11,524 research outputs found

    Organic Cation Transporter 3 (OCT3) Is Localized to Intracellular and Surface Membranes in Select Glial and Neuronal Cells Within the Basolateral Amygdaloid Complex of Both Rats and Mice

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    Organic cation transporter 3 (OCT3) is a high-capacity, low-affinity transporter that mediates corticosterone-sensitive uptake of monoamines including norepinephrine, epinephrine, dopamine, histamine and serotonin. OCT3 is expressed widely throughout the amygdaloid complex and other brain regions where monoamines are key regulators of emotional behaviors affected by stress. However, assessing the contribution of OCT3 to the regulation of monoaminergic neurotransmission and monoamine-dependent regulation of behavior requires fundamental information about the subcellular distribution of OCT3 expression. We used immunofluorescence and immuno-electron microscopy to examine the cellular and subcellular distribution of the transporter in the basolateral amygdaloid complex of the rat and mouse brain. OCT3-immunoreactivity was observed in both glial and neuronal perikarya in both rat and mouse amygdala. Electron microscopic immunolabeling revealed plasma membrane-associated OCT3 immunoreactivity on axonal, dendritic, and astrocytic processes adjacent to a variety of synapses, as well as on neuronal somata. In addition to plasma membrane sites, OCT3 immunolabeling was also observed associated with neuronal and glial endomembranes, including Golgi, mitochondrial and nuclear membranes. Particularly prominent labeling of the outer nuclear membrane was observed in neuronal, astrocytic, microglial and endothelial perikarya. The localization of OCT3 to neuronal and glial plasma membranes adjacent to synaptic sites is consistent with an important role for this transporter in regulating the amplitude, duration, and physical spread of released monoamines, while its localization to mitochondrial and outer nuclear membranes suggests previously undescribed roles for the transporter in the intracellular disposition of monoamines

    Paraklooramfetamiini mĂľju psĂźhhomotoorsele aktiivsusele ja serotoniini ja dopamiini tasemetele septumis ja prefrontaalkorteksis erineva pĂźsisotsiaalsusega loomadel

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    Social behaviour plays important role in many psychopathologies. Sociability has been shown to be a stable trait in animals and individual differences in sociability are related to 5-HT transmission in septum and prefrontal cortex. The aim of the current study was to investigate whether animals with different levels of sociability are differently affected by p-chloroamphetamine treatment. 5-HT, 5-HIAA and DA levels were measured in septum and PFC and locomotor activity was recorded. Although there was no difference in monoamine levels or locomotor activity between LS- and HS-animals after PCA treatment, our findings confirm previous research on the different neurodegenerative effect of PCA in different brain regions. PCA had stronger neurodegenerative effect in PFC as 5-HT and 5-HIAA levels there were lower than in septum

    MAO-A and the EEG Recognition Memory Signal in Left Parietal Cortex

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    A key part of episodic memory, or memory for the events of our lives, is recognition memory. Recognition memory is the ability to remember previously encountered stimuli. Studies have linked recognition memory to the old/new effect, an EEG indicator of stimulus familiarity. Monoamine oxidase A (MAO-A) is an enzyme that catalyzes monoamines, leading to the depletion of norepinephrine, epinephrine, serotonin, and dopamine. MAO-A is more efficiently transcribed in individuals with a 4 repeating sequence variation (4R) of the MAO-A gene leading to less monoamine availability. As many of these monoamines have been linked to episodic memory, we hypothesized that individuals homozygous for the 4R MAO-A polymorphism would show differences in mean EEG signal amplitudes during recognition memory. EEG data was recorded as participants viewed both new words and words that had been previously presented. Our results show that mean peak amplitudes over the left parietal cortex 500-800 ms post-stimulus presentation for hits were greater than those for correct rejections, indicating the old/new effect. Critically, our results revealed an interaction between mean hit and correct rejection amplitude over the left parietal cortex and MAO-A group. Individuals homozygous for the 4R variation (the High MAO-A group) do not show an old/new effect due to increased correct rejection amplitudes. These results suggest that less monoamine availability leads to new stimuli being identified as old by the left parietal cortex

    Roles for the Uptake\u3csub\u3e2\u3c/sub\u3e Transporter OCT3 in Regulation of Dopaminergic Neurotransmission and Behavior

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    Transporter-mediated uptake determines the peak concentration, duration, and physical spread of released monoamines. Most studies of monoamine clearance focus on the presynaptic uptake1 transporters SERT, NET and DAT. However, recent studies have demonstrated the expression of the uptake2 transporter OCT3 (organic cation transporter 3), throughout the rodent brain. In contrast to NET, DAT and SERT, OCT3 has higher capacity and lower affinity for substrates, is sodium-independent, and is multi-specific, with the capacity to transport norepinephrine, dopamine, serotonin and histamine. OCT3is insensitive to inhibition by cocaine and antidepressant drugs but is inhibited directly by the glucocorticoid hormone corticosterone. Thus, OCT3 represents a novel, stress hormone-sensitive, monoamine transport mechanism. Incorporating this transporter into current models of monoaminergic neurotransmission requires information on: A) the cellular and subcellular localization of the transporter; B) the effects of OCT3 inhibitors on monoamine clearance; and C) the consequences of decreased OCT3-mediated transport on physiology and/or behavior. This review summarizes studies describing the anatomical distribution of OCT3, its cellular and subcellular localization, its contribution to the regulation of dopaminergicsignaling, and its roles in the regulation of behavior. Together, these and other studies suggest that both Uptake1 and Uptake2 transporters play key roles in regulating monoaminergic neurotransmission and the effects of monoamines on behavior

    Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

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    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

    Preclinical discovery of duloxetine for the treatment of depression

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    Introduction: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases areIntroduction: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases are associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several newantidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD. Areas covered: The article reviews and discusses the biochemical and functional profile of duloxetine splitting the review into acute and long-term treatment with this dual monoamine reuptake inhibitor. In addition, the authors summarize available preclinical behavioral research data, which have demonstrated among other effects, the antidepressant-like activity of duloxetine in several animal models. The authors focus on the most recent literature on synaptic neuroplasticity modulation of this antidepressant drug. Finally, the authors briefly mention other approved indications of duloxetine. Expert opinion: Duloxetine inhibits 5-HT and NA reuptake, effectively desensitizes various autoreceptors and promotes neuroplasticity. Clinically, duloxetine is an effective antidepressant that is well tolerated and has significant efficacy in the treatment of MDD. associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several new antidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD

    Organic Cation Transporter 3: A Cellular Mechanism Underlying Rapid, Non-Genomic Glucocorticoid Regulation of Monoaminergic Neurotransmission, Physiology, and Behavior

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    Corticosteroid hormones act at intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) to alter gene expression, leading to diverse physiological and behavioral responses. In addition to these classical genomic effects, corticosteroid hormones also exert rapid actions on physiology and behavior through a variety of non-genomic mechanisms, some of which involve GR or MR, and others of which are independent of these receptors. One such GR-independent mechanism involves corticosteroid-induced inhibition of monoamine transport mediated by “uptake2” transporters, including organic cation transporter 3 (OCT3), a low-affinity, high-capacity transporter for norepinephrine, epinephrine, dopamine, serotonin and histamine. Corticosterone directly and acutely inhibits OCT3-mediated transport. This review describes the studies that initially characterized uptake2 processes in peripheral tissues, and outlines studies that demonstrated OCT3 expression and corticosterone-sensitive monoamine transport in the brain. Evidence is presented supporting the hypothesis that corticosterone can exert rapid, GR-independent actions on neuronal physiology and behavior by inhibiting OCT3-mediated monoamine clearance. Implications of this mechanism for glucocorticoid-monoamine interactions in the context-dependent regulation of behavior are discussed

    Meeting report : Neuropathology and Neuropharmacology of Monoaminergic systems

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    The third EU COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain” Annual Conference entitled “Neuropathology and Neuropharmacology of Monoaminergic Systems” was hosted by the University of Bordeaux, France on 8-10 October 2014. The conference, organized by Prof. De Deurwaerdère, was supported by COST (European Cooperation in Science and Technology) and LABEX (LABEX Brain, University of Bordeaux). The program took the form of a three-day meeting, comprising a series of French and international invited talks and breakout sessions designed to identify key gaps in current knowledge and potential future research questions. The aims of this Conference were two-fold: 1. To identify the current state-of-the-art in the understanding of the pathological mechanisms that contribute to different neuropsychiatric disorders, and to what extent, monoamines a multi-target drugs and/or other interventions might prevent these changes. 2. To identify specific areas of research where information is sparse but which are likely to yield data that will impact on future strategies to treat neurodegenerative disorders.peer-reviewe

    Characterization of Vesicular Monoamine Transporter 2 and its role in Parkinson\u27s Disease Pathogenesis using Drosophila

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    Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of the dopaminergic neurons in the Substantia nigra pars compacta region of the brain. PD is also the most common neurodegenerative disorder and the second most common movement disorder. PD patients exhibit the cardinal symptoms, including tremor of the extremities, rigidity, slowness of movement, and postural instability, after 70-80% of DA neurons degenerate. It is, therefore, imperative to elucidate the underlying mechanisms involved in the selective degeneration of DA neurons. Although increasing numbers of PD genes have been identified, why these largely widely expressed genes induce selective loss of DA neurons is still not known. Notably, dopamine (DA) itself is a chemically labile molecule and can become oxidized to toxic by-products while induce the accumulation of harmful molecules such as Reactive Oxygen Species (ROS). Accordingly, DA toxicity has long been suspected to play a role in selective neuronal loss in PD. Vesicular Monoamine Transporter (VMAT) is essential for proper vesicular storage of monoamines such as DA and their regulated release. Increasing evidence have linked VMAT dysfunction with Parkinson’s disease. In this study, we re-examine the gain- and loss-of-function phenotypes of the sole VMAT homologue in Drosophila. Our results suggest that the C-terminal sequences in the two encoded VMAT isoforms not only determine their differential subcellular localizations, but also their activities in content release. In particular, VMAT2 orthologue potentially poses a unique, previously unexplored activity in promoting DA release. On the other hand, by examining DA distribution in wildtype and VMAT mutant animals, we find that there exists intrinsic difference in the dynamics of intracellular DA handling among DA neurons clustered in different brain regions. Furthermore, loss of VMAT causes severe loss of total DA levels and a redistribution of DA in Drosophila brain. Lastly, removal of both VMAT and another PD gene parkin, which is also conserved in Drosophila, results in the selective loss of DA neurons, primarily in the protocerebral anterior medial (PAM) clusters of the brain. Our results suggest a potential involvement of cytoplasmic DA in selective degeneration of DA neurons and also implicating a role for a differential intracellular DA handling mechanism underlying the regional specificity of neuronal loss in PD patients
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