Ethanol-Associated Behaviors of Mice Lacking Norepinephrine

Weinshenker, David; Rust, Nicole C.; Miller, Nicole S.; Palmiter, Richard D.

doi:10.1523/jneurosci.20-09-03157.2000

Cited by 90 publications

(67 citation statements)

References 54 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expression are remarkably normal (Weinshenker et al, 2002b;Jin et al, 2004; Sanders et al, in press; D. Weinshenker unpublished observations).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.…”

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confidence: 99%

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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%

mentioning

confidence: 99%

Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

Paladini

Beckstead

2007

Neuroscience

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“…Because CPP is an associative learning paradigm, manipulations of NE could alter the development or expression of a psychostimulant CPP in the absence of any effect on the rewarding properties of the drugs. However, this is unlikely, as mice that completely lack NE still express a normal conditioned taste aversion to lithium chloride and ethanol and show a CPP to food (Weinshenker et al, 2000;Schank et al, 2006;Olson et al, 2006). Interestingly, NE depletion early in development either has no effect (neonatal 6-OHDA lesion; Spyraki et al, 1982a) or even enhances (DBH knockout mice; Schank et al, 2006) psychostimulant CPP, probably due to compensatory changes in the DA system during development (see below).…”

Section: Ne and Psychostimulant Cppmentioning

confidence: 99%

“…DBH knockout mice demonstrate a reduced voluntary ethanol consumption (Weinshenker et al, 2000), and while this reduction may result from a deficit in ethanol reward, it also may be due to the increased sensitivity of these mice to ethanol's aversive effects, such as sedation and hypothermia (Weinshenker et al, 2000). Another study showed that reducing NE transmission via activation of the a2AR autoreceptor with lofexidine attenuates alcohol SA, whereas increasing NE via blockade of this receptor enhances alcohol SA (Le et al, 2005).…”

Section: Ne and Ethanol Sa: A Reassessmentmentioning

confidence: 99%

“…For example, chemical lesions of the NE system, blocking NE synthesis via DBH inhibitors, or genetic deletion of DBH will reduce voluntary ethanol intake, whereas DA lesions do not Kiianmaa et al, 1979;Rassnick et al, 1993b;Weinshenker et al, 2000). Again, evidence does suggest that pharmacologic or genetic manipulation of D1 and D2 receptors can modulate ethanol SA in some circumstances (Weiss et al, 1990;Hubbell et al, 1991;Dyr et al, 1993;Rassnick et al, 1993a;Ng and George, 1994;Silvestre et al, 1996;Cohen et al, 1998Cohen et al, , 1999El-Ghundi et al, 1998;Phillips et al, 1998;Risinger et al, 2000;Boyce and Risinger, 2002;D'Souza et al, 2003;Zocchi et al, 2003).…”

Section: Some Effects Of Ne On Drug Responses May Be Independent Of Damentioning

confidence: 99%

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There and Back Again: A Tale of Norepinephrine and Drug Addiction

Weinshenker

Schroeder

2006

Neuropsychopharmacol

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277

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Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could distinguish between the noradrenergic and dopaminergic systems resulted in the prevailing view that dopamine (DA) was the primary 'reward transmitter' (a belief holding some sway still today), thereby pushing NE into the background. Most damaging to the NE hypothesis of reward were studies demonstrating that NE receptor antagonists and NE reuptake inhibitors failed to impact drug self-administration. In recent years new tools, such as genetically engineered mice, and new experimental paradigms, such as reinstatement of drug seeking following withdrawal, have propelled NE back into the awareness of addiction researchers. Of particular interest is disulfiram, an inhibitor of the NE biosynthetic enzyme dopamine b-hydroxylase, which has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials. The purpose of this review is to synthesize the new data linking NE to critical aspects of DA signaling and drug addiction, with a focus on psychostimulants (eg, cocaine), opiates (eg, morphine), and alcohol.

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Addiction and Genes: Animal Models

Phillips¹

2006

Encyclopedia of Life Sciences

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Gene products (i.e. proteins that may be enzymes, receptors, hormones, etc.) influence susceptibility to alcoholism, drug abuse and other addictions. Progress in gene discovery has been fueled by the Human Genome Project, and by utilization of classical (e.g. standard inbred strains, selected lines) and new‐era genetic models and techniques (e.g. transgenics, microarray analyses). The ultimate goal is to identify the genes of importance to addiction and to define their interactions with other genes and with environmental influences.

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Ethanol-Associated Behaviors of Mice Lacking Norepinephrine

Cited by 90 publications

References 54 publications

Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Addiction and Genes: Animal Models

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