Reduced Levels of Norepinephrine Transporters in the Locus Coeruleus in Major Depression

Klimek, Violetta; Stockmeier, Craig A.; Overholser, James C.; Meltzer, Herbert Y.; Kalka, Sheila; Dilley, Ginny E.; Ordway, Gregory A.

doi:10.1523/jneurosci.17-21-08451.1997

Cited by 364 publications

(252 citation statements)

References 50 publications

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“…Previous observations reveal that depression is associated with altered concentrations of several noradrenergic proteins in the LC. For example, elevated levels of tyrosine hydroxylase (TH) (Ordway et al, 1994a;Zhu et al, 1999), increased agonist binding to a 2 -adrenergic receptors (Ordway et al, 1994b(Ordway et al, , 2003, and reduced levels of norepinephrine transporters (Klimek et al, 1997) were previously reported in the LC from major depression and in suicide victims. Interestingly, depletion of norepinephrine or repeated stress in rats can increase TH expression, increase binding to a 2 -adrenergic receptors, and/or decrease binding to the norepinephrine transporter (Cubells et al, 1995;Lee et al, 1983;Melia et al, 1992;Torda et al, 1985;U'Prichard et al, 1979;Wang et al, 1998;Zafar et al, 1997).…”

Section: Introductionmentioning

confidence: 94%

“…Abnormalities that have been observed in the LC from human depressives (Klimek et al, 1997;Ordway et al, 1994aOrdway et al, , 1994bOrdway et al, , 2003Zhu et al, 1999) can be reproduced, in part, by chronic stress or pharmacological depletion of norepinephrine in rats (Cubells et al, 1995;Lee et al, 1983;Melia et al, 1992;Torda et al, 1985;U'Prichard et al, 1979;Wang et al, 1998;Zafar et al, 1997). Given that stress activates the LC in laboratory animals (Pavcovich et al, 1990), that chronic stress depletes norepinephrine in the LC (Weiss and Simson, 1986), and that stress is a common precipitator of depression in humans, it seems possible that depression may be associated with elevated excitatory input to the LC.…”

Section: Role Of Glutamatergic Signaling In Depressionmentioning

confidence: 99%

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Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz

Stockmeier

Ordway

2005

Neuropsychopharmacol

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Low levels of the intracellular mediator of glutamate receptor activation, neuronal nitric oxide synthase (nNOS) were previously observed in locus coeruleus (LC) from subjects diagnosed with major depression. This finding implicates abnormalities in glutamate signaling in depression. Receptors responding to glutamate in the LC include ionotropic N-methyl-D-aspartate receptors (NMDARs). The functional NMDAR is a hetero-oligomeric structure composed of NR1 and NR2 (A-D) subunits. Tissue containing the LC and a nonlimbic LC projection area (cerebellum) was obtained from 13 and 9 matched pairs, respectively, of depressed subjects and control subjects lacking major psychiatric diagnoses. NMDAR subunit composition in the LC was evaluated in a psychiatrically normal subject. NR1 and NR2C subunit immunoreactivities in LC homogenates showed prominent bands at 120 and 135 kDa, respectively. In contrast to NR1 and NR2C, very weak immunoreactivity of NR2A and NR2B subunits was observed in the LC. Possible changes in concentrations of NR1 and NR2C that might occur in depression were assessed in the LC and cerebellum. The overall amount of NR1 immunoreactivity was normal in the LC and cerebellum in depressed subjects. Amounts of NR2C protein were significantly higher ( þ 61%, p ¼ 0.003) in the LC and modestly, but not significantly, elevated in the cerebellum ( þ 35%) of depressives as compared to matched controls. Higher levels of NR2C subunit implicate altered glutamatergic input to the LC in depressive disorders.

