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Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine.
Pirzgalska RM, Seixas E, Seidman JS, Link VM, Sánchez NM, Mahú I, Mendes R, Gres V, Kubasova N, Morris I, Arús BA, Larabee CM, Vasques M, Tortosa F, Sousa AL, Anandan S, Tranfield E, Hahn MK, Iannacone M, Spann NJ, Glass CK, Domingos AI
(2017) Nat Med 23: 1309-1318
MeSH Terms: Animals, CX3C Chemokine Receptor 1, Gene Expression Profiling, Homeostasis, Macrophages, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Obesity, Sympathetic Nervous System
Show Abstract · Added February 9, 2018
The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.
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13 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
Acute hemodynamic effects of a selective serotonin reuptake inhibitor in postural tachycardia syndrome: a randomized, crossover trial.
Mar PL, Raj V, Black BK, Biaggioni I, Shibao CA, Paranjape SY, Dupont WD, Robertson D, Raj SR
(2014) J Psychopharmacol 28: 155-61
MeSH Terms: Adult, Blood Pressure, Cross-Over Studies, Female, Heart Rate, Hemodynamics, Humans, Male, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome, Serotonin Uptake Inhibitors, Sertraline
Show Abstract · Added March 7, 2014
BACKGROUND - Selective serotonin reuptake inhibitors (SSRIs) are often prescribed in patients with postural tachycardia syndrome (POTS), and act at synaptic terminals to increase monoamine neurotransmitters. We hypothesized that they act to increase blood pressure and attenuate reflex tachycardia, thereby improving symptoms. Acute hemodynamic profiles after SSRI administration in POTS patients have not previously been reported.
METHODS - Patients with POTS (n=39; F=37, 39 ±9 years) underwent a randomized crossover trial with sertraline 50mg and placebo. Heart rate, systolic, diastolic, and mean blood pressure were measured with the patient seated and standing for 10 min prior to drug or placebo administration, and then hourly for 4 h. The primary endpoint was standing heart rate at 4 h.
RESULTS - At 4 h, standing heart rate and systolic blood pressure were not significantly different between sertraline and placebo. Seated systolic (106±12 mmHg vs. 101±8 mmHg; p=0.041), diastolic (72±8 mmHg vs. 69±8 mmHg; p=0.022), and mean blood pressure (86±9 mmHg vs. 81±9 mmHg; p=0.007) were significantly higher after sertraline administration than placebo. At 4 h, symptoms were worse with sertraline than placebo.
CONCLUSIONS - Sertraline had a modest pressor effect in POTS patients, but this did not translate into a reduced heart rate or improved symptoms.
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12 MeSH Terms
Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis.
Ma Y, Krueger JJ, Redmon SN, Uppuganti S, Nyman JS, Hahn MK, Elefteriou F
(2013) J Biol Chem 288: 30105-13
MeSH Terms: Animals, Antidepressive Agents, Biological Transport, Active, Bone Remodeling, Bone Resorption, Humans, Mice, Mice, Mutant Strains, Morpholines, Neurons, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Osteoclasts, Psychomotor Disorders, Reboxetine, Sympathetic Nervous System
Show Abstract · Added November 14, 2013
Changes in bone remodeling induced by pharmacological and genetic manipulation of β-adrenergic receptor (βAR) signaling in osteoblasts support a role of sympathetic nerves in the regulation of bone remodeling. However, the contribution of endogenous sympathetic outflow and nerve-derived norepinephrine (NE) to bone remodeling under pathophysiological conditions remains unclear. We show here that differentiated osteoblasts, like neurons, express the norepinephrine transporter (NET), exhibit specific NE uptake activity via NET and can catabolize, but not generate, NE. Pharmacological blockade of NE transport by reboxetine induced bone loss in WT mice. Similarly, lack of NE reuptake in norepinephrine transporter (Net)-deficient mice led to reduced bone formation and increased bone resorption, resulting in suboptimal peak bone mass and mechanical properties associated with low sympathetic outflow and high plasma NE levels. Last, daily sympathetic activation induced by mild chronic stress was unable to induce bone loss, unless NET activity was blocked. These findings indicate that the control of endogenous NE release and reuptake by presynaptic neurons and osteoblasts is an important component of the complex homeostatic machinery by which the sympathetic nervous system controls bone remodeling. These findings also suggest that drugs antagonizing NET activity, used for the treatment of hyperactivity disorders, may have deleterious effects on bone accrual.
