Neurotensin-deficient mice show altered responses to antipsychotic drugs

Dobner, Paul R.; Fadel, Jim R.; Deitemeyer, Nancy; Carraway, Robert E.; Deutch, Ariel Y.

doi:10.1073/pnas.141042198

Cited by 44 publications

(31 citation statements)

References 59 publications

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“…Our results confirm and extend the previous findings of Fadel et al (2001) and Dobner et al (2001) concerning the involvement of NT neurotransmission in APD-induced Fos expression in the CPu. We did not, however, observe any common effects of the NT receptor antagonist on APDinduced Fos-expression in limbic brain regions.…”

Section: Discussionsupporting

confidence: 92%

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Neurotensin Receptor Antagonist SR 142948A Alters Fos Expression and Extrapyramidal Side Effect Profile of Typical and Atypical Antipsychotic Drugs

Binder

Kinkead

Owens

et al. 2004

Neuropsychopharmacol

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Antipsychotic drugs (APDs) have previously been shown to alter Fos expression in a regionally specific manner. Increases in Fos expression in the nucleus accumbens (NAcc) are common to all clinically effective APDs. In contrast, APD-induced Fos expression increases in the caudate-putamen (CPu) and prefrontal cortex (PFC) are associated with the extrapyramidal side effect liability of typical APDs or the effectiveness against negative symptoms of atypical APDs, respectively. Considerable evidence suggests that the neuropeptide neurotensin (NT) mediates some of the effects of APDs. To determine whether NT neurotransmission is also involved in APD-induced Fos expression in brain regions relevant for therapeutic efficacy, the NT receptor antagonist SR 142948A (10 or 100 mg/ kg i.p.) was coadministered with APDs (haloperidol (2.0 mg/kg s.c.), olanzapine (5 mg/kg i.p.), or clozapine (20 mg/kg s.c.)). Fos expression was evaluated in the PFC, NAcc shell, dorsomedial, and dorsolateral CPu and the lateral septum. SR 142948A attenuated haloperidolinduced Fos expression in the CPu but, in contrast, increased olanzapine-induced Fos expression in this brain region. The effects of the NT receptor antagonist were paralleled by its effects on catalepsy in olanzapineFbut not haloperidolFtreated animals.

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Section: Discussionsupporting

confidence: 92%

“…Two recent studies have confirmed that NT neurotransmission partly mediates haloperidol-induced Fos expression in the CPu, but not in the NAcc Dobner et al, 2001). This was shown using the NT receptor antagonist SR 48692 and transgenic mice lacking a functional NT/NN gene, respectively.…”

Section: Introductionmentioning

confidence: 96%

Neurotensin Receptor Antagonist SR 142948A Alters Fos Expression and Extrapyramidal Side Effect Profile of Typical and Atypical Antipsychotic Drugs

Binder

Kinkead

Owens

et al. 2004

Neuropsychopharmacol

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“…Catalepsy was evaluated using the inclined plan procedure (Dobner et al, 2001). Mice were placed in a mesh wire grid inclined to an angle of 701.…”

Section: Catalepsymentioning

confidence: 99%

“…The two main families of transcripts studied so far include Fos and striatal neuropeptides such as enkephalin and neurotensin (Herdegen and Leah, 1998;Steiner and Gerfen, 1998). The effect of neuroleptics on opioid neuropeptide expression is seen as an adaptative phenomenon to re-establish the normal activity of dopamine systems (Steiner and Gerfen, 1998), whereas it has been suggested that neurotensin is required for the activation of specific populations of striatal neurons by typical antipsychotics (Dobner et al, 2001). Our results demonstrate that the genetic deletion of NGFI-B also interferes with the effect of haloperidol on striatal enkephalin and neurotensin expression.…”

Section: Ngfi-b(+/+) Ngfi-b(-/-) Ngfi-b(+/+) Ngfi-b(-/mentioning

confidence: 99%

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

Éthier

Beaudry

St-Hilaire

et al. 2003

Neuropsychopharmacol

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Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. We have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacological approaches, we investigated the role of NGFI-B and retinoids in acute behavioral and biochemical responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D 2 /D 3 antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D 1 agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addition, we demonstrate that haloperidol enhances colocalization of NGFI-B and RXRg1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. Our data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the molecular cascade induced by neuroleptic drugs.

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“…To examine the potential role of NT in fat deposition and obesity, we initially compared NT-deficient mice 10,11 to wild type littermates fed a standard diet (18% kcal from fat) for 6 months. Average body length, small bowel weight and length, villus height and crypt number did not differ between genotypes (Extended Data Fig.…”

mentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

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219

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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Neurotensin-deficient mice show altered responses to antipsychotic drugs

Cited by 44 publications

References 59 publications

Neurotensin Receptor Antagonist SR 142948A Alters Fos Expression and Extrapyramidal Side Effect Profile of Typical and Atypical Antipsychotic Drugs

Neurotensin Receptor Antagonist SR 142948A Alters Fos Expression and Extrapyramidal Side Effect Profile of Typical and Atypical Antipsychotic Drugs

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

An obligatory role for neurotensin in high-fat-diet-induced obesity

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