Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine

Kelz, Max B.; Chen, Jingshan; Carlezon, William A.; Whisler, Kim; Gilden, Lauren; Beckmann, Alison M.; Steffen, Cathy; Zhang, Yajun; Marotti, Louis A.; Self, David W.; Tkatch, Tatiana; Baranauskas, Gytis; Surmeier, D. James; Neve, Rachael L.; Duman, Ronald S.; Picciotto, Marina; Nestler, Eric J.

doi:10.1038/45790

Cited by 584 publications

(603 citation statements)

References 27 publications

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“…The increased level of Narp protein expression detected 48 hours after either 5 or 6 seizure episodes occurs in the absence of elevations in Narp mRNA at those times. These findings suggest that as found for ⌬ Fos-B (Chen et al 1997;Kelz et al 1999), the relatively long half-life of Narp protein may lead to its accumulation after repeated stimulation. Since Narp mRNA is induced in striatum by manipulations of the dopamine system (Berke et al 1998), it will be interesting to assess whether repeated administration of drugs affecting dopaminergic tone also lead to long-lasting elevations in Narp protein levels.…”

Section: Discussionsupporting

confidence: 65%

Sustained Increase in Narp Protein Expression Following Repeated Electroconvulsive Seizure

Reti¹,

Baraban²

2000

Neuropsychopharmacology

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The delayed response to many psychiatric treatment regimens has focused attention on identifying enduring changes in gene expression following repeated stimulation that may contribute to these responses. Recent studies have identified Narp protein as a neuronal immediate early gene product that remains elevated in the hippocampus nearly 24 hours after a single episode of electroconvulsive seizure (ECS). To examine how Narp expression responds to repeated stimulation, we have examined the effect of repeated ECS on Narp expression in the hippocampusA central focus of current research in psychopharmacology is to understand the molecular alterations that underlie the long-term effects of psychiatric treatments. Accordingly, there has been intense interest in identifying slowly developing or prolonged changes in gene expression that are induced by repeated administration of psychotropic drugs or ECT (Hyman and Nestler 1996). Although a single ECS episode triggers a rapid induction of multiple immediate early genes (IEG), in most cases examined to date, the expression of these IEGs follows a rapid and transient time course making it unclear whether they contribute to long-term changes elicited by these treatments. Two notable exceptions to this pattern are ⌬ Fos B (Chen et al. 1997;Hiroi et al. 1998) and BDNF (Duman andNibuya et al. 1995;Zetterstrom et al. 1998), which display enduring changes in expression following chronic treatment regimens.In recent studies, Narp has been identified as an IEG product that also displays an atypical, sluggish time course of expression, as it takes 4-8 hours to reach peak levels and remains elevated for nearly 24 hours after a single ECS (O'Brien et al. 1999;Tsui et al. 1996). Functional analysis of Narp has provided compelling evidence that it regulates clustering of AMPA receptors at synaptic sites and may therefore contribute to alterations in excitatory synaptic transmission induced by neuronal stimulation. Both the distinctive time course displayed by Narp and its link to synaptic plasticity make it an attractive candidate gene that might mediate long-term effects of psychiatric treatments. Accordingly, as an initial step in examining how its expression is affected by repeated stimulation, we have monitored the expression of Narp protein following repeated ECS. MATERIALS AND METHODSMaximal ECS was administered to male Sprague-Dawley rats (175-200 g) (Harlan, Indianapolis, IN) as described in Cole et al. (1990). Sham treated rats were handled identically to those receiving ECS except for administration of the electrical current. For repeated ECS, stimulation was administered at 48 hour intervals.To monitor Narp protein levels at various times after single or repeated ECS, animals were killed by decapitation with a small animal guillotine. Hippocampal tissues were dissected and then placed in Laemmli sample buffer (BioRad, Hercules, CA) with additional SDS (3% final concentration). Samples were homogenized, then heated for 1 minute at 65 Њ C. Except where explicitly stated, highe...

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Section: Discussionsupporting

confidence: 65%

Sustained Increase in Narp Protein Expression Following Repeated Electroconvulsive Seizure

Reti¹,

Baraban²

2000

Neuropsychopharmacology

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“…Activation of the D1 receptor by cocaine leads to activation of the transcription factors c-Fos, DFosB, and CREB (Graybiel et al, 1990;Moratalla et al, 1996;Carlezon et al, 1998;Kelz et al, 1999;Nestler et al, 1999;Nestler, 2000;Zhang et al, 2002;Colby et al, 2003). These observations suggest that AP-1 transcription complexes and CREB may participate in the regulation of target genes upon repeated exposure to cocaine.…”

