Organic cation transporter 2 contributes to SSRI antidepressant efficacy by controlling tryptophan availability in the brain.

Selective serotonin reuptake inhibitors (SSRI) are common first-line treatments for major depression. However, a significant number of depressed patients do not respond adequately to these pharmacological treatments. In the present preclinical study, we demonstrate that organic cation transporter 2 (OCT2), an atypical monoamine transporter, contributes to the effects of SSRI by regulating the routing of the essential amino acid tryptophan to the brain.

Contrasting Functions of Mitogen- and Stress-activated Protein Kinases 1 and 2 in Recognition Memory and In Vivo Hippocampal Synaptic Transmission.

The mitogen-activated protein kinases (MAPK) are major signaling components of intracellular pathways required for memory consolidation. Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2) mediate signal transduction downstream of MAPK. MSKs are activated by Extracellular-signal Regulated Kinase 1/2 (ERK1/2) and p38 MAPK.

Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression.

Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood.

Viral vector-mediated Cre recombinase expression in substantia nigra induces lesions of the nigrostriatal pathway associated with perturbations of dopamine-related behaviors and hallmarks of programmed cell death.

Cre/loxP recombination is a widely used approach to study gene function in vivo, using mice models expressing the Cre recombinase under the control of specific promoters or through viral delivery of Cre-expressing constructs. A profuse literature on transgenic mouse lines points out the deleterious effects of Cre expression in various cell types and tissues, presumably by acting on illegitimate loxP-like sites present in the genome. However, most studies reporting the consequences of Cre-lox gene invalidation often omit adequate controls to exclude the potential toxic effects of Cre, compromising the interpretation of data.

Cartography of hevin-expressing cells in the adult brain reveals prominent expression in astrocytes and parvalbumin neurons.

Hevin, also known as SPARC-like 1, is a member of the secreted protein acidic and rich in cysteine family of matricellular proteins, which has been implicated in neuronal migration and synaptogenesis during development. Unlike previously characterized matricellular proteins, hevin remains strongly expressed in the adult brain in both astrocytes and neurons, but its precise pattern of expression is unknown. The present study provides the first systematic description of hevin mRNA distribution in the adult mouse brain.

Characterization of Serious Adverse Drug Reactions in Hospital to Determine Potential Implications of Mandatory Reporting.

Background: The will eventually require institutions to report all serious adverse drug reactions (ADRs), although the proposed regulations do not yet define what will need to be reported and by whom. Knowledge about the occurrence of serious ADRs in the hospital setting is needed to optimize the effectiveness of reporting and to determine the potential implications of mandatory reporting.

Objectives: To quantify and characterize suspected serious ADRs in patients admitted to a general medicine service, to assess the likelihood of causality, and to determine inter-rater agreement for identification of ADRs and assessment of their likelihood.

Antidepressive effects of targeting ELK-1 signal transduction.

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted.

Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons.

Role of organic cation transporters (OCTs) in the brain.

Organic cation transporters (OCTs) are polyspecific facilitated diffusion transporters that contribute to the absorption and clearance of various physiological compounds and xenobiotics in mammals, by mediating their vectorial transport in kidney, liver or placenta cells. Unexpectedly, a corpus of studies within the last decade has revealed that these transporters also fulfill important functions within the brain. The high-affinity monoamine reuptake transporters (SERT, NET and DAT) exert a crucial role in the control of aminergic transmission by ensuring the rapid clearance of the released transmitters from the synaptic cleft and their recycling into the nerve endings.

Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling.

Interactions between genetic and environmental factors, like exposure to stress, have an important role in the pathogenesis of mood-related psychiatric disorders, such as major depressive disorder. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the stress hormone corticosterone in vitro, suggesting that these transporters might have a physiologic role in the response to stress. Here, we report that OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamic-pituitary-adrenocortical (HPA) axis.

Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3.

Besides the three antidepressant-sensitive, Na(+)- and Cl(-)-dependent monoamine transporters, Na(+)-independent organic cation transporters (OCTs) are known to transport monoamines. However, little is known about the interactions of psychotropic drugs with human (h) OCTs. In the present study, a series of diverse antidepressant and antipsychotic drugs were examined for their inhibitory potency at hOCT1, hOCT2 and hOCT3 by measuring inhibition of [(3)H]-MPP(+) uptake into HEK293 cells stably expressing one of the three hOCTs.

Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice.

Background And Purpose: Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT](ext)). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA](ext)).

Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response.

High-affinity transporters for norepinephrine (NE) and serotonin (5-HT), which ensure neurotransmitter clearance at the synapse, are the principal targets of widely used antidepressant drugs. Antidepressants targeting these high-affinity transporters, however, do not provide positive treatment outcomes for all patients. Other monoamine transport systems, with lower affinity, have been detected in the brain, but their role is largely unknown.

Downregulation of basophil-derived IL-4 and in vivo T(H)2 IgE responses by serotonin and other organic cation transporter 3 ligands.

Background: Murine basophils can contribute to the T(H)2 polarization of the immune response by providing rapidly large amounts of IL-4, which suggests that pharmacologic downregulation of this cytokine might provide a strategy to attenuate pathologies associated with excessive production.

Objective: We examined a number of physiological and pharmacologic ligands of the organic cation transporter 3 (OCT3), a membrane carrier of biogenic amines, for their inhibitory effect on IL-4 production by basophils, selecting the most efficient compounds for in vivo evaluation in basophil-dependent experimental models.

