Norepinephrine-Deficient Mice Have Increased Susceptibility to Seizure-Inducing Stimuli

Szot, Patricia; Weinshenker, David; White, Sylvia S.; Robbins, Carol A.; Rust, Nicole C.; Schwartzkroin, Philip A.; Palmiter, Richard D.

doi:10.1523/jneurosci.19-24-10985.1999

Cited by 126 publications

(93 citation statements)

References 68 publications

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“…Because NE is required for embryonic development, we pharmacologically rescue Dbh −/− mice during gestation, but they lack NE starting at birth. Our results presented here indicate that these postnatal changes can still occur in the absence of NE.Administration of DOPS partially restores brain NE levels and reverses most of the known Dbh −/− phenotypes Palmiter, 1997, 1998;Szot et al, 1999;Weinshenker et al, 2000;Murchison et al, 2004). We have previously shown that NE transporter expression is normal in Dbh −/− mice , and our current study indicates that normal LC neuron firing and α-2 autoreceptor function are also preserved.…”

supporting

confidence: 71%

“…NE neurons are intact and make proper connections in Dbh −/− mice, and receptor levels and co-transmitter expression are remarkably normal (Weinshenker et al, 2002b;Jin et al, 2004; Sanders et al, in press; D. Weinshenker unpublished observations). Many Dbh −/− phenotypes are reversible by acute pharamcological restoration of NE, indicating that the phenotypes are specifically due to NE deficiency (Thomas and Palmiter., 1997b;Szot et al, 1999;Weinshenker et al, 2000). However, it is unclear whether NE replacement truly restores the NE system to a "wild-type" state.…”

Section: Nih Public Accessmentioning

confidence: 99%

“…Dbh −/− mice were bred as described and maintained on a mixed C57BL6/J and 129SvEv genetic background . Dbh +/− mice have normal brain NE content and are behaviorally indistinguishable from wild-type mice, and were used as controls Szot et al, 1999;Marino et al, 2005). Because complete NE deficiency is lethal embryonically in mice (Thomas et al, 1995), NE was restored to knockout embryos by supplementing the drinking water of pregnant dams with adrenergic agonists from E 9.5 to E 14.5, and L-3,4-dihydroxyphenylserine (DOPS) from E 14.5 until birth (Thomas et al, 1995;.…”

Section: Experimental Procedures Animalsmentioning

confidence: 99%

“…However, it is not known whether NE depletion affects the basic physiological properties of NE or DA neurons. Dopamine β-hydroxylase knockout (Dbh −/−) mice completely lack NE and have many brainmediated behavioral abnormalities, including impaired maternal and social behavior, defects in memory retrieval, increased seizure susceptibility, dysregulation of DA signaling, and hypersensitivity to psychostimulants (Thomas et al, 1995;Szot et al, 1999;Murchison et al, 2004;Marino et al, 2005;Schank et al, 2005). NE neurons are intact and make proper connections in Dbh −/− mice, and receptor levels and co-transmitter expression are remarkably normal (Weinshenker et al, 2002b;Jin et al, 2004;Sanders et al, in press; D. Weinshenker unpublished observations).…”

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Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

