An essential role for DeltaFosB in the nucleus accumbens in morphine action. Nat Neurosci 9:205-211

Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA.
Nature Neuroscience (Impact Factor: 14.98). 03/2006; 9(2):205-11. DOI: 10.1038/nn1636
Source: PubMed

ABSTRACT The transcription factor DeltaFosB is induced in the nucleus accumbens (NAc) and dorsal striatum by the repeated administration of drugs of abuse. Here, we investigated the role of DeltaFosB in the NAc in behavioral responses to opiates. We achieved overexpression of DeltaFosB by using a bitransgenic mouse line that inducibly expresses the protein in the NAc and dorsal striatum and by using viral-mediated gene transfer to specifically express the protein in the NAc. DeltaFosB overexpression in the NAc increased the sensitivity of the mice to the rewarding effects of morphine and led to exacerbated physical dependence, but also reduced their sensitivity to the analgesic effects of morphine and led to faster development of analgesic tolerance. The opioid peptide dynorphin seemed to be one target through which DeltaFosB produced this behavioral phenotype. Together, these experiments demonstrated that DeltaFosB in the NAc, partly through the repression of dynorphin expression, mediates several major features of opiate addiction.

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Available from: Olivier Berton, Aug 17, 2015
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    • "Regulation of PDYN gene expression is a complex phenomenon that may implicate several transcription factors including avian myelocytomatosis viral oncogene homolog (c-Myc), neuron restrictive silencer factor (NRSF)/RE1-silencing transcription factor (REST) [36] [52] [53], USF1/2, AP-1 family protein, FBJ murine osteosarcoma viral oncogene homolog B (FosB), cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), downstream regulatory element (DRE) antagonist modulator (DREAM), yin-yang1 (YY1) and NF-kB [54] [55] [56] [57]. c-Myc may directly interact with its binding motif in PDYN gene to regulate its function while AP-1 may either interact directly or recruit other proteins to regulate PDYN expression. "
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) both in coding and non-coding regions govern gene functions prompting differential vulnerability to diseases, heterogeneous response to pharmaceutical regimes and environmental anomalies. These genetic variations, SNPs, may alter an individual's susceptibility for alcohol dependence by remodeling DNA-protein interaction patterns in prodynorphin (PDYN) and the κ-opioid receptor (OPRK1) genes. In order to elaborate the underlying molecular mechanism behind these susceptibility differences we used bioinformatics tools to retrieve differential DNA-protein interactions at PDYN and OPRK1 SNPs significantly associated with alcohol dependence. Our results show allele-specific DNA-protein interactions depicting allele-specific mechanisms implicated in differential regulation of gene expression. Several transcription factors, for instance, VDR, RXR-alpha, NFYA, CTF family, USF-1, USF2, ER, AR and predominantly SP family show an allele-specific binding affinity with PDYN gene; likewise, GATA, TBP, AP-1, USF-2, C/EBPbeta, Cart-1 and ER interact with OPRK1 SNPs on intron 2 in an allele-specific manner. In a nutshell, transition of a single nucleotide may modify differential DNA-protein interactions at OPRK1 and PDYN's SNPs, significantly associated with pathology that may lead to altered individual vulnerability for alcohol dependence.
    Computers in Biology and Medicine 10/2014; 53. DOI:10.1016/j.compbiomed.2014.07.021 · 1.46 Impact Factor
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    • "For instance, repeated morphine injections produce a marked decrease in brain μ-opioid receptor (MOP receptor) density (Davis et al., 1979; Tao et al., 1987; Diaz et al., 2000), down-regulation of the high-affinity MOP receptor site in rats and reduction of MOP receptor signalling in sensory neurons and brainstem nuclei (Sim et al., 1996; Johnson et al., 2006). Changes in transcription factor activation following chronic opioid treatment have also been proposed to play a relevant role in opioid tolerance and addiction (Carlezon et al., 2005; Zachariou et al., 2006). "
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    ABSTRACT: Background And PurposeOpioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of relevant side effects, including drug dependence and addiction. Here, we investigated the role of Peroxisome Proliferator Activated Receptor gamma (PPARγ) on the development of analgesic tolerance to morphine in mice.Experimental ApproachWe monitored analgesia on alternate days using the tail immersion test.Key ResultsThe results demonstrated that daily administration of morphine (30 mg/kg, bid) results in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg/kg, bid) significantly attenuated the development and expression of tolerance. However, pre-treatment with GW-9662 (5 mg/kg, bid), a selective PPARγ antagonist completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg/kg, bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared to wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent morphine tolerance development.Conclusions And ImplicationsOverall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest the possibility of combining PPARγ agonists with opioid analgesics to reduce the development of tolerance and possibly to attenuate the potential for opioid abuse.
    British Journal of Pharmacology 07/2014; 171(23). DOI:10.1111/bph.12851 · 4.99 Impact Factor
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    • "DFosB-mediated regulation of target genes in these regions could therefore affect behaviors that contribute to the motivational effects of THC as well as other drugs of abuse. In fact, overexpression of DFosB in D1/ dynorphin-containing striatal medium spiny neurons enhanced the rewarding effects of morphine and cocaine (Colby et al., 2003; Zachariou et al., 2006). Moreover, if DFosB or its target genes regulate CB 1 R desensitization and/or downregulation in these Fig. 5. Representative images showing CB 1 R-ir (green), FosB/DFosB-ir (red) and DAPI (blue) in the caudate-putamen and nucleus accumbens of mice that received repeated THC treatment. "
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    ABSTRACT: Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB1Rs) in the brain, but the magnitude of these adaptations varies among regions. CB1Rs in the striatum and its output regions exhibit the least magnitude and slowest development of desensitization and downregulation. The molecular mechanisms that confer these region-dependent differences are not known. The stable transcription factor, ΔFosB, is induced in the striatum following repeated THC administration and could regulate CB1Rs. To directly compare the regional profile of ΔFosB induction and CB1R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [(35)S]GTPγS autoradiography and immunohistochemistry were performed to measure CB1R desensitization and downregulation, respectively, and ΔFosB expression was measured by immunoblot. Significant CB1R desensitization and downregulation occurred in the prefrontal cortex, lateral amygdala and hippocampus; desensitization was found in the basomedial amygdala and no changes were seen in remaining regions. ΔFosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between ΔFosB expression and CB1R desensitization was found, such that regions with the greatest ΔFosB induction did not exhibit CB1R desensitization and areas without ΔFosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB1R co-localization with ΔFosB in cells and CB1R puncta surrounding ΔFosB-positive cells. THC-induced expression of ΔFosB was absent in the striatum of CB1R knockout mice. These data suggest that transcriptional targets of ΔFosB might inhibit CB1R desensitization and/or that ΔFosB induction could be limited by CB1R desensitization.
    Neuropharmacology 09/2013; 77. DOI:10.1016/j.neuropharm.2013.09.019 · 4.82 Impact Factor
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