Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system

Zetterström, Rolf; Williams, Richard C.; Perlmann, Thomas; Olson, Lar̀s

doi:10.1016/0169-328x(96)00074-5

Cited by 291 publications

(218 citation statements)

References 21 publications

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“…Nr4a1, known previously as NGFI-B/Nur77, is a nuclear orphan receptor expressed in many dopaminergic terminal regions (Zetterstrom et al, 1996). Previously, both we and others have described induction of mPFC and/or NAc mRNA levels of Nr4a1 with noncontingent and selfadministered cocaine (Werme et al, 2000;Freeman et al, 2002a b).…”

Section: Discussionmentioning

confidence: 89%

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Freeman

Patel

Brucklacher

et al. 2007

Neuropsychopharmacol

108

126

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Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine selfadministration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens cfos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGR1. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence.Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.

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Section: Discussionmentioning

confidence: 89%

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Freeman

Patel

Brucklacher

et al. 2007

Neuropsychopharmacol

108

126

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“…We found that methylphenidate increased NGFI-B mRNA in the accumbens and striatum only in the WKY strain. Recent anatomical evidence suggests a close relationship between NGFI-B and the dopaminergic system (Xiao et al 1996;Zetterstrom et al 1996;Gervais et al 1999). Moreover, NGFI-B gene expression has been shown to be modulated by drugs interacting with dopamine.…”

Section: Discussionmentioning

confidence: 99%

Comparisons of Behavioral and Neurochemical Characteristics between WKY, WKHA, and Wistar Rat Strains

Drolet

Proulx

Pearson

et al. 2002

Neuropsychopharmacology

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WKHA rats constitute a recombinant inbred rat strain derived by phenotypic selection of the progeny of hybrid F2 crosses between SHR and WKY rats. WKHA are normotensive and show some features of hyperactivity and of hyper-reactivity to stress, but their utility as model of attention deficit/hyperactivity disorder (ADHD) has not yetWistar-Kyoto-derived Hyperactive (WKHA) rats constitute an inbred strain that has been derived from the progeny of hybrid Wistar-Kyoto (WKY)/ Spontaneously Hypertensive Rats (SHR) F2 crosses. The WKHA rats were developed initially in 1980 by Hendley and associates in the attempt to remove a prominent behavioral abnormality (hyperactivity) from the hypertensive trait of SHR that had been fixed in this strain during intensive inbreeding (Hendley and Ohlsson 1991;Hendley 2000). Using cross-breeding of SHR with WKY followed by recombinant selected inbreeding, Hendley and Ohlsson (1991) (Deschepper et al. 1997). WKHA display marked locomotor hyperactivity and hyperreactivity to stress when compared with WKY. The activity score obtained with WKHA in an exploration test in a novel environment is much higher than the score observed in the WKY strain (Sagvolden et al. 1992). Moreover, the WKHA also seems to display "attentional problems" when compared with WKY (Sagvolden et al. 1992). Although these characteristics are reminiscent of those observed in children diagnosed with attention deficit disorder (ADHD), the utility of this strain as a potential model of ADHD has not received extensive experimental attention.Accordingly, the present study was conducted to assess the face validity of the WKHA strain as a model of ADHD. To do so, we compared the performance of WKHA to both WKY (genetic control) and Wistar (outbred control) strains in two behavioral tests. First, we measured activity levels of the three strains in an exploration test in a novel environment. Second, we examined the behavior of the three strains in the prepulse inhibition (PPI) test of the acoustic startle reflex. This test assesses sensorimotor gating, or the extent to which a weak acoustic stimulus draws cognitive processing away from a more pronounced acoustic stimulus (Ralph et al. 1999;Wood et al. 1998). Although there is considerable debate as to whether PPI reflects the operation of an attentional (as opposed to a preattentional) mechanism, it is clear that PPI is involved in stimulus selection or stimulus filtering, a process that appears to be aberrant in ADHD (Ralph et al. 1999). Moreover, some evidence also exists for a deficit in sensorimotor gating in a sub-population of ADHD children (Castellanos et al. 1996). A third reason justifying our use of the PPI test is that, like locomotor activity, sensorimotor gating is modulated by central dopaminergic substrates (Swerdlow et al. 1994), and there is extensive clinical evidence implicating alterations in dopaminergic function in the pathophysiology of ADHD (Pliszka et al. 1996).We also examined the extent to which the performances of the three strains in both the locom...

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“…Nerve Growth Factor inducible-B (NGFI-B, also known as Nur77) is another transcription factor, which is closely associated with DA systems in the brain. This orphan ligand-activated nuclear receptor belongs to the steroid/thyroid hormone receptor family and is constitutively expressed in target structures of DA systems (Zetterström et al, 1996). NGFI-B mRNA expression can be modulated by DA and serotoninergic drugs (Gervais et al, 1999).…”

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confidence: 99%

Effects of Cocaine on c-Fos and NGFI-B mRNA Expression in Transgenic Mice Underexpressing Glucocorticoid Receptors

St-Hilaire

Tremblay

Lévesque

et al. 2002

Neuropsychopharmacol

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Numerous evidences suggest that stress and stress-related hormones can modulate the activity of the brain reward pathway and thus may account for individual vulnerability towards the reinforcing effects of drugs of abuse. Transgenic (TG) mice expressing an antisense mRNA against the glucocorticoid receptor (GR), which partially blocks GR expression, were used to assess the role of GR dysfunction on cocaine (COC)-induced c-fos and Nerve-Growth Factor Inducible-B (NGFI-B, or Nur77) gene expression. These two genes belong to different families of transcription factors and have been shown to be modulated by various dopaminergic drugs. TG and wild-type (WT) mice were both acutely and repeatedly treated with COC (20 mg/kg, i.p.). In the chronic experiment, mice received a 5-day treatment of COC and were challenged 5 days later with COC or vehicle. Locomotor activity was assessed during the entire chronic experiment in the mouse home cages. Animals were sacrificed 1 h after the last injection and NGFI-B and c-fos mRNA levels in the prefrontal cortex, the nucleus accumbens and the striatum were measured by in situ hybridization. Acute COC administration led to significantly smaller c-fos increases in TG mice compared to WT, whereas repeated COC treatment potentiated c-fos induction both in TG and WT mice to equivalent levels. TG mice displayed higher basal NGFI-B expression in the nucleus accumbens and the level of NGFI-B mRNA was differently modulated by COC in TG mice compared to WT mice. In accordance with data on c-fos expression, behavioral data indicate a blunted locomotor effect on the first COC injection in TG mice, a phenomenon corrected by the repeated COC treatment. These results suggest that an alteration of the hypothalamus-pituitary-adrenal axis can modify COC-induced regulation of the transcription factors c-fos and NGFI-B, and that these changes parallel those seen at the behavioral level. It also demonstrates that the differences at the behavioral and molecular levels noted between TG and WT mice after acute COC injection disappear following repeated COC administration, suggesting that repeated COC has a greater impact in TG mice underexpressing GRs.

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Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system

Cited by 291 publications

References 21 publications

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Comparisons of Behavioral and Neurochemical Characteristics between WKY, WKHA, and Wistar Rat Strains

Effects of Cocaine on c-Fos and NGFI-B mRNA Expression in Transgenic Mice Underexpressing Glucocorticoid Receptors

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