Norepinephrine transporter-deficient mice respond to anxiety producing and fearful environments with bradycardia and hypotension

Keller, Nancy R.; Diedrich, André; Appalsamy, Martin; Miller, Lindsey; Caron, Marc G.; McDonald, Michael P.; Shelton, Richard C.; Blakely, Randy D.; Robertson, David L.

doi:10.1016/j.neuroscience.2006.01.008

Cited by 24 publications

(16 citation statements)

References 49 publications

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“…The sucrose preference and CPP alteration in VMAT2-HET mice was not replicated in our conditional models, suggesting that the alteration of only 1 monoamine system is not sufficient to induce anhedonic behaviour. Because the NET-KO mice have reduced anxiety as well as a depression-resistant phenotype 28 that is similar to that induced by antidepressant treatment, 41 the depressive phenotype of VMAT2-HET mice could be explained by the NE component. However, the absence of depressive-like behaviour in our experiments with VMAT2 DBHcre -HET mice does not support this hypothesis, and further studies using the homozygous deletion of VMAT2 in NE neurons will be needed to better understand the role of NE in the regulation of affective behaviour.…”

Section: Altering 1 Monoaminergic System Is Not Sufficient To Induce mentioning

confidence: 99%

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Isingrini¹,

Perret²,

Rainer³

et al. 2016

jpn

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IntroductionMonoaminergic neurotransmitters, namely dopamine (DA), noradrenaline (NE) and serotonin (5-HT), extensively modulate cognitive, affective, neuroendocrine and motor functions in the brain. 1 The role of the monoaminergic systems in psychi atric pathology has been clearly established based on the observation that effective psychotropic drugs primarily target these systems. [2][3][4] However, the functional subdivision of the monoamine systems indicates a disparity in cerebral distribution, receptor subtypes and mechanisms of action. Unravelling the independent roles of the monoaminergic systems in patients with neuropsychiatric disorders remains a challenge that is complicated by their large anatomic, pharmacological and functional overlaps.At the molecular level, the monoaminergic systems share common properties. The intra-and extracellular concentrations of monoamines are primarily controlled by 2 types of transporters. The plasma membrane transporters (norepinephrine transporter [NET], serotonin transporter [SERT] and dopamine transporter [DAT]) play an essential role in the clearance and recycling of monoamines via uptake from the extracellular space, and the vesicular monoamine transporter (VMAT) accumulates monoamines in synaptic vesicles and is essential for their release. 5 Two VMAT genes have been cloned, 6,7 and although the proteins encoded by these genes are structurally related, they fulfill distinct roles. VMAT1 is primarily expressed in the peripheral nervous system; VMAT2 is primarily expressed in the neurons of the central nervous system. 8,9 The functions of VMAT2 include storage of monoamines, protection of monoamines from cytoplasmic oxi dation and regulation of stimulated monoamine quantal release. 10 Thus, VMAT2 deficiency contributes to a decrease in the synaptic release of monoamines and an increase in the degradation of intracellular monoamines.To better understand the physiologic and behavioural roles of monoaminergic signalling, several investigators have created VMAT2-knockout (KO) mice by disrupting the gene that Background:The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions. Methods: To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2 lox/lox mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system. Results: Conditional VMAT2-KO mice reveale...

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Section: Altering 1 Monoaminergic System Is Not Sufficient To Induce mentioning

confidence: 99%

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Isingrini¹,

Perret²,

Rainer³

et al. 2016

jpn

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“…Interestingly, both of these KO mice have altered anxiety/ depression phenotypes (Schramm et al, 2001;Lahdesmaki et al, 2002;Dziedzicka-Wasylewska et al, 2006;Keller et al, 2006) including increased anxiety-like behavior in the elevated plus maze (a 2A -AR KOs), increased response to injection stress (a 2A -AR KOs), decreased struggling/mobility in the forced swim and tail suspension tests (NET KOs) and bradycardia to stressful stimuli (NET KOs). In addition the NET KO animals have heightened sensitivity to psychostimulants, enhanced conditioned place preference to cocaine, and increased analgesia to opiates Xu et al, 2000;Hall et al, 2002).…”

Section: Ne Induces Ltd In a Time-dependent Mannermentioning

confidence: 99%

α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

McElligott

Winder

2007

Neuropsychopharmacol

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The glutamatergic synapse in specific brain regions has been shown to be a site for convergence of stress and addictive substances. The bed nucleus of the stria terminalis (BNST), a nucleus that relays between higher order processing centers and classical reward and stress pathways, receives dense noradrenergic inputs that are known to influence behavioral paradigms of both anxiety and stress-induced relapse to drug seeking. a 1 -Adrenergic receptors (a 1 -ARs) within this region have been implicated in modulation of the HPA axis and anxiety responses. We found that application of an a 1 -AR agonist produced a long-term depression (LTD) of excitatory transmission in an acute mouse BNST slice preparation. This effect was mimicked by a 20 min, but not a 10 min, application of 100 mM norepinephrine (NE) in a prazosin-sensitive manner. This a 1 -AR LTD was independent of N-methyl-D-aspartate receptor (NMDAR) function unlike previously described a 1 -AR LTD in the hippocampus and visual cortex; however, it was dependent on the activation of L-type voltage gated calcium channels (VGCCs). In addition, a 1 -AR LTD was induced independently of the activation of mGluR5 which can also induce LTD in this region. Furthermore, a 1 -AR LTD was intact in mice receiving an intraperitoneal injection of cocaine but was disrupted in a 2a -AR and NE transporter (NET) knockout (KO) mice. Thus a loss of this plasticity at glutamatergic synapses in BNST could contribute to affective behavioral phenotypes of these mice.

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“…For example, variants in genes that regulate 5-HT or NE levels alter adult emotional behavior in humans (Reif and Lesch, 2003;D'Souza and Craig, 2006;Kim et al, 2006;Zhang et al, 2006), nonhuman primates (Barr et al, 2004;Newman et al, 2005) and mice (Gross et al, 2000;Xu et al, 2000;Popova et al, 2001;Lira et al, 2003;Dziedzicka-Wasylewska et al, 2006;Kalueff et al, 2006;Keller et al, 2006). In the case of 5-HT transporter (5-HTT), genetically driven inhibition constitutes a risk factor for affectiverelated abnormalities in rodents, primates, and humans Ansorge et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Serotonin But Not Norepinephrine Transport during Development Produces Delayed, Persistent Perturbations of Emotional Behaviors in Mice

Ansorge¹,

Morelli²,

Gingrich³

2008

J. Neurosci.

284

262

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Norepinephrine transporter-deficient mice respond to anxiety producing and fearful environments with bradycardia and hypotension

Cited by 24 publications

References 49 publications

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

Inhibition of Serotonin But Not Norepinephrine Transport during Development Produces Delayed, Persistent Perturbations of Emotional Behaviors in Mice

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