent with a stabilizing stereoelectronic effect on the enzyme adduct caused by N-methylation which hinders free rotation and prevents the sp3-orbital containing the nitrogen nonbonded electrons from being trans to the active site amino acid leaving group. PMID:8246228

  9. Selective inhibition of monoamine oxidase B by aminoethyl substituted benzyl ethers.

    PubMed

    Woodroofe, C C; Mostashari, R; Lu, X; Ramsay, R R; Silverman, R B

    2000-01-01

    Aminoethyl 3-chlorobenzyl ether was shown previously (Ding, C.Z. and Silverman, R.B. (1993). Bioorg. Med. Chem. Lett., 3, 2077-2078) to be a potent and selective time-dependent, but reversible inhibitor of monoamine oxidase B (MAO B). Based on this result, a series of novel aminoethyl substituted benzyl ethers was synthesized and the compounds were examined as potential inhibitors of both isozymic forms of MAO. Each compound in the series inhibits both MAO A and MAO B competitively, and IC50 values for each compound were determined. In general, the B isozyme is much more sensitive to these inhibitors than the A isozyme (except for the o- and p-substituted nitro analogues), in some cases by more than two orders of magnitude. The selectivity in favor of MAO B inhibition is relatively high for all of the meta-substituted analogues and quite low for all of the ortho-substituted analogues. Having the substituent at the ortho-position is most favorable for MAO A inhibition. With MAO B the meta-analogues were, in general, more potent than the corresponding ortho- and para-analogues with respect to their reversible binding constants. The meta-iodo analogue is the most potent analogue. PMID:10850952

  10. Selective Inhibition of Monoamine Oxidase B by Aminoethyl Substituted Benzyl Ethers.

    PubMed

    Woodroofe; Mostashari; Lu; Ramsay; Silverman

    1999-11-01

    Aminoethyl 3-chlorobenzyl ether was shown previously (Ding, C.Z. and Silverman, R.B. (1993). Bioorg. Med. Chem. Lett., 3, 2077-2078) to be a potent and selective time-dependent, but reversible inhibitor of monoamine oxidase B (MAO B). Based on this result, a series of novel aminoethyl substituted benzyl ethers was synthesized and the compounds were examined as potential inhibitors of both isozymic forms of MAO. Each compound in the series inhibits both MAO A and MAO B competitively, and IC(50) values for each compound were determined. In general, the B isozyme is much more sensitive to these inhibitors than the A isozyme (except for the o- and p-substituted nitro analogues), in some cases by more than two orders of magnitude. The selectivity in favor of MAO B inhibition is relatively high for all of the meta-substituted analogues and quite low for all of the ortho-substituted analogues. Having the substituent at the ortho-position is most favorable for MAO A inhibition. With MAO B the meta-analogues were, in general, more potent than the corresponding ortho- and para-analogues with respect to their reversible binding constants. The meta-iodo analogue is the most potent analogue. PMID:10938531