<i>Lmx1b</i>Is Required for Maintenance of Central Serotonergic Neurons and Mice Lacking Central Serotonergic System Exhibit Normal Locomotor Activity

Zhao, Zhong Qiu; Scott, Michael M.; Chiechio, Santina; Wang, Jin Shan; Renner, Kenneth J.; Gereau, Robert W.; Johnson, Randy L.; Deneris, Evan S.; Chen, Zhou Feng

doi:10.1523/jneurosci.4143-06.2006

Cited by 189 publications

(243 citation statements)

References 37 publications

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“…In this study we report opioid-mediated behaviors of Lmx1b f/f/p mice in which central 5-HT neurons fail to survive because of the genetic elimination of Lmx1b in Pet1-expressing neurons (21). By taking the advantage of this animal model, we provide genetic evidence indicating that central 5-HT neurons are necessary for the full expression of opioid analgesia.…”

Section: Discussionmentioning

confidence: 85%

“…We have generated a line of conditional knockout mice called Lmx1b f/f/p mice in which the transcription factor Lmx1b, which is essential for the development of 5-HT neurons in the hindbrain, is selectively deleted in cells expressing Pet1 (19)(20)(21). Because 5-HT neurons lacking Lmx1b fail to survive, the deletion of Lmx1b results in the specific loss of the central 5-HT neurons in Lmx1b f/f/p mice (21).…”

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confidence: 99%

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confidence: 99%

“…Because 5-HT neurons lacking Lmx1b fail to survive, the deletion of Lmx1b results in the specific loss of the central 5-HT neurons in Lmx1b f/f/p mice (21). While the central 5-HT system is ablated, Lmx1b f/f/p mice have normal expression levels of peripheral 5-HT, dopamine, and norepinephrine (21). These mutant mice display normal locomotor activity, acute thermal pain, and enhanced inflammatory pain (22) and thus provide a unique model for assessing the involvement of central 5-HT neurons in opioid-mediated processes.…”

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confidence: 99%

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Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Zhao¹,

Gao²,

Sun³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1b f/f/p ), which lack central serotonergic neurons, and we report that opioid analgesia is differentially dependent on the central serotonergic system. Analgesia induced by a opioid receptor agonist administered at the supraspinal level was abolished in Lmx1b f/f/p mice compared with their wild-type littermates. Furthermore, compared with their wild-type littermates Lmx1b f/f/p mice exhibited significantly reduced analgesic effects of and ␦ opioid receptor agonists at both spinal and supraspinal sites. In contrast to the attenuation in opioid analgesia, Lmx1b f/f/p mice developed tolerance to morphine analgesia and displayed normal morphine reward behavior as measured by conditioned place preference. Our results provide genetic evidence supporting the view that the central serotonergic system is a key component of supraspinal pain modulatory circuitry mediating opioid analgesia. Furthermore, our data suggest that the mechanisms of morphine tolerance and morphine reward are independent of the central serotonergic system. serotonin ͉ pain ͉ conditioned place preference ͉ behavior ͉ mouse

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Zhao¹,

Gao²,

Sun³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Preliminary phenotypic analysis of these mice demonstrated an increase in anxiety-like behavior in some of the standard assays such as the novel open field and elevated zero-maze (for description and discussion of these tests, see Cryan and Holmes, 2005), as well as an increase in conspecific aggression (Hendricks et al, 2003). Pet-1 mice represent a powerful model for studying the stress-related consequences of genetically driven lifelong loss of brain serotonin (see also Lmx1b knockout mice (Zhao et al, 2006b)) and further data on these mice is eagerly anticipated.…”

Section: Serotonin Synthesismentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

249

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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Molecular Genetics of Nail–Patella Syndrome

McIntosh¹

2012

Encyclopedia of Life Sciences

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Nail–patella Syndrome (NPS) is a pleiotropic disorder affecting development of the limbs, kidneys, eyes and central nervous system, which is the result of heterozygous, loss‐of‐function mutations in the transcription factor, LIM‐homeobox 1β (LMX1B). There is no correlation between the type or nature of individual mutations and the severity of the phenotype. The availability of animal models, together with analysis of gene expression patterns during development, has substantiated that the range of clinically relevant signs and symptoms is greater than appreciated previously. Evidence is building that attention deficit±hyperactivity disorder and depression may be constituent parts of the syndrome. The variation in the range and severity of symptoms, and the diverse range of affected tissues, make NPS an appropriate model in which to study the effects of gene interactions on the observed phenotype. Key Concepts: NPS is a pleiotropic, clinically variable autosomal dominant disorder. LMX1B is a member of a gene family primarily involved in regulating neuronal patterning. Loss of function mutations in LMX1B cause NPS but do not predict disease severity. Analysis of Lmx1b expression has helped explain previously unknown neural aspects of NPS. Physicians should be aware of the extra‐skeletal aspects of NPS and institute appropriate monitoring and treatment.

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Lmx1bIs Required for Maintenance of Central Serotonergic Neurons and Mice Lacking Central Serotonergic System Exhibit Normal Locomotor Activity

Cited by 189 publications

References 37 publications

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Molecular Genetics of Nail–Patella Syndrome

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