Enhancement of Behavioral Sensitization, Anxiety-Like Behavior, and Hippocampal and Frontal Cortical CREB Levels Following Cocaine Abstinence in Mice Exposed to Cocaine during Adolescence
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Adolescence has been linked to greater risk-taking and novelty-seeking behavior and a higher prevalence of drug abuse and risk of relapse. Decreases in cyclic adenosine monophosphate response element binding protein (CREB) and phosphorylated CREB (pCREB) have been reported after repeated cocaine administration in animal models. We compared the behavioral effects of cocaine and abstinence in adolescent and adult mice and investigated possible age-related differences in CREB and pCREB levels. Adolescent and adult male Swiss mice received one daily injection of saline or cocaine (10 mg/kg, i.p.) for 8 days. On day 9, the mice received a saline injection to evaluate possible environmental conditioning. After 9 days of withdrawal, the mice were tested in the elevated plus maze to evaluate anxiety-like behavior. Twelve days after the last saline/cocaine injection, the mice received a challenge injection of either cocaine or saline, and locomotor activity was assessed. One hour after the last injection, the brains were extracted, and CREB and pCREB levels were evaluated using Western blot in the prefrontal cortex (PFC) and hippocampus. The cocaine-pretreated mice during adolescence exhibited a greater magnitude of the expression of behavioral sensitization and greater cocaine withdrawal-induced anxiety-like behavior compared with the control group. Significant increases in CREB levels in the PFC and hippocampus and pCREB in the hippocampus were observed in cocaine-abstinent animals compared with the animals treated with cocaine in adulthood. Interestingly, significant negative correlations were observed between cocaine sensitization and CREB levels in both regions. These results suggest that the behavioral and neurochemical consequences of psychoactive substances in a still-developing nervous system can be more severe than in an already mature nervous system.Keywords:
Elevated plus maze
This chapter contains sections titled: Abstract Introduction The CREB Family of Transcription Factors CREB Family Members and Close Friends Structural Features of the CREB Family of Transcription Factors Gene Structure and the Regulation of Expression of CREB Family Members The CREB Binding Protein Structure and Multifunction The CREB Activation Pathway Post-Translational Regulation of CREB Activity Regulation of CBP Function Other Modulators of the CREB Pathway CRE-Binding Activity and CREB Downstream Genes Functions of the CREB Activation Pathway in the Nervous System Regulation of Cellular Responses by the CREB Pathway CREB is Important for Neuronal Survival and Neuroprotection CREB is Required for Axonal Outgrowth and Regeneration CREB has a Role in Neurogenesis and Neuronal Differentiation CBP, Epigenetics and Long-Term Changes in Neuronal Function Regulation of Systemic Responses by the CREB Pathway CREB and Memory CREB and Circadian Rhythms CREB Function and Development Dysregulation of CREB Function and Disease in the Nervous System CREB and Addiction Mental Retardation CREB and Age-Related Memory Impairment CREB and Neurodegenerative Diseases Huntington Disease Alzheimer's Disease CREB and Mental Disorders: Depression and other Disorders of Mood Conclusions Abbreviations
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CREB (cAMP-responsive element binding protein), which can be activated after phosphorylation by protein kinase A, plays an important role in cAMP-induced gene expression. Several recent studies have suggested that a co-activator designated as CREB binding protein (CBP) is crucial in mediating the transcriptional activity of CREB. In nervous system, in addition to playing a role in neurotransmitter-induced gene transcription, CREB may take part in mediating neurotrophin signals that ultimately lead to such cellular responses as proliferation, differentiation and survival.
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The cAMP response element binding protein(CREB) is a nuclear regulatory factor in eukaryotic cells.CREB is one of eight subtypes of the CREB / ATF family.CREB contains two regions in the structure,a N-terminal region which regulates transcription and a C-terminal region which binds to promoters of target genes.CREB can be regulated through many signaling pathways,such as cAMP,MAPK,and Ca2 +-CaMK pathways.CREB phosphorylation is required for the transcription modulation in various neuronal processes,including neurogenesis,synaptic plasticity,learning and memory.CREB and its regulatory factors can be attractive drug candidates for nervous system diseases.As the role of CREB in memory and learning drew much attention in recent years.This review summarizes recent discoveries in structural analysis,related signaling pathways,and target gene expression of CREB,especially in Alzheimer's disease.