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16 MeSH Terms
Effects of norepinephrine reuptake inhibition on postural tachycardia syndrome.
Green EA, Raj V, Shibao CA, Biaggioni I, Black BK, Dupont WD, Robertson D, Raj SR
(2013) J Am Heart Assoc 2: e000395
MeSH Terms: Adrenergic Uptake Inhibitors, Adult, Atomoxetine Hydrochloride, Cross-Over Studies, Female, Heart Rate, Humans, Male, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome, Propylamines, Severity of Illness Index
Show Abstract · Added March 7, 2014
BACKGROUND - Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance accompanied by excessive orthostatic tachycardia. Patients with POTS commonly have comorbid conditions such as attention deficit hyperactivity disorder, depression, or fibromyalgia that are treated with medications that inhibit the norepinephrine reuptake transporter (NRI). NRI medications can increase sympathetic nervous system tone, which may increase heart rate (HR) and worsen symptoms in POTS patients. We sought to determine whether NRI with atomoxetine increases standing tachycardia or worsens the symptom burden in POTS patients.
METHODS AND RESULTS - Patients with POTS (n = 27) underwent an acute drug trial of atomoxetine 40 mg and placebo on separate mornings in a randomized, crossover design. Blood pressure (BP), HR, and symptoms were assessed while seated and after standing prior to and hourly for 4 hours following study drug administration. Atomoxetine significantly increased standing HR compared with placebo (121 ± 17 beats per minute versus 105 ± 15 beats per minute; P = 0.001) in POTS patients, with a trend toward higher standing systolic BP (P = 0.072). Symptom scores worsened with atomoxetine compared to placebo (+4.2 au versus -3.5 au; P = 0.028) from baseline to 2 hours after study drug administration.
CONCLUSION - Norepinephrine reuptake inhibition with atomoxetine acutely increased standing HR and symptom burden in patients with POTS.
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12 MeSH Terms
Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.
Shirey-Rice JK, Klar R, Fentress HM, Redmon SN, Sabb TR, Krueger JJ, Wallace NM, Appalsamy M, Finney C, Lonce S, Diedrich A, Hahn MK
(2013) Dis Model Mech 6: 1001-11
MeSH Terms: Animals, Baroreflex, Behavior, Animal, Biological Transport, Catecholamines, Disease Models, Animal, Female, Gene Knock-In Techniques, Humans, Methoxyhydroxyphenylglycol, Mice, Mutant Proteins, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome, Telemetry
Show Abstract · Added June 2, 2014
Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.
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16 MeSH Terms
Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes.
Conrad KL, Davis AR, Silberman Y, Sheffler DJ, Shields AD, Saleh SA, Sen N, Matthies HJ, Javitch JA, Lindsley CW, Winder DG
(2012) Neuropsychopharmacology 37: 2253-66
MeSH Terms: Adrenergic alpha-1 Receptor Antagonists, Adrenergic alpha-2 Receptor Antagonists, Animals, Behavior, Animal, Cocaine, Drug-Seeking Behavior, Extinction, Psychological, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Morpholines, Neuropeptides, Neurotransmitter Agents, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Orexin Receptors, Orexins, Patch-Clamp Techniques, Reboxetine, Receptors, Adrenergic, alpha-2, Receptors, Corticotropin-Releasing Hormone, Receptors, Neuropeptide, Reward, Septal Nuclei, Synaptic Transmission, Yohimbine
Show Abstract · Added September 17, 2013
The alpha2 adrenergic receptor (α(2)-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of α(2)-AR signaling. Recent studies show yohimbine-induced drug-seeking behavior is attenuated by orexin receptor 1 (OX(1)R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR(1)) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX(1)R-dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX(1)R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.
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28 MeSH Terms
Synergistic effect of norepinephrine transporter blockade and α-2 antagonism on blood pressure in autonomic failure.