Methods: IL-4 production by basophils isolated ex vivo or from bone marrow cultures was assessed in response to various stimuli with or without biogenic monoamines or pharmacologic analogs.

Inhibitory and facilitory actions of isocyanine derivatives at human and rat organic cation transporters 1, 2 and 3: a comparison to human alpha 1- and alpha 2-adrenoceptor subtypes.

Organic cation transporters (OCTs), comprising OCT1, OCT2 and OCT3 subtypes, control absorption and elimination of xenobiotics and endogenous compounds in kidney, liver and placenta. In addition, they ensure "uptake2", low-affinity catecholamine clearance in sympathetically-innervated tissue and the CNS. The prototypical OCT ligand, disprocynium24 (D24), recognises OCT3, but its actions at OCT1 and OCT2 remain unknown.

Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice.

Organic cation transporters (OCTs) are carrier-type polyspecific permeases known to participate in low-affinity extraneuronal catecholamine uptake in peripheral tissues. OCT3 is the OCT subtype most represented in the brain, yet its implication in central aminergic neurotransmission in vivo had not been directly demonstrated. In a detailed immunohistochemistry study, we show that OCT3 is expressed in aminergic pathways in the mouse brain, particularly in dopaminergic neurons of the substantia nigra compacta, non-aminergic neurons of the ventral tegmental area, substantia nigra reticulata (SNr), locus coeruleus, hippocampus and cortex.

Neurochemical characterization of pathways expressing plasma membrane monoamine transporter in the rat brain.

Neurotransmitter transporters play an important role in the control of synaptic transmission by ensuring the clearance of transmitters liberated in the synaptic cleft. In the case of monoaminergic neurotransmitters, this clearance is carried out by high-affinity reuptake transporters located in the plasma membrane of the presynaptic terminals. Recently plasma membrane monoamine transporter (PMAT), a transporter from the SLC29 (equilibrative nucleoside transporter) family, was shown to transport in vitro monoaminergic neurotransmitters, in particular dopamine and serotonin, nearly as efficiently as the high-affinity transporters.

Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.

Organic cation transporters (OCTs) are polyspecific carriers implicated in low-affinity, corticosteroid-sensitive extraneuronal catecholamine uptake in peripheral tissues. The three main OCT subtypes, OCT1, OCT2 and OCT3, are also present in the brain, but their central role remains unclear. In the present study, we investigated by comparative in situ hybridization analysis the regional distribution of these transporters in rat brain and compared their functional properties in stably transfected HEK293 cells expressing human or rat OCTs.

Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation.

Organic cation transporters (OCTs) are carrier-type permeases known to participate in general detoxification functions in peripheral tissues. Previous in vitro studies have suggested that OCTs ensure Uptake2, a low-affinity, corticosteroid-sensitive catecholamine removal system, which was characterized initially in sympathetically innervated tissues. Although the presence of both Uptake(2)-like transport and most OCT subtypes has also been demonstrated in the brain, the physiological role of this family of transporters in CNS remained totally unknown.

Isolation and structural characterization of anionic and neutral compounds resulting from the oxidative addition of HI or CH3I to [IrI2(CO)2](-).

The active iridium species in the methanol carbonylation reaction has been crystallized as the [PPN][IrI(2)(CO)(2)] complex and the X-ray structure solved, showing a cis-geometry and a square planar environment. Hydriodic acid reacts very quickly with this compound to provide [PPN][IrHI(3)(CO)(2)], the X-ray crystal structure of which has been determined. The two CO ligands remain in mutual cis-position in a pseudooctahedral environment.

Genetic and epigenetic control of the Na-G ion channel expression in glia.

The Na-G ion channel, previously cloned from a rat astroglia cDNA library, belongs to a new family of ion channels, related to but distinct from the predominant brain and muscle fast voltage-gated Na(+) channels. In vivo, the corresponding transcripts are widely expressed in peripheral nervous system neurons and glia, but only in selected subpopulations of neuronal and glia-like cells of the central nervous system. In the present report, we show that Na-G messenger RNA level in astrocyte and Schwann cell cultures is modulated in a cell-specific manner by several growth factors, hormones, and intracellular second messengers pathways.

The Na-G ion channel is transcribed from a single promoter controlled by distinct neuron- and Schwann cell-specific DNA elements.

Na-G is a putative sodium (or cationic) channel expressed in neurons and glia of the PNS, in restricted neuronal subpopulations of the brain, and in several tissues outside the nervous system, like lung and adrenal medulla. To analyze the mechanisms underlying tissue-specific expression of this channel, we isolated the 5' region of the corresponding gene and show that Na-G mRNA transcription proceeds from a single promoter with multiple initiation sites. By transgenic mice studies, we demonstrate that 600 bp containing the Na-G proximal promoter region and the first exon are sufficient to drive the expression of a beta-galactosidase reporter gene in neurons of both CNS and PNS, whereas expression in Schwann cells depends on more remote DNA elements lying in the region between -6,500 and -1,050 bp upstream of the main transcription initiation sites.

The glial voltage-gated sodium channel: cell- and tissue-specific mRNA expression.

Previous electrophysiological and pharmacological studies on central and peripheral glia revealed the presence of voltage-gated Na channels with properties that are similar but not identical to those of neuronal Na channels. Here we report the isolation and characterization of a cDNA encoding the C-terminal portion of a putative glial Na-channel (Na-G) alpha subunit. The amino acid sequence deduced from this cDNA indicates that the Na-G represents a separate molecular class within the mammalian Na-channel multigene family.