Neuronal memory allocation
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The cAMP response element-binding protein (CREB) gene transcription factor has been shown to play a role in the synaptic plasticity associated with drug addictive behaviors; however, the causal role of the CREB gene in alcohol-drinking behaviors is unknown. The present investigation evaluated alcohol-drinking behaviors in mice that are haplodeficient in CREB as a result of targeted CREB (α and Δ) gene disruption. It was found that CREB-haplodeficient (+/-) mice have higher preference for ethanol but not for sucrose solution than wild-type (+/+) littermates. The functional aspects of the CREB gene transcription factor were also investigated by measuring the protein levels of phosphorylated CREB (p-CREB) and the expression of cAMP-inducible genes such as neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). Deletion of the CREB (α and Δ) gene significantly decreases total CREB, p-CREB levels and the expression of NPY and BDNF in the brain structures of CREB-deficient (+/-) mice. It was also found that CREB-deficient (+/-) mice displayed more anxiety-like behaviors and that acute ethanol exposure produced anxiolytic effects and significantly increased protein levels of p-CREB and NPY in the central and medial but not in the basolateral amygdala of wild-type mice, but these effects are attenuated in CREB-deficient mice compared with wild-type mice. These results provide the first direct evidence that a haplodeficiency of the CREB gene is associated with increased alcohol-drinking behaviors. Furthermore, alcohol drinking and anxiety-like behaviors in CREB-haplodeficient mice may possibly be related to decreased expression of NPY and BDNF in the brains of these mice.
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The cAMP response element binding protein (CREB) mediates transcriptional activation in response to the cAMP signaling pathway. Several recent studies have suggested that phosphorylation-dependent interaction of CREB with a co-activator designated CREB binding protein (CBP) is a crucial step in mediating transcriptional responses to cAMP. In the present study we have determined that replacement of Ser142 of CREB with Asp greatly decreases the ability of the cAMP-dependent protein kinase to activate CREB. As Ser142 is located within the region of CREB that interacts with CBP, it seemed quite likely that mutations at this site might interfere with binding to CBP. However, both in vitro and in vivo protein-protein interaction assays revealed that replacement of Ser142 with Asp does not interfere with the binding of CREB to CBP. These studies argue strongly that although the binding of CREB to CBP is necessary, it is not sufficient for transcriptional responses to cAMP. The cAMP response element binding protein (CREB) mediates transcriptional activation in response to the cAMP signaling pathway. Several recent studies have suggested that phosphorylation-dependent interaction of CREB with a co-activator designated CREB binding protein (CBP) is a crucial step in mediating transcriptional responses to cAMP. In the present study we have determined that replacement of Ser142 of CREB with Asp greatly decreases the ability of the cAMP-dependent protein kinase to activate CREB. As Ser142 is located within the region of CREB that interacts with CBP, it seemed quite likely that mutations at this site might interfere with binding to CBP. However, both in vitro and in vivo protein-protein interaction assays revealed that replacement of Ser142 with Asp does not interfere with the binding of CREB to CBP. These studies argue strongly that although the binding of CREB to CBP is necessary, it is not sufficient for transcriptional responses to cAMP.
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Ser-133 phosphorylation of the cAMP-responsive element-binding protein (CREB) is sufficient to induce cellular gene expression in response to cAMP, but additional promoter-bound factors are required for target gene activation by CREB in response to mitogen/stress signals. To compare the relative effects of different signals on recruitment of the coactivator CREB-binding protein (CBP) to CREB in living cells, we developed a fluorescence resonance energy transfer (FRET) assay. cAMP promoted the interaction of CREB with CBP in a phosphorylation-dependent manner by FRET analysis, but mitogen/stress signals were far less effective in stimulating complex formation even though they induced comparable levels of Ser-133 phosphorylation. cAMP and non-cAMP stimuli were comparably active in promoting this interaction in the cytosol; the formation of CREB⋅CBP complexes in response to non-cAMP signals was specifically inhibited in the nucleus. Non-cAMP signals had no effect on intrinsic CREB- or CBP-binding activities by Far Western blot assay, thereby supporting the presence of a distinct CREB⋅CBP antagonist. Our studies indicate that the relative effects of cAMP and mitogen/stress signals on CREB⋅CBP complex formation impart selectivity to gene activation through CREB phosphorylated at Ser-133.
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