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Serotonin transporter inhibition and 5-HT receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice.
Stewart A, Davis GL, Gresch PJ, Katamish RM, Peart R, Rabil MJ, Gowrishankar R, Carroll FI, Hahn MK, Blakely RD
(2019) Neuropsychopharmacology 44: 994-1006
MeSH Terms: Animals, Behavior, Animal, Cocaine, Conditioning, Classical, Disease Models, Animal, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Fluoxetine, Locomotion, Methylphenidate, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Neostriatum, Receptor, Serotonin, 5-HT2C, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors
Show Abstract · Added January 8, 2019
Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.
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19 MeSH Terms
Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx.
Dadi PK, Vierra NC, Days E, Dickerson MT, Vinson PN, Weaver CD, Jacobson DA
(2017) ACS Chem Neurosci 8: 558-568
MeSH Terms: Action Potentials, Animals, Antibodies, Calcium, Dinoprostone, Electric Stimulation, Fluoxetine, Ganglia, Spinal, HEK293 Cells, Humans, Lectins, Mice, Mice, Inbred C57BL, Mutation, Nociceptors, Potassium Channel Blockers, Potassium Channels, Tandem Pore Domain, Protein Synthesis Inhibitors, Tetracycline
Show Abstract · Added November 13, 2017
The two-pore-domain potassium (K2P) channel TREK-2 serves to modulate plasma membrane potential in dorsal root ganglia c-fiber nociceptors, which tunes electrical excitability and nociception. Thus, TREK-2 channels are considered a potential therapeutic target for treating pain; however, there are currently no selective pharmacological tools for TREK-2 channels. Here we report the identification of the first TREK-2 selective activators using a high-throughput fluorescence-based thallium (Tl) flux screen (HTS). An initial pilot screen with a bioactive lipid library identified 11-deoxy prostaglandin F2α as a potent activator of TREK-2 channels (EC ≈ 0.294 μM), which was utilized to optimize the TREK-2 Tl flux assay (Z' = 0.752). A HTS was then performed with 76 575 structurally diverse small molecules. Many small molecules that selectively activate TREK-2 were discovered. As these molecules were able to activate single TREK-2 channels in excised membrane patches, they are likely direct TREK-2 activators. Furthermore, TREK-2 activators reduced primary dorsal root ganglion (DRG) c-fiber Ca influx. Interestingly, some of the selective TREK-2 activators such as 11-deoxy prostaglandin F2α were found to inhibit the K2P channel TREK-1. Utilizing chimeric channels containing portions of TREK-1 and TREK-2, the region of the TREK channels that allows for either small molecule activation or inhibition was identified. This region lies within the second pore domain containing extracellular loop and is predicted to play an important role in modulating TREK channel activity. Moreover, the selective TREK-2 activators identified in this HTS provide important tools for assessing human TREK-2 channel function and investigating their therapeutic potential for treating chronic pain.
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19 MeSH Terms
Selective serotonin reuptake inhibitor exposure constricts the mouse ductus arteriosus in utero.
Hooper CW, Delaney C, Streeter T, Yarboro MT, Poole S, Brown N, Slaughter JC, Cotton RB, Reese J, Shelton EL
(2016) Am J Physiol Heart Circ Physiol 311: H572-81
MeSH Terms: Animals, Aorta, Ductus Arteriosus, Female, Fluoxetine, Immunohistochemistry, Mice, Myography, Persistent Fetal Circulation Syndrome, Pregnancy, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptors, Serotonin, Reverse Transcriptase Polymerase Chain Reaction, Serotonin Uptake Inhibitors, Sertraline, Vasoconstriction
Show Abstract · Added April 6, 2017
Use of selective serotonin reuptake inhibitors (SSRIs) is common during pregnancy. Fetal exposure to SSRIs is associated with persistent pulmonary hypertension of the newborn (PPHN); however, a direct link between the two has yet to be established. Conversely, it is well known that PPHN can be caused by premature constriction of the ductus arteriosus (DA), a fetal vessel connecting the pulmonary and systemic circulations. We hypothesized that SSRIs could induce in utero DA constriction. Using isolated vessels and whole-animal models, we sought to determine the effects of two commonly prescribed SSRIs, fluoxetine and sertraline, on the fetal mouse DA. Cannulated vessel myography studies demonstrated that SSRIs caused concentration-dependent DA constriction and made vessels less sensitive to prostaglandin-induced dilation. Moreover, in vivo studies showed that SSRI-exposed mice had inappropriate DA constriction in utero. Taken together, these findings establish that SSRIs promote fetal DA constriction and provide a potential mechanism by which SSRIs could contribute to PPHN.
Copyright © 2016 the American Physiological Society.
