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Randy blakely

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https://www.readbyqxmd.com/read/28964912/functional-coding-variation-in-the-presynaptic-dopamine-transporter-associated-with-neuropsychiatric-disorders-drives-enhanced-motivation-and-context-dependent-impulsivity-in-mice
#1
Gwynne L Davis, Adele Stewart, Gregg D Stanwood, Raajaram Gowrishankar, Maureen K Hahn, Randy D Blakely
Recent genetic analyses have provided evidence that clinical commonalities associated with different psychiatric diagnoses often have shared mechanistic underpinnings. The development of animal models expressing functional genetic variation attributed to multiple disorders offers a salient opportunity to capture molecular, circuit and behavioral alterations underlying this hypothesis. In keeping with studies suggesting dopaminergic contributions to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BPD) and autism spectrum disorder (ASD), subjects with these diagnoses have been found to express a rare, functional coding substitution in the dopamine (DA) transporter (DAT), Ala559Val...
January 30, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/28939120/synthesis-characterization-and-cellular-localization-of-a-fluorescent-probe-of-the-antimalarial-8-aminoquinoline-primaquine
#2
Adonis McQueen, Lynn D Blake, Ala Azhari, M Trent Kemp, Tommy W McGaha, Niranjan Namelikonda, Randy W Larsen, Roman Manetsch, Dennis E Kyle
Primaquine (PQ) is the only commercially available drug that clears dormant liver stages of malaria and blocks transmission to mosquito vectors. Although an old drug, much remains to be known about the mechanism(s) of action. Herein we develop a fluorescent tagged PQ to discover cellular localization in the human malaria parasite, Plasmodium falciparum. Successful synthesis and characterization of a primaquine-coumarin fluorescent probe (PQCP) demonstrated potency equivalent to the parent drug and the probe was not cytotoxic to HepG2 carcinoma cells...
October 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28882630/spatial-gene-expression-analysis-of-neuroanatomical-differences-in-mouse-models
#3
Darren J Fernandes, Jacob Ellegood, Rand Askalan, Randy D Blakely, Emanuel Dicicco-Bloom, Sean E Egan, Lucy R Osborne, Craig M Powell, Armin Raznahan, Diane M Robins, Michael W Salter, Ameet S Sengar, Jeremy Veenstra-VanderWeele, Jason P Lerch
MRI is a powerful modality to detect neuroanatomical differences that result from mutations and treatments. Knowing which genes drive these differences is important in understanding etiology, but candidate genes are often difficult to identify. We tested whether spatial gene expression data from the Allen Brain Institute can be used to inform us about genes that cause neuroanatomical differences. For many single-gene-mutation mouse models, we found that affected neuroanatomy was not strongly associated with the spatial expression of the altered gene and there are specific caveats for each model...
September 4, 2017: NeuroImage
https://www.readbyqxmd.com/read/28842414/the-atypical-map-kinase-swip-13-erk8-regulates-dopamine-transporters-through-a-rho-dependent-mechanism
#4
Daniel P Bermingham, J Andrew Hardaway, Osama Refai, Christian R Marks, Sam L Snider, Sarah M Sturgeon, William C Spencer, Roger J Colbran, David M Miller, Randy D Blakely
The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly in vivo, remain poorly understood, though recent studies have implicated rho-linked pathways in psychostimulant action...
September 20, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28711621/length-of-axons-expressing-the-serotonin-transporter-in-orbitofrontal-cortex-is-lower-with-age-in-depression
#5
Grazyna Rajkowska, Gouri Mahajan, Beata Legutko, Lavanya Challagundla, Michael Griswold, Paul R Albert, Mireille Daigle, Jose J Miguel-Hidalgo, Mark C Austin, Randy D Blakely, David C Steffens, Craig A Stockmeier
Studies of major depressive disorder (MDD) in postmortem brain tissue report enhanced binding to inhibitory serotonin-1A autoreceptors in midbrain dorsal raphe and reductions in length of axons expressing the serotonin transporter (SERT) in dorsolateral prefrontal cortex. The length density of axons expressing SERT in the orbitofrontal cortex (OFC) was determined in 18 subjects with MDD and 17 age-matched control subjects. A monoclonal antibody was used to immunohistochemically label the SERT in fixed sections of OFC...
