Region-specific induction of ?FosB by repeated administration of typical versus atypical antipsychotic drugs

Atkins, Joshua B.; Chlan-Fourney, Jennifer; Nye, Heather E.; Hiroi, Noboru; Carlezon, William A.; Nestler, Eric J.

doi:10.1002/(sici)1098-2396(199908)33:2<118::aid-syn2>3.0.co;2-l

Cited by 87 publications

(22 citation statements)

References 55 publications

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“…In contrast, the FosB gene codes for a splice variant called ⌬FosB (33 kDa), which is induced ϳ6 h after stimulation (32). ⌬FosB protein accumulates with chronic exposure to stimuli such as drugs of abuse, stressors, or antipsychotic drugs and is stably expressed in cells for up to 1 mo after withdrawal of the stimulus (1,32,37). Therefore, we used ⌬FosB as an independent marker of neuronal activation to determine whether there were sites other than those expressing pSTAT3 that were selectively activated in LL rats.…”

Section: Discussionsupporting

confidence: 82%

“…The purpose of this experiment was to localize brain nuclei showing increased activation due to the chronic infusion of low-dose leptin simultaneously into both the third and fourth ventricles. We used pSTAT3 as a marker for nuclei that were activated directly by leptin (2) and ⌬FosB as a marker for chronic neuronal activation that was not limited to leptin (1). A total of 30 male Sprague-Dawley rats in 2 cohorts of 20 and 10 rats with all groups represented in each cohort were housed and maintained in wire mesh cages throughout the study.…”

Section: Experiments Experimentsmentioning

confidence: 94%

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Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus

Desai

Harris

2015

American Journal of Physiology-Endocrinology and Metabolism

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Desai BN, Harris RB. Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus. Am J Physiol Endocrinol Metab 308: E351-E361, 2015. First published December 30, 2014; doi:10.1152/ajpendo.00501.2014 in the forebrain and hindbrain have been independently recognized as important mediators of leptin responses. We recently used low-dose leptin infusions to show that chronic activation of both hypothalamic and hindbrain ObRs is required to reduce body fat. The objective of the present study was to identify the brain nuclei that are selectively activated in rats that received chronic infusion of leptin in both the forebrain and hindbrain. Either saline or leptin was infused into third and fourth ventricles (0.1 g/24 h in the third ventricle and 0.6 g/24 h in the fourth ventricle) of male Sprague-Dawley rats for 6 days using Alzet pumps. Rats infused with leptin into both ventricles (LL rats) showed a significant increase in phosphorylated (p)STAT3 immunoreactivity in the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and posterior hypothalamus compared with other groups. No differences in pSTAT3 immunoreactivity were observed in midbrain or hindbrain nuclei despite a sixfold higher infusion of leptin into the fourth ventricle than the third ventricle. ⌬FosB immunoreactivity, a marker of chronic neuronal activation, showed that multiple brain nuclei were chronically activated due to the process of infusion, but only the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and ventral tuberomamillary nucleus showed a significant increase in LL rats compared with other groups. These data demonstrate that low-dose leptin in the hindbrain increases pSTAT3 in areas of the hypothalamus known to respond to leptin, supporting the hypothesis that leptin-induced weight loss requires an integrated response from both the hindbrain and forebrain. distributed model; hindbrain; forebrain; food intake; body weight; signal transducer and activator of transcription THE HORMONE LEPTIN, released primarily by white adipose tissue, circulates in proportion to fat mass and has been shown to function as a negative feedback signal in the control of energy balance (49). Leptin is proposed to act through the central nervous system to reduce body fat by inhibiting food intake and maintaining or increasing energy expenditure (23, 36). Leptin-induced changes in food intake, energy expenditure, and metabolism are mediated primarily by the long isoform of the leptin receptor (ObRb), and leptin-induced phosphorylation of the transcription factor STAT3 has been established and widely accepted as a marker for ObRb activation (2, 48).ObRbs are expressed in multiple areas of the brain, with a high level of expression in hypothalamic nuclei, including the arcuate nucleus (Arc), ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), and lateral hypothalamus and moderate levels of expression in other midbrain and hindbrain nuclei, including the ventral tegmental area, dorsal raphae, nuc...