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17 MeSH Terms
Acute blockade of the Caenorhabditis elegans dopamine transporter DAT-1 by the mammalian norepinephrine transporter inhibitor nisoxetine reveals the influence of genetic modifications of dopamine signaling in vivo.
Bermingham DP, Hardaway JA, Snarrenberg CL, Robinson SB, Folkes OM, Salimando GJ, Jinnah H, Blakely RD
(2016) Neurochem Int 98: 122-8
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Fluoxetine, Gene Deletion, Mutation, Norepinephrine Plasma Membrane Transport Proteins, Paralysis, Plasmids, Signal Transduction, Swimming
Show Abstract · Added February 15, 2016
Modulation of neurotransmission by the catecholamine dopamine (DA) is conserved across phylogeny. In the nematode Caenorhabditis elegans, excess DA signaling triggers Swimming-Induced Paralysis (Swip), a phenotype first described in animals with loss of function mutations in the presynaptic DA transporter (dat-1). Swip has proven to be a phenotype suitable for the identification of novel dat-1 mutations as well as the identification of novel genes that impact DA signaling. Pharmacological manipulations can also induce Swip, though the reagents employed to date lack specificity and potency, limiting their use in evaluation of dat-1 expression and function. Our lab previously established the mammalian norepinephrine transporter (NET) inhibitor nisoxetine to be a potent antagonist of DA uptake conferred by DAT-1 following heterologous expression. Here we demonstrate the ability of low (μM) concentrations of nisoxetine to trigger Swip within minutes of incubation, with paralysis dependent on DA release and signaling, and non-additive with Swip triggered by dat-1 deletion. Using nisoxetine in combination with genetic mutations that impact DA release, we further demonstrate the utility of the drug for demonstrating contributions of presynaptic DA receptors and ion channels to Swip. Together, these findings reveal nisoxetine as a powerful reagent for monitoring multiple dimensions of DA signaling in vivo, thus providing a new resource that can be used to evaluate contributions of dat-1 and other genes linked to DA signaling without the potential for compensations that attend constitutive genetic mutations.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.
Gunduz-Cinar O, Flynn S, Brockway E, Kaugars K, Baldi R, Ramikie TS, Cinar R, Kunos G, Patel S, Holmes A
(2016) Neuropsychopharmacology 41: 1598-609
MeSH Terms: Amidohydrolases, Amygdala, Animals, Anti-Anxiety Agents, Arachidonic Acids, Endocannabinoids, Extinction, Psychological, Fear, Fluoxetine, Male, Mice, Mice, Inbred Strains, Polyunsaturated Alkamides
Show Abstract · Added March 14, 2018
Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.
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13 MeSH Terms
Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter.
Mason JN, Deecher DC, Richmond RL, Stack G, Mahaney PE, Trybulski E, Winneker RC, Blakely RD
(2007) J Pharmacol Exp Ther 323: 720-9
MeSH Terms: Binding Sites, Binding, Competitive, Blotting, Western, Cells, Cultured, Cocaine, Cyclohexanols, Desvenlafaxine Succinate, Fluoxetine, Humans, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Radioligand Assay
Show Abstract · Added July 10, 2013
Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of DVS.
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12 MeSH Terms
A new, non-SSRI mechanism of action for Prozac.
Daniels RN, Lindsley CW
(2007) Curr Top Med Chem 7: 1039
MeSH Terms: Animals, Antidepressive Agents, Second-Generation, Behavior, Animal, Brain, Fluoxetine, Humans, Mice, Pregnanolone, Serotonin
Added March 5, 2014
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9 MeSH Terms
Methamphetamine administration reduces hippocampal vesicular monoamine transporter-2 uptake.
Rau KS, Birdsall E, Volz TJ, Riordan JA, Baucum AJ, Adair BP, Bitter R, Gibb JW, Hanson GR, Fleckenstein AE
(2006) J Pharmacol Exp Ther 318: 676-82
MeSH Terms: Animals, Benzylamines, Data Interpretation, Statistical, Dopamine, Dopamine Uptake Inhibitors, Fluoxetine, Male, Methamphetamine, Neurons, Rats, Rats, Sprague-Dawley, Serotonin, Serotonin Agents, Serotonin Uptake Inhibitors, Synaptic Vesicles, Vesicular Monoamine Transport Proteins, p-Chloroamphetamine
Show Abstract · Added December 7, 2012
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.
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17 MeSH Terms
Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants.