Section: Many Of the Differentially Expressed Genes Contain Ap-1 Bindmentioning

confidence: 88%

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Zhang

Tang

et al. 2005

Neuropsychopharmacol

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Drug addiction involves compulsive drug-seeking and drug-taking despite known adverse consequences. The enduring nature of drug addiction suggests that repeated exposure to abused drugs leads to stable alterations that likely involve changes in gene expression in the brain. The dopamine D1 receptor has been shown to mediate the long-term behavioral effects of cocaine. To examine how the persistent behavioral effects of cocaine correlate with underlying changes in gene expression, we have used D1 receptor mutant and wild-type mice to identify chronic cocaine-induced gene expression changes mediated via the D1 receptors. We focused on the caudoputamen and nucleus accumbens, two key brain regions that mediate the long-term effects of cocaine. Our analyses demonstrate that repeated cocaine administration induces changes in the expression of 109 genes, including those encoding the stromal cell-derived factor 1, insulin-like growth factor binding protein 6, sigma 1 receptor, regulators of G-protein signaling protein 4, Wnt1 responsive Cdc42 homolog, Ca 2 þ /calmodulin-dependent protein kinase II a subunit, and cyclin D2, via the D1 receptors. Moreover, the seven genes contain AP-1 binding sites in their promoter regions. These results suggest that genes encoding certain extracellular factors, membrane receptors and modulators, and intracellular signaling molecules, among others, are regulated by cocaine via the D1 receptor, and these AP-1 transcription complex-regulated genes might contribute to persistent cocaine-induced behavioral changes.

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“…Recently, cyclin-dependent kinase-5 (Cdk5) was identified as a downstream target of the transcription factor ΔFosB which is persistently expressed in NAc of mice repeatedly treated with cocaine. Overexpression of ΔFosB increases Cdk5 expression and activity (Kelz et al, 1999;Bibb et al, 2001). Cdk5 is a protein serine/threonine kinase that regulates neurite outgrowth (Dhavan and Tsai, 2001) and modulates dopamine signaling (Bibb et al, 1999a).…”

mentioning

confidence: 99%

Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5

et al. 2003

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Repeated exposure to cocaine produces an enduring increase in dendritic spine density in adult rat nucleus accumbens. It has been shown previously that chronic cocaine administration increases the expression of cyclin-dependent kinase-5 in this brain region and that this neuronal protein kinase regulates cocaine-induced locomotor activity. Moreover, cyclin-dependent kinase-5 has been implicated in neuronal function and synaptic plasticity. Therefore, we studied the involvement of this enzyme in cocaine's effect on dendritic spine density. Adult male rats, receiving intra-accumbens infusion of the cyclin-dependent kinase-5 inhibitor roscovitine or saline, were administered a 28-day cocaine treatment regimen. Animals were killed 24-48 h after the final cocaine injection and their brains removed and processed for Golgi-Cox impregnation. Our findings demonstrate that roscovitine attenuates cocaine-induced dendritic spine outgrowth in nucleus accumbens core and shell and such inhibition reduces spine density in nucleus accumbens shell of control animals. These data indicate that cyclin-dependent kinase-5 is involved in regulation of, as well as cocaine-induced changes in, dendritic spine density. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2015 January 16. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptLong-term exposure to psychostimulant drugs produces enduring neuronal alterations in intracellular signaling pathways and structural changes in dendritic morphology (Nestler, 2001). For example, repeated exposure to cocaine increases spine density on dendrites of dopaminoceptive medium spiny neurons in the shell (but not core) division of nucleus accumbens (NAc) (Robinson and Kolb, 1999;Robinson et al., 2001) and increases the expression of several transcription factors that mediate gene expression in these neurons (Nestler, 2001). Recently, cyclin-dependent kinase-5 (Cdk5) was identified as a downstream target of the transcription factor ΔFosB which is persistently expressed in NAc of mice repeatedly treated with cocaine. Overexpression of ΔFosB increases Cdk5 expression and activity (Kelz et al., 1999;Bibb et al., 2001). Cdk5 is a protein serine/threonine kinase that regulates neurite outgrowth (Dhavan and Tsai, 2001) and modulates dopamine signaling (Bibb et al., 1999a). Interestingly, acute inhibition of Cdk5 activity in NAc potentiates the locomotor effects of chronic cocaine (Bibb et al., 2001). The purpose of the present study was to determine if this neuronal protein kinase is involved in cocaine-induced dendritic spine proliferation in rat NAc.The potent Cdk5 inhibitor roscovitine (or vehicle) was bilaterally infused into NAc shell via ALZET mini-pump. The effect of a 4-week regimen of repeated i.p. injections of cocaine (or saline) on dendritic spine density was assessed by a modified Golgi staining technique. Detailed anatomical features along dendrites were easily discernible and dendritic spines were readily resolved (Fig. 1). Re...

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Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine

Cited by 584 publications

References 27 publications

Sustained Increase in Narp Protein Expression Following Repeated Electroconvulsive Seizure

Sustained Increase in Narp Protein Expression Following Repeated Electroconvulsive Seizure

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5

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