Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disturbances of retinoid activated transcription mechanisms have recently been implicated as risk factors for schizophrenia. In this study we have compared the regulation of mRNAs for the nuclear orphan receptor NGFI-B, which forms a functional heterodimer with the retinoid x receptor and the related orphan nuclear receptor Nor1 with c-fos mRNA after acute and chronic treatments with haloperidol and clozapine. The antipsychotic drugs haloperidol and clozapine have different clinical profiles. Haloperidol is a typical neuroleptic giving extrapyramidal side effects (EPS), whereas the atypical compound clozapine does not. Acute haloperidol treatment increased NGFI-B, Nor1 and c-fos mRNAs in nucleus accumbens shell and core as well as medial and lateral caudate putamen. In contrast, clozapine lead to an increase of NGFI-B, Nor1 and c-fos only in the accumbens shell. No haloperidol or clozapine effect on these mRNAs was detected in cingulate, sensory or motor cortex. Chronic haloperidol lead to an increase of NGFI-B mRNA in the accumbens core. Acutely, it is possible that the increased levels of NGFI-B, Nor1 and c-fos mRNA levels in striatum and accumbens might indicate a neural activation which possibly can be used when screening for drugs that do not produce EPS. Also, the increased levels of NGFI-B, which is an important component in retinoid signaling, both after acute and chronic treatments of haloperidol suggests altered sensitivity to retinoids which could be an important component for the beneficial antipsychotic effect.
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PMID:Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine. 1077 99

Nurr1, an orphan nuclear receptor, is essential for the differentiation of the midbrain dopamine (DA) neurons; however, its function in adult midbrain DA neurons has not been determined. The present study compared regional brain levels of catecholamines and spontaneous and pharmacologically induced locomotor behaviors between mice heterozygous for the Nurr1-null allele (+/-) and wild type (+/+) littermates. The Nurr1 +/- mice had significantly lower levels of DA in whole brain, midbrain, prefrontal cortex and nucleus accumbens, although no significant differences were observed in the striatum, olfactory bulb or hippocampus. Nurr1 +/- mice displayed significantly greater locomotor activity in a novel open field and after saline injection with no significant difference in activity after treatment with amphetamine (2.5 or 5.0 mg/kg) or MK 801 (0.2 or 0.4 mg/kg). A similar elevation in locomotor activity was observed in Nurr1 +/- mice at 35 days old as was found in 70 days old adults. These data demonstrate that the loss of a single Nurr1 allele results in reduced DA levels in mesolimbic and mesocortical pathways and increased locomotor activity in response to mild stress. The involvement of Nurr1 in DA neurotransmission and the implications for schizophrenia are discussed.
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PMID:Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity. 1238 13

Converging evidence in schizophrenia suggests prefrontal cortical neuronal deficits that correlate with exaggerated subcortical dopamine (DA) functions: Excitotoxic lesion of the ventral hippocampus (VH) in neonatal rats is widely considered a putative animal model of schizophrenia as they lead to characteristic post-pubertal emergence of behavioral and cognitive abnormalities suggesting a developmental change in the neural circuits comprising the prefrontal cortex (PFC) and subcortical DA. Nerve growth factor inducible-B (NGFI-B, also known as Nur77), an orphan nuclear receptor and transcriptional regulator, is constitutively expressed in the target structures of DA pathways. It acts as an immediate early gene with rapid modulation of its mRNA expression by stress, DA and antipsychotic drugs. The present study assessed the effects of neonatal VH (nVH) lesion and amphetamine treatment on the expression of NGFI-B mRNA in pre- and post-pubertal rats. Sprague-Dawley rat pups received bilateral injection of ibotenic acid or phosphate buffered saline in VH at postnatal (PD) 7. At PD35 and PD56, groups of sham and lesioned animals were administered with D-amphetamine (1.5 mg/kg) or saline and killed 20 min later. In situ hybridization analyses showed that the basal level of NGFI-B mRNA in saline-treated lesioned rats was significantly reduced in the medial PFC (mPFC) and cingulate cortex (CC) only at post-pubertal (PD56) age. No significant difference in NGFI-B mRNA levels was seen in the dorsal striatum or nucleus accumbens (NAcc). Amphetamine treatment increased the expression of NGFI-B mRNA in the mPFC, CC, striatum and NAcc in both control and lesioned animals of both ages. Interestingly, however, striatal and NAcc regions of lesioned rats showed a significantly greater effect of amphetamine at PD56. The data suggest that nVH lesions lead to delayed changes in PFC gene expression along with functional DAergic hyperactivity in subcortical regions.
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PMID:Neonatal ventral hippocampus lesion leads to reductions in nerve growth factor inducible-B mRNA in the prefrontal cortex and increased amphetamine response in the nucleus accumbens and dorsal striatum. 1462 10