September 17, 2017: Neuroscience
https://www.readbyqxmd.com/read/28585320/blockade-of-the-5-ht-transporter-contributes-to-the-behavioural-neuronal-and-molecular-effects-of-cocaine
#6
Linda D Simmler, Allison M J Anacker, Michael H Levin, Nina M Vaswani, Paul J Gresch, Alex G Nackenoff, Noelle C Anastasio, Sonja J Stutz, Kathryn A Cunningham, Jing Wang, Bing Zhang, L Keith Henry, Adele Stewart, Jeremy Veenstra-VanderWeele, Randy D Blakely
BACKGROUND AND PURPOSE: The psychostimulant cocaine induces complex molecular, cellular and behavioural responses as a consequence of inhibiting presynaptic dopamine, noradrenaline and 5-HT transporters. To elucidate 5-HT transporter (SERT)-specific contributions to cocaine action, we evaluated cocaine effects in the SERT Met172 knock-in mouse, which expresses a SERT coding substitution that eliminates high-affinity cocaine recognition. EXPERIMENTAL APPROACH: We measured the effects of SERT Met172 on cocaine antagonism of 5-HT re-uptake using ex vivo synaptosome preparations and in vivo microdialysis...
August 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28577989/hemicholinium-3-sensitive-choline-transport-in-human-t-lymphocytes-evidence-for-use-as-a-proxy-for-brain-choline-transporter-cht-capacity
#7
Ajeesh Koshy Cherian, Vinay Parikh, Qi Wu, Yang Mao-Draayer, Qin Wang, Randy D Blakely, Martin Sarter
The synaptic uptake of choline via the high-affinity, hemicholinium-3-dependent choline transporter (CHT) strongly influences the capacity of cholinergic neurons to sustain acetylcholine (ACh) synthesis and release. To advance research on the impact of CHT capacity in humans, we established the presence of the neuronal CHT protein in human T lymphocytes. Next, we demonstrated CHT-mediated choline transport in human T cells. To address the validity of T cell-based choline uptake as a proxy for brain CHT capacity, we isolated T cells from the spleen, and synaptosomes from cortex and striatum, of wild type and CHT-overexpressing mice (CHT-OXP)...
September 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28406285/serotonin-and-serotonin-transporters-in-the-adrenal-medulla-a-potential-hub-for-modulation-of-the-sympathetic-stress-response
#8
Rebecca L Brindley, Mary Beth Bauer, Randy D Blakely, Kevin P M Currie
Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling...
May 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28345868/immune-system-activation-and-depression-roles-of-serotonin-in-the-central-nervous-system-and-periphery
#9
Matthew J Robson, Meagan A Quinlan, Randy D Blakely
Serotonin (5-hydroxytryptamine, 5-HT) has long been recognized as a key contributor to the regulation of mood and anxiety and is strongly associated with the etiology of major depressive disorder (MDD). Although more known for its roles within the central nervous system (CNS), 5-HT is recognized to modulate several key aspects of immune system function that may contribute to the development of MDD. Copious amounts of research have outlined a connection between alterations in immune system function, inflammation status, and MDD...
April 3, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28272863/serotonin-transporter-independent-actions-of-the-antidepressant-vortioxetine-as-revealed-using-the-sert-met172-mouse
#10
Alex G Nackenoff, Linda D Simmler, Nicole L Baganz, Alan L Pehrson, Connie Sánchez, Randy D Blakely
Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets. At therapeutic doses, vortioxetine interacts with SERT as well as 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors. We assessed the SERT-dependency of vortioxetine action using the SERT Met172 mouse model, which disrupts high-affinity interactions of many antidepressants with the transporter...
May 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28193693/unresponsive-choline-transporter-as-a-trait-neuromarker-and-a-causal-mediator-of-bottom-up-attentional-biases
#11
Ajeesh Koshy Cherian, Aaron Kucinski, Kyle Pitchers, Brittney Yegla, Vinay Parikh, Youngsoo Kim, Paulina Valuskova, Sarika Gurnani, Craig W Lindsley, Randy D Blakely, Martin Sarter
Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane...
March 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27913309/sequence-determinants-of-the-caenhorhabditis-elegans-dopamine-transporter-dictating-in-vivo-axonal-export-and-synaptic-localization
#12
Sarah B Robinson, J Andrew Hardaway, Shannon L Hardie, Jane Wright, Ryan M Glynn, Daniel P Bermingham, Qiao Han, Sarah M Sturgeon, Phyllis Freeman, Randy D Blakely
The monoamine neurotransmitter dopamine (DA) acts across phylogeny to modulate both simple and complex behaviors. The presynaptic DA transporter (DAT) is a major determinant of DA signaling capacity in ensuring efficient extracellular DA clearance. In humans, DAT is also a major target for prescribed and abused psychostimulants. Multiple structural determinants of DAT function and regulation have been defined, though largely these findings have arisen from heterologous expression or ex vivo cell culture studies...
January 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/27591044/kinase-dependent-regulation-of-monoamine-neurotransmitter-transporters
#13
REVIEW
Daniel P Bermingham, Randy D Blakely
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...