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Section: Discussionsupporting

confidence: 82%

Section: Experiments Experimentsmentioning

confidence: 94%

Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus

Desai

Harris

2015

American Journal of Physiology-Endocrinology and Metabolism

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“…The ⌬FosB product is remarkably resistant to degradation, and it accumulates after repeated exposure to various treatments. Indeed, chronic administration of typical and atypical antipsychotics produce similar contrasting patterns on ⌬FosB immunoreactivity, as observed previously on Foslike immunoreactivity after acute treatment (Doucet et al, 1996;Vahid-Ansari et al, 1996;Atkins et al, 1999).…”

supporting

confidence: 90%

Induction Patterns of Transcription Factors of the Nur Family (Nurr1, Nur77, and Nor-1) by Typical and Atypical Antipsychotics in the Mouse Brain: Implication for Their Mechanism of Action

Maheux

Éthier²,

Rouillard³

et al. 2004

J Pharmacol Exp Ther

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Monitoring gene expression has been intensively used to identify neurobiological and neuroanatomical substrates associated with administration of antipsychotic drugs. Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors that have been recently associated with dopamine neurotransmission. Nurr1 is involved in midbrain dopamine neuron development. Nur77 and Nor-1 are expressed in dopaminoceptive areas such as the striatum, nucleus accumbens, and prefrontal cortex. To better understand the relationship between Nur and antipsychotic drug effects, we conducted a comprehensive evaluation of the effect of various typical and atypical antipsychotic drugs on the modulation of Nur mRNA levels. We show that differential patterns of Nur expression can be obtained with typical and atypical antipsychotic drugs. Modulation of Nur77 and Nor-1 mRNA expression by antipsychotics can be used to calculate an index that is predictive of the typical or atypical profile of antipsychotic drugs. Inductions of Nur by antipsychotic drugs are correlated with dopamine D 2 receptor in the striatum and D 2 and D 3 receptor subtypes in the nucleus accumbens. The 5-hydroxytryptamine 2A /D 2 affinity ratio of antipsychotics can also predict these patterns of inductions. In addition to classical gene patterns induced in the striatal complex (striatum, accumbens) and cortex, most antipsychotic drugs tested strongly induced Nur77, Nor-1, and increased Nurr1 mRNA levels in the substantia nigra and ventral tegmental area. These data suggest that typical and atypical antipsychotic drugs might induce in multiple brain regions distinct Nur-dependent transcriptional activities, which may contribute to their pharmacological effects.

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“…These drugs also increase the expression of FosB in many of the same brain structures that we have observed in this study (Atkins et al, 1999;Robertson et al, 2004;Rodriguez et al, 2001). Despite these apparent similarities, there are several marked differences in both the pattern and magnitude of DFosB expression induced by neuroleptics and in the increase we observed following neonatal VH lesion.…”

Section: Functional Implications Of Dfosb Expressionmentioning

confidence: 99%

Neonatal Ventral Hippocampal Lesions Produce an Elevation of ΔFosB-Like Protein(s) in the Rodent Neocortex

Powell

Binder

Hori

et al. 2005

Neuropsychopharmacol

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Rats that have sustained bilateral excitotoxic lesions of the ventral hippocampus (VH) as neonates develop behavioral abnormalities as adults (hyper-responsiveness to stress, diminished prepulse inhibition, and increased sensitivity to dopamine agonists), which resemble certain aspects of schizophrenia. Although this behavioral profile is thought to reflect dysregulation of the mesolimbic dopamine system, the precise neuroanatomical and neurochemical substrates that mediate the emergence of these abnormalities during brain maturation are unclear. In order to identify putative sites responsible for the development of behavioral abnormalities following neonatal lesions of the VH, we utilized the chronic neuronal activity marker DFosB. By comparison to sham lesioned animals, bilateral destruction of the VH elevated DFosB expression throughout the caudate putamen and neocortex of animals lesioned as neonates. These increases were not observed in rats lesioned as young-adults, suggesting that DFosB induction in the cortex of neonatally lesioned rats may be related to altered cortical neurodevelopment. Accumulating evidence implicates DFosB in mediation of the long-lasting effects of altered dopaminergic neurotransmission on behavior. The present findings are consistent with this proposal and suggest that elevated expression of DFosB identifies overactive neurons that may contribute to the enhanced sensitivity to stress and dopaminergic agonists of rats that have sustained bilateral ventral hippocampal lesions as neonates.

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Region-specific induction of ?FosB by repeated administration of typical versus atypical antipsychotic drugs

Cited by 87 publications

References 55 publications

Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus

Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus

Induction Patterns of Transcription Factors of the Nur Family (Nurr1, Nur77, and Nor-1) by Typical and Atypical Antipsychotics in the Mouse Brain: Implication for Their Mechanism of Action

Neonatal Ventral Hippocampal Lesions Produce an Elevation of ΔFosB-Like Protein(s) in the Rodent Neocortex

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