Okamoto LE, Shibao C, Gamboa A, Choi L, Diedrich A, Raj SR, Black BK, Robertson D, Biaggioni I
(2012) Hypertension 59: 650-6
MeSH Terms: Adrenergic Uptake Inhibitors, Adrenergic alpha-2 Receptor Antagonists, Aged, Atomoxetine Hydrochloride, Blood Pressure, Cross-Over Studies, Dose-Response Relationship, Drug, Drug Synergism, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Middle Aged, Norepinephrine Plasma Membrane Transport Proteins, Postural Balance, Propylamines, Prospective Studies, Shy-Drager Syndrome, Single-Blind Method, Treatment Outcome, Yohimbine
Show Abstract · Added December 10, 2013
Patients with autonomic failure have disabling orthostatic hypotension because of impaired sympathetic activity. Norepinephrine transporter blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the α-2 antagonist yohimbine would potentiate the pressor effect of norepinephrine transporter blockade with atomoxetine and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg or atomoxetine 18.0 mg, and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for ≤10 minutes before and 1 hour postdrug. Neither yohimbine nor atomoxetine significantly increased seated systolic blood pressure or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated systolic blood pressure and orthostatic tolerance (P<0.001 and P=0.016, respectively) in a synergistic manner. The maximal increase in seated systolic blood pressure seen with the combination was 31±33 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination of yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of norepinephrine in peripheral sympathetic neurons by α-2 antagonism combined with a reduced norepinephrine clearance by norepinephrine transporter blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.
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22 MeSH Terms
The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA ("ecstasy") in humans.
Hysek CM, Simmler LD, Ineichen M, Grouzmann E, Hoener MC, Brenneisen R, Huwyler J, Liechti ME
(2011) Clin Pharmacol Ther 90: 246-55
MeSH Terms: 3,4-Methylenedioxyamphetamine, Adrenergic Uptake Inhibitors, Adult, Blood Pressure, Cross-Over Studies, Double-Blind Method, Drug Interactions, Female, Hallucinogens, Heart Rate, Humans, Male, Morpholines, N-Methyl-3,4-methylenedioxyamphetamine, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Reboxetine, Young Adult
Show Abstract · Added August 3, 2013
This study assessed the pharmacodynamic and pharmacokinetic effects of the interaction between the selective norepinephrine (NE) transporter inhibitor reboxetine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in 16 healthy subjects. The study used a double-blind, placebo-controlled crossover design. Reboxetine reduced the effects of MDMA including elevations in plasma levels of NE, increases in blood pressure and heart rate, subjective drug high, stimulation, and emotional excitation. These effects were evident despite an increase in the concentrations of MDMA and its active metabolite 3,4-methylenedioxyamphetamine (MDA) in plasma. The results demonstrate that transporter-mediated NE release has a critical role in the cardiovascular and stimulant-like effects of MDMA in humans.
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18 MeSH Terms
Genetic variation in the presynaptic norepinephrine transporter is associated with blood pressure responses to exercise in healthy humans.
Kohli U, Hahn MK, English BA, Sofowora GG, Muszkat M, Li C, Blakely RD, Stein CM, Kurnik D
(2011) Pharmacogenet Genomics 21: 171-8
MeSH Terms: Adult, Blood Pressure, Catecholamines, Cohort Studies, Exercise, Female, Genetic Variation, Genotype, Humans, Male, Middle Aged, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins
Show Abstract · Added December 10, 2013
BACKGROUND - The presynaptic norepinephrine transporter (NET) mediates synaptic clearance and recycling of norepinephrine. NET-deficient transgenic mice have elevated blood pressure (BP), heart rate, and catecholamine concentrations. However, the in-vivo effects of common NET variants on cardiovascular regulation at rest and during exercise are unknown.
METHODS - We studied cardiovascular responses and plasma catecholamine concentrations at rest and during bicycle exercise at increasing workloads (25, 50, and 75 W) in 145 healthy participants. We used multiple linear regressions to analyze the effect of common, purportedly functional polymorphisms in NET (rs2242446 and rs28386840) on cardiovascular measures.
RESULTS - 44 and 58.9% of participants carried at least one variant allele for NET T-182C and A-3081T, respectively. Systolic BP during exercise and systolic BP-area under the curve were higher in carriers of variant NET alleles (P=0.003 and 0.009 for T-182C and A-3081T, respectively) and NET haplotype -182C/-3081T compared with -182T/-3081A (all P<0.01). Diastolic BP during exercise was also higher at lower, but not at higher exercise stages in carriers of NET -182C (P<0.01) and -3081T variants (P<0.05). NET genotypes were not associated with catecholamine concentrations or heart rate.
CONCLUSION - Common genetic NET variants (-182C and -3081T) are associated with greater BP response to exercise in humans.
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13 MeSH Terms