Henry LK, Field JR, Adkins EM, Parnas ML, Vaughan RA, Zou MF, Newman AH, Blakely RD
(2006) J Biol Chem 281: 2012-23
MeSH Terms: Adrenergic Uptake Inhibitors, Amino Acid Sequence, Animals, Antidepressive Agents, Binding Sites, Binding, Competitive, Blotting, Western, Cadmium, Cell Line, Cell Membrane, Citalopram, Clomipramine, Cocaine, Cysteine, Dopamine Uptake Inhibitors, Fluoxetine, HeLa Cells, Humans, Immunoprecipitation, Isoleucine, Kinetics, LLC-PK1 Cells, Mazindol, Methionine, Mice, Models, Chemical, Molecular Sequence Data, Mutation, N-Methyl-3,4-methylenedioxyamphetamine, Nomifensine, Protein Binding, Protein Structure, Tertiary, Protein Transport, Radiopharmaceuticals, Receptors, Serotonin, Serotonin, Serotonin Uptake Inhibitors, Species Specificity, Stereoisomerism, Substrate Specificity, Tyrosine
Show Abstract · Added July 10, 2013
In previous studies examining the structural determinants of antidepressant and substrate recognition by serotonin transporters (SERTs), we identified Tyr-95 in transmembrane segment 1 (TM1) of human SERT as a major determinant of binding for several antagonists, including racemic citalopram ((RS)-CIT). Here we described a separate site in hSERT TM3 (Ile-172) that impacts (RS)-CIT recognition when switched to the corresponding Drosophila SERT residue (I172M). The hSERT I172M mutant displays a marked loss of inhibitor potency for multiple inhibitors such as (RS)-CIT, clomipramine, RTI-55, fluoxetine, cocaine, nisoxetine, mazindol, and nomifensine, whereas recognition of substrates, including serotonin and 3,4-methylenedioxymethamphetamine, is unaffected. Selectivity for antagonist interactions is evident with this substitution because the potencies of the antidepressants tianeptine and paroxetine are unchanged. Reduced cocaine analog recognition was verified in photoaffinity labeling studies using [(125)I]MFZ 2-24. In contrast to the I172M substitution, other substitutions at this position significantly affected substrate recognition and/or transport activity. Additionally, the mouse mutation (mSERT I172M) exhibits similar selective changes in inhibitor potency. Unlike hSERT or mSERT, analogous substitutions in mouse dopamine transporter (V152M) or human norepinephrine transporter (V148M) result in transporters that bind substrate but are deficient in the subsequent translocation of the substrate. A double mutant hSERT Y95F/I172M had a synergistic impact on (RS)-CIT recognition ( approximately 10,000-fold decrease in (RS)-CIT potency) in the context of normal serotonin recognition. The less active enantiomer (R)-CIT responded to the I172M substitution like (S)-CIT but was relatively insensitive to the Y95F substitution and did not display a synergistic loss at Y95F/I172M. An hSERT mutant with single cysteine substitutions in TM1 and TM3 resulted in formation of a high affinity cadmium metal coordination site, suggesting proximity of these domains in the tertiary structure of SERT. These studies provided evidence for distinct binding sites coordinating SERT antagonists and revealed a close interaction between TM1 and TM3 differentially targeted by stereoisomers of CIT.
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41 MeSH Terms
The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics.
Meredith EJ, Holder MJ, Chamba A, Challa A, Drake-Lee A, Bunce CM, Drayson MT, Pilkington G, Blakely RD, Dyer MJ, Barnes NM, Gordon J
(2005) FASEB J 19: 1187-9
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Antineoplastic Agents, Apoptosis, Burkitt Lymphoma, Cell Line, Tumor, Clomipramine, Fenfluramine, Fluoxetine, Humans, Lymphoma, B-Cell, N-Methyl-3,4-methylenedioxyamphetamine, Proto-Oncogene Proteins c-bcl-2, Psychotropic Drugs, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added July 10, 2013
Following our previous description of the serotonin transporter (SERT) acting as a conduit to 5-hydroxytryptamine (5-HT)-mediated apoptosis, specifically in Burkitt's lymphoma, we now detail its expression among a broad spectrum of B cell malignancy, while exploring additional SERT substrates for potential therapeutic activity. SERT was readily detected in derived B cell lines with origins as diverse as B cell precursor acute lymphoblastic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and multiple myeloma. Concentration and timecourse kinetics for the antiproliferative and proapoptotic activities of the amphetamine derivatives fenfluramine (an appetite suppressant) and 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") revealed them as being similar to the endogenous indoleamine. A tricyclic antidepressant, clomipramine, instead mirrored the behavior of the selective serotonin reuptake inhibitor fluoxetine, both being effective in the low micromolar range. A majority of neoplastic clones were sensitive to one or more of the serotonergic compounds. Dysregulated bcl-2 expression, either by t(14;18)(q32;q21) translocation or its introduction as a constitutively active transgene, provided protection from proapoptotic but not antiproliferative outcomes. These data indicate a potential for SERT as a novel anti-tumor target for amphetamine analogs, while evidence is presented that the seemingly more promising antidepressants are likely impacting malignant B cells independently of the transporter itself.
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14 MeSH Terms