Paladini

Beckstead

2007

Neuroscience

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To determine how norepinephrine affects the basic physiological properties of catecholaminergic neurons, brain slices containing the Substantia Nigra Pars Compacta and Locus Coeruleus were studied with cell-attached and whole-cell recordings in control and dopamine β-hydroxylase knockout (Dbh −/−) mice that lack norepinephrine. In the cell-attached configuration, the spontaneous firing rate and pattern of Locus Coeruleus neurons recorded from Dbh −/− mice was the same as the firing rate and pattern recorded from heterozygous littermates (Dbh +/−). During whole-cell recordings, synaptic stimulation produced an α-2 receptor-mediated outward current in the Locus Coeruleus of control mice that was absent in Dbh −/− mice. Normal α-2 mediated outward currents were restored in Dbh −/− slices after pre-incubation with norepinephrine. Locus Coeruleus neurons also displayed similar changes in holding current in response to bath application of norepinephrine, UK 14304, and methionine-enkephalin. Dopamine neurons recorded in the Substantia Nigra Pars Compacta similarly showed no differences between slices harvested from Dbh −/− and control mice. These results indicate that endogenous norepinephrine is not necessary for the expression of catecholaminergic neuron firing properties or responses to direct agonists, but is necessary for auto-inhibition mediated by indirect α-2 receptor stimulation. Keywordsdopamine β-hydroxylase knockout; locus coeruleus; substantia nigra pars compacta; cocaine The activity of norepinephrine (NE) neurons in the locus coeruleus (LC) has an important role in selective attention, general arousal, and stress reactions upon challenging environmental situations (Foote et al., 1983;Levine et al., 1990;Berridge and Waterhouse, 2003;Aston-Jones and Cohen, 2005), and NE depletion may underlie some affective disorders and disease states (Ressler and Nemeroff, 1999). In addition, the LC projects directly to, and modulates the activity of, midbrain dopamine (DA) neurons (Swanson and Hartman, 1975;Jones and Moore, 1977;Liprando et al., 2004), which are critical for reward and motor related behaviors (Girault and Greengard, 2004;Montague et al., 2004). In an intact animal, NE neurons recorded in vitro fire spontaneously in a single-spike Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. pattern at a rate of up to 5 spikes per second (Williams et al., 1984). However, it is not known whether NE depletion affects the basic physiological properties of NE or DA neurons. NIH Public AccessDopamine β-hydroxylase knockout (Dbh −/−) mice completely lack NE and have many bra...

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supporting

confidence: 71%

Section: Nih Public Accessmentioning

confidence: 99%

Section: Experimental Procedures Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

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Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

Paladini

Beckstead

2007

Neuroscience

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“…It is likely that METH-induced glutamate release in limbic brain regions may reach the threshold to trigger convulsive seizures in the absence of endogenous NE. In fact, METH is a powerful glutamate releaser [67-69], while NE is considered to be a pivotal endogenous seizure suppressive mechanism [20, 140-143]. …”

Section: The Role Of Ne In Methamphetamine-induced Behavioural Changesmentioning

confidence: 99%

The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

Ferrucci

Giorgi

Bartalucci

et al. 2013

Current Neuropharmacology

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The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters.

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Long‐term effects of decreased noradrenergic central nervous system innervation on pain behavior and opioid antinociception

Jasmin¹,

Boudah²,

Ohara³

2003

J of Comparative Neurology

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Here we examine whether a permanent reduction in the noradrenergic (NA) innervation of the spinal cord leads to a chronic decreased nociceptive threshold. NA denervation of rats was achieved by intrathecal injection of dopamine beta-hydroxylase antibodies conjugated to the toxin saporin. A subset of animals also underwent unilateral L5 spinal nerve ligature to induce sustained neuropathic pain behavior. NA fibers and terminals were lost throughout the spinal cord 2 weeks after toxin application and were still absent 12 months later, indicating that regeneration did not occur. There was also a widespread loss of NA terminals in the cerebral cortex, whereas innervation of the hypothalamus and amygdala were close to normal and NA innervation of the brainstem was moderately reduced. There was extensive loss of NA cells in the locus coeruleus and A5 and A7 cell groups. Dopaminergic and serotoninergic innervation was normal. Intracerebroventricular injection of the toxin resulted in additional NA reduction in the hypothalamus, amygdala, and A1 and A2 cell groups. Long-term removal of NA afferents did not affect nociceptive thresholds. Neuropathic animals showed greater mechanical hyperalgesia in the affected hindpaw only during the first 60 days after toxin. Rats lacking NA spinal afferents were less responsive to the antinociceptive effects of morphine, especially in the neuropathic hindpaw, and did not display opioid-dependent stress analgesia. Finally, in the spinal cord of toxin-treated rats, immunoreactivity for substance P was decreased, whereas that of its receptor (NK1) was increased. These animals exhibited antinociception to a low dose of an NK1 receptor antagonist. Our results suggest that NA contributes only modestly to determining the nociceptive threshold and that its antinociceptive effects are closely linked to opioidergic and tachykinergic neurotransmission.

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Norepinephrine-Deficient Mice Have Increased Susceptibility to Seizure-Inducing Stimuli

Cited by 126 publications

References 68 publications

Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

Long‐term effects of decreased noradrenergic central nervous system innervation on pain behavior and opioid antinociception

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