The present study investigates the association of mutations in the nuclear receptor NR4A2 in schizophrenic patients. The human Nur-related receptor 1, NR4A2, is an orphan nuclear receptor that can be constitutively active as a transcription factor and for which no natural ligand has yet been identified. Alone or with retinoid X receptor, RXR, NR4A2 influences the expression of several genes important for human brain development and regulation. In the absence of Nurr1 (the mouse homologue to human NR4A2), ventral mesencephalic dopaminergic mouse neurons evidence severe developmental failure, a condition that is lethal soon after birth. Nurr1 involvement in the dopaminergic system makes it a good candidate for study in neuropsychiatric disorders such as schizophrenia and Parkinson disease. Evidence by others support this hypothesis (1) mapping of the NR4A2 gene to chromosome 2q22-23, a region with suggestive linkage to schizophrenia and (2) identification of mutations in patients with schizophrenia (c.366-369delTAC, c.308A > G, c.-469delG), manic depression (c.289A > G), and familial Parkinson's disease (c.-291delT, c.-245T > G). To further extend these observations, we searched for all these mutations in 176 Caucasian Portuguese and 82 Caucasian Brazilian subjects with lifetime diagnosis of schizophrenia. The study failed to identify any of the described mutations in patients or controls. Nevertheless, these negative results do not exclude altered expression of nuclear receptors in schizophrenia or the presence of other mutations.
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PMID:NR4A2 and schizophrenia: lack of association in a Portuguese/Brazilian study. 1521 29

Attention deficit hyperactivity disorder (ADHD) is a highly heritable and common disorder thought to arise, in part, from alterations in dopamine function. NR4A2, or Nurr1, is an orphan nuclear receptor implicated in the development of dopaminergic cells of the ventral tegmental area (VTA) and the substantia nigra (SN). Dopaminergic cells of the VTA provide innervation to the prefrontal cortex, believed to be of major importance in the etiology of ADHD, suggesting that NR4A2 is a potential candidate gene for ADHD susceptibility. This study aimed to identify polymorphisms in NR4A2 and test their association to ADHD. Database analysis revealed a CA repeat polymorphism in the 3' UTR of NR4A2 that was confirmed by PCR. SSCP screening revealed a common DeltaC polymorphism, 254 bp 5' to the transcriptional start site. These polymorphisms were tested for an association with ADHD in both a case control study of individuals from the Milwaukee Longitudinal Study of ADHD (103 cases and 66 controls), and in 35 families composed of trios or affected sib pairs (ASP) with ADHD. Functional effects of the promoter polymorphism were tested in vitro. The non-deleted allele was significantly more active in undifferentiated SK-N-MC cells compared to differentiated SK-N-MC and HeLa cells while a trend for increased activity for the DeltaC allele was observed in undifferentiated SK-N-MC cells. Identification of these polymorphisms may aid future candidate gene studies in disorders with altered dopamine signaling, such as schizophrenia Parkinson's disease and ADHD.
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PMID:Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder. 1563 1

The orphan nuclear receptor Nurr1 has been implicated in a number of conditions including Parkinson's disease and Schizophrenia. As such, it is of interest to study its interactions with other proteins, possibly mediated by small molecules, considering possible use as a drug target. We produced (2)H, (15)N, (13)C labelled-Nurr1 to generate the backbone amide NH, carbonyl C', C(alpha) and C(beta) assignments. About 84.0% of residues could be assigned. Most of the 37 missing assignments fall in 3 regions of the protein. Two of these surround a putative ligand-binding region of Nurr1, suggesting that this region of the protein is flexible, despite the ligand-binding pocket being filled with hydrophobic side-chains from residues surrounding the ligand binding pocket.
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PMID:Assignment of the orphan nuclear receptor Nurr1 by NMR. 2030 Aug 92

Schizophrenia and bipolar disorder are associated with dopamine neurotransmission and show high comorbidity with tobacco dependence. Recent evidence indicates that the family of the NR4A orphan nuclear receptors, which are expressed in dopamine neurons and in dopaminoceptive brain areas, may play a role in dopamine-mediated effects. We have, therefore, analysed the association of six single nucleotide polymorphisms (SNPs) within the three genes belonging to the NR4A orphan nuclear receptor family, NR4A1 (rs2603751, rs2701124), NR4A2 (rs12803, rs834835) and NR4A3 (rs1131339, rs1405209), with the degree of smoking in a sample of 204 unrelated schizophrenia patients, which included 126 smokers and 78 non-smokers. SNPs within the NR4A3 gene (rs1131339 and rs1405209) were significantly associated with heavy smoking in this cohort, using a stepwise analysis of the escalated number of cigarettes smoked per day (P = 0.008 and 0.006, respectively; satisfying the Nyholt significance threshold of 0.009, an adjustment for multiple testing). We then repeated the association analysis of the NR4A3 markers (rs1131339 and rs1405209) in a larger cohort of 319 patients with bipolar disorder, which included 167 smokers and 152 non-smokers. We have replicated the positive association with smoking of the NR4A3 SNP rs1131339 in this group (P = 0.04), providing an important confirmation of the involvement of the NR4A3 gene in nicotine addiction in patients with mental health disease, a population significantly at risk for nicotine addiction.
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PMID:Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder. 2065 74

Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the dopaminergic development and survival. Altered expression of Nurr1 has been suggested as a potential genetic risk factor for dopamine-related brain disorders, including schizophrenia. In support of this, recent experimental work in genetically modified mice shows that mice with a heterozygous constitutive deletion of Nurr1 show a facilitation of the development of schizophrenia-related behavioral abnormalities. However, the behavioral characterization of this Nurr1-deficient mouse model remains incomplete. This study therefore used a comprehensive behavioral test battery to evaluate schizophrenia-relevant phenotypes in Nurr1-deficient mice. We found that these mice displayed increased spontaneous locomotor activity and potentiated locomotor reaction to systemic treatment with the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). In addition, male but not female Nurr1-deficient mice showed significant deficits in the prepulse inhibition and prepulse-elicited reactivity. However, Nurr1 deletion did not induce overt abnormalities in other cardinal behavioral and cognitive functions known to be impaired in schizophrenia, including social interaction and recognition, spatial recognition memory or discrimination reversal learning. Our findings thus suggest that heterozygous constitutive deletion of Nurr1 results in a restricted phenotype characteristic of schizophrenia symptomatology, which primarily relates to motor activity, sensorimotor gating and responsiveness to the psychomimetic drug MK-801. This study further emphasizes a critical role of altered dopaminergic development in the precipitation of specific brain dysfunctions relevant to human psychotic disorder.
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PMID:Schizophrenia-relevant behaviors in a genetic mouse model of constitutive Nurr1 deficiency. 2154 4

Inflammation-induced disruption of fetal neurodevelopmental processes has been linked to the precipitation of long-lasting behavioral abnormalities and associated neuropathology. Recent longitudinal investigations in prenatal immune activation models have revealed developmental correspondences between the ontogeny of specific dopaminergic neuropathology and the postnatal onset of distinct forms of dopamine-dependent functional abnormalities implicated in schizophrenia. Two examples of such developmental correspondences are increased expression of the orphan nuclear receptor Nurr1 (NR4A2) in ventral midbrain areas and disruption of prepulse inhibition of the acoustic startle reflex, with both the neuroanatomical and behavioral effects emerging only in adult but not pre-pubertal subjects exposed to prenatal maternal inflammation. In the present study, we tested the hypothesis that Nurr1 may be a critical molecular mediator of prepulse inhibition deficits induced by prenatal immune activation. To this end, we compared the effects of prenatal immune challenge on adult PPI in wild-type (wt) mice and mice with a heterozygous constitutive deletion of Nurr1 (Nurr1+/-) using a well established mouse model of maternal immune activation by exposure to the viral mimetic poly(I:C) (=polyriboinosinic-polyribocytidilic acid). We found that prenatal poly(I:C) treatment on gestation day 9 was similarly effective in disrupting prepulse inhibition in adult wt and Nurr1+/- mice. Prenatal poly(I:C) treatment also generally increased midbrain Nurr1-positive cells and counteracted the genetically driven Nurr1 deficit in the substantia nigra. Our data thus suggest that at least under the present experimental conditions, Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.
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PMID:Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation. 2172 40

Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the development and maintenance of dopaminergic neurons. Reduced expression of Nurr1 has been linked to the etiopathogenesis of Parkinson's disease and other dopamine-related disorders such as schizophrenia. Recent experimental work in mice with a heterozygous constitutive deletion of Nurr1 has revealed that this genetic manipulation leads to the presence of sensorimotor gating dysfunctions in the form of reduced prepulse inhibition of the acoustic startle reflex. However, the neuronal substances for this behavioral manifestation remain essentially unknown. Since converging evidence supports a key role of the central dopamine system in the regulation of prepulse inhibition, we hypothesized that the emergence of prepulse inhibition deficits in adult Nurr1-deficient mice may be linked to dopaminergic neuroanatomical changes. To test this hypothesis, we followed a within-subject approach in which sensorimotor gating performance was correlated with post-mortem expression of several dopaminergic markers in relevant striatal and midbrain regions. We found that prepulse inhibition deficits in Nurr1-deficient mice were paralleled by reduced numbers of substantia nigra dopamine cells expressing tyrosine hydroxylase, and by decreased tyrosine hydroxylase and dopamine transporter immunoreactivity in ventral parts of the striatum. Most interestingly, we also revealed a striking negative correlation between prepulse inhibition levels and tyrosine hydroxylase immunoreactivity in Nurr1-deficient mice in dorsal striatal regions (caudate putamen) and ventral striatal regions (nucleus accumbens core and shell). Our findings thus suggest that the emergence of prepulse inhibition deficits induced by heterozygous constitutive deletion of Nurr1 is, at least in part, related to alterations in presynaptic components of the striatal dopamine system. The constellation of neuroanatomical and behavioral alterations in Nurr1-deficient mice observed here confirms previous impressions that the consequences of Nurr1 down-regulation capture neuronal and behavioral pathologies relevant especially for (but not limited to) Parkinson's disease.
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PMID:Relationship between sensorimotor gating deficits and dopaminergic neuroanatomy in Nurr1-deficient mice. 2182 Apr 32


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