October 2016: Pharmacological Reviews
https://www.readbyqxmd.com/read/27575469/optimization-of-the-choline-transporter-cht-inhibitor-ml352-development-of-vu6001221-an-improved-in-vivo-tool-compound
#14
Jeanette L Bertron, Elizabeth A Ennis, Christopher J Tarr, Jane Wright, Jonathan W Dickerson, Charles W Locuson, Anna L Blobaum, Jerri M Rook, Randy D Blakely, Craig W Lindsley
This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR)...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27550733/impact-of-maternal-serotonin-transporter-genotype-on-placental-serotonin-fetal-forebrain-serotonin-and-neurodevelopment
#15
Christopher L Muller, Allison Mj Anacker, Tiffany D Rogers, Nick Goeden, Elizabeth H Keller, C Gunnar Forsberg, Travis M Kerr, Carly LA Wender, George M Anderson, Gregg D Stanwood, Randy D Blakely, Alexandre Bonnin, Jeremy Veenstra-VanderWeele
Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo...
January 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27544824/an-interplay-between-the-serotonin-transporter-sert-and-5-ht-receptors-controls-stimulus-secretion-coupling-in-sympathoadrenal-chromaffin-cells
#16
Rebecca L Brindley, Mary Beth Bauer, Randy D Blakely, Kevin P M Currie
Adrenal chromaffin cells (ACCs), the neuroendocrine arm of the sympathetic nervous system, secrete catecholamines to mediate the physiological response to stress. Although ACCs do not synthesize 5-HT, they express the serotonin transporter (SERT). Genetic variations in SERT are linked to several CNS disorders but the role(s) of SERT/5-HT in ACCs has remained unclear. Adrenal glands from wild-type mice contained 5-HT at ≈ 750 fold lower abundance than adrenaline, and in SERT(-/-) mice this was reduced by ≈80% with no change in catecholamines...
November 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27404793/cholinergic-genetics-of-visual-attention-human-and-mouse-choline-transporter-capacity-variants-influence-distractibility
#17
REVIEW
Martin Sarter, Cindy Lustig, Randy D Blakely, Ajeesh Koshy Cherian
The basal forebrain cholinergic projection system to the cortex mediates essential aspects of visual attention performance, including the detection of cues and the response to performance challenges (top-down control of attention). Higher levels of top-down control are mediated via elevated levels of cholinergic neuromodulation. The neuronal choline transporter (CHT) strongly influences the synthesis and release of acetylcholine (ACh). As the capacity of the CHT to import choline into the neuron is a major, presynaptic determinant of cholinergic neuromodulation, we hypothesize that genetically-imposed CHT capacity variation impacts the balance of bottom-up versus top-down control of visual attention...
September 2016: Journal of Physiology, Paris
https://www.readbyqxmd.com/read/27111230/serotonin-transporter-variant-drives-preventable-gastrointestinal-abnormalities-in-development-and-function
#18
Kara Gross Margolis, Zhishan Li, Korey Stevanovic, Virginia Saurman, Narek Israelyan, George M Anderson, Isaac Snyder, Jeremy Veenstra-VanderWeele, Randy D Blakely, Michael D Gershon
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT...
June 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27013347/differential-impact-of-genetically-modulated-choline-transporter-expression-on-the-release-of-endogenous-versus-newly-synthesized-acetylcholine
#19
Hideki Iwamoto, M Wade Calcutt, Randy D Blakely
The efficient import of choline into cholinergic nerve terminals by the presynaptic, high-affinity choline transporter (CHT, SLC5A7) dictates the capacity for acetylcholine (ACh) synthesis and release. Tissue levels of ACh are significantly reduced in mice heterozygous for a loss of function mutation in Slc5a7 (HET, CHT(+/-)), but significantly elevated in overexpressing, Slc5a7 BAC-transgenic mice (BAC). Since the readily-releasable pool of ACh is thought to constitute a small fraction of the total ACh pool, these genotype-dependent changes raised the question as to whether CHT expression or activity might preferentially influence the size of reserve pool ACh vesicles...
September 2016: Neurochemistry International
https://www.readbyqxmd.com/read/26930558/generation-and-characterization-of-mice-expressing-a-conditional-allele-of-the-interleukin-1-receptor-type-1
#20
Matthew J Robson, Chong-Bin Zhu, Meagan A Quinlan, David A Botschner, Nicole L Baganz, Kathryn M Lindler, Jason G Thome, William A Hewlett, Randy D Blakely
The cytokines IL-1α and IL-1β exert powerful pro-inflammatory actions throughout the body, mediated primarily by the intracellular signaling capacity of the interleukin-1 receptor (IL-1R1). Although Il1r1 knockout mice have been informative with respect to a requirement for IL-1R1 signaling in inflammatory events, the constitutive nature of gene elimination has limited their utility in the assessment of temporal and spatial patterns of cytokine action. To pursue such questions, we have generated C57Bl/6J mice containing a floxed Il1r1 gene (Il1r1loxP/loxP), with loxP sites positioned to flank exons 3 and 4 and thereby the ability to spatially and temporally eliminate Il1r1 expression and signaling...
2016: PloS One
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