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Section: Introductionmentioning

confidence: 94%

Section: Role Of Glutamatergic Signaling In Depressionmentioning

confidence: 99%

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz

Stockmeier

Ordway

2005

Neuropsychopharmacol

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“…A reduction in the level of NE in the synapse appears to down regulate the level of NET [3]. Recent research has clearly demonstrated a close association between the changes in the distribution of NET in the human brain and various diseases including CNS disorders like depression [4] attention deficit hyperactivity disorder (ADHD) [5,6] and Alzheimer's disease [7]. Non-invasive imaging with highly selective radiolabeled probes would allow us to monitor and quantify the effect of treatment (drug occupancy) or the lack thereof on NET.…”

Section: Introductionmentioning

confidence: 99%

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Balagopal¹,

Kung²,

Lieberman³

et al. 2008

Nuclear Medicine and Biology

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Alterations in the serotonin and norepinephrine neuronal functions have been observed in patients with major depression. Several antidepressants bind to both serotonin transporters (SERT) and norepinephrine transporters (NET). The ability to image NET in the human brain would be a useful step toward understanding how alterations in NET relate to disease. In this study, we report the synthesis and characterization of a new series of derivatives of iodo-nisoxetine (INXT), a known radioiodinated probe. The most promising, (R)-N-methyl-3-(3-iodopyridin-2-yloxy)-3-phenylpropylamine (PYINXT) 9, displayed a high and saturable binding to NET with a K d value of 0.53 ± 0.03 nM. Biodistribution studies of [ 125 I]PYINXT in rats showed moderate initial brain uptake (0.54 %dose/organ at 2 min) with a relatively fast washout from the brain (0.16 %dose/organ at 2 hr) as compared to [ 125 I]INXT, 7. The hypothalamus (a NET rich region) to striatum (a region devoid of NET) ratio was found to be 2.14 at 4 hr post i.v. injection. The preliminary results suggest that this improved iodinated ligand, when labeled with 123 I, may be useful for mapping NET binding sites with SPECT in the living human brain.

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“…However, more recently, a positive association between a T182C polymorphism in the NET gene and susceptibility to major depressive disorder has been reported in a Japanese population (Inoue et al, 2004). Using brain tissues collected post mortem from patients diagnosed with major depression, Klimek et al (1997) have shown reduced expression of the NET (decreased [ 3 H]nisoxetine binding) in the locus coeruleus as compared to age-matched normal control subjects. These data as well as differential region-specific effects on the NET of repeated administration of ADs (Herbert et al, 2001) have been interpreted as reflecting a compensatory downregulation of the NET in response to an insufficient availability of its substrate NE at the synapse.…”

Section: Introductionmentioning

confidence: 99%

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Dziedzicka-Wasylewska

Faron-Górecka

Kuśmider

et al. 2006

Neuropsychopharmacol

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One of the main theories concerning the mechanism of action of antidepressant drugs (ADs) is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) in the synaptic gap. Many ADs increase synaptic NE availability by inhibition of the reuptake of NE. Using mice lacking NE transporter (NET À/À ) we examined their baseline phenotype as well as the response in the forced swim test (FST) and in the tail suspension test (TST) upon treatment with ADs that display different pharmacological profiles. In both tests, the NET À/À mice behaved like wild-type (WT) mice acutely treated with ADs. Autoradiographic studies showed decreased binding of the b-adrenergic ligand [ 3 H]CGP12177 in the cerebral cortex of NET À/À mice, indicating the changes at the level of b-adrenergic receptors similar to those obtained with ADs treatment. The binding of [ 3 H]prazosin to a 1 -adrenergic receptors in the cerebral cortex of NET À/À mice was also decreased, most probably as an adaptive response to the sustained elevation of extracellular NE levels observed in these mice. A pronounced NET knockout-induced shortening of the immobility time in the TST (by ca 50%) compared to WT mice was not reduced any further by NET-inhibiting ADs such as reboxetine, desipramine, and imipramine. Citalopram, which is devoid of affinity for the NET, exerted a significant reduction of immobility time in the NET À/À mice. In the FST, reboxetine, desipramine, imipramine, and citalopram administered acutely did not reduce any further the immobility time shortened by NET knockout itself (ca 25%); however, antidepressant-like action of repeatedly (7 days) administered desipramine was observed in NET À/À mice, indicating that the chronic presence of this drug may also affect other neurochemical targets involved in the behavioral reactions monitored by this test. From the present study, it may be concluded that mice lacking the NET may represent a good model of some aspects of depression-resistant behavior, paralleled with alterations in the expression of adrenergic receptors, which result as an adaptation to elevated levels of extracellular NE.

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Reduced Levels of Norepinephrine Transporters in the Locus Coeruleus in Major Depression

Cited by 364 publications

References 50 publications

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

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