CREB Gene Transcription Factors: Role in Molecular Mechanisms of Alcohol and Drug Addiction

Pandey, Subhash C.; Chartoff, Elena H.; Carlezon, William A.; Zou, Jian; Zhang, Huaibo; Kreibich, Arati Sadalge; Blendy, Julie A.; Crews, Fulton T.

doi:10.1097/01.alc.0000153550.31168.1d

Cited by 55 publications

(41 citation statements)

References 79 publications

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“…NAc CREB has also been implicated in modulating motivational valance associated with drugs of abuse Chartoff et al, 2003;Pandey et al, 2005). A number of pathways are known to be responsible for CREB activation Chao and Nestler, 2004;Nestler, 2001).…”

Section: Introductionmentioning

confidence: 99%

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

Neuropsychopharmacol

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The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.

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Section: Introductionmentioning

confidence: 99%

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

Neuropsychopharmacol

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“…These systems might include increased GABA release from nerve endings in appropriate circuits (Siggins et al, 2005) and G-protein coupled receptors pathways, in particular adenosine, β-adrenergic and GABA B receptors that have all been proposed to lead to changes in alcohol sensitivity (Proctor & Dunwiddie, 1984;Allan et al, 1991;Lee et al, 1995;Dar & Meng, 2004). The downstream effectors of these G-protein-coupled receptors could be related in function to effects on a common reward circuit that is activated by all drugs of abuse which seems to involve the cyclic AMP-mediated signaling pathway, in particular cAMP-activated protein kinase (Diamond & Gordon, 1997;Yao et al, 2003;Newton & Messing, 2006) and potential downstream effectors like CREB (Pandey et al, 2005) and DARPP-32 (Svenningsson et al, 2005).…”

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confidence: 99%

Low dose acute alcohol effects on GABAA receptor subtypes

Wallner

Hanchar

Olsen

2006

Pharmacology & Therapeutics

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GABA A receptors (GABA A Rs) are the main inhibitory neurotransmitter receptors and have long been implicated in mediating at least part of the acute actions of ethanol. For example, ethanol and GABAergic drugs including barbiturates and benzodiazepines share many pharmacological properties. Besides the prototypical synaptic GABA A R subtypes, nonsynaptic GABA A Rs have recently emerged as important regulators of neuronal excitability. While high doses (≥100 mM) of ethanol have been reported to enhance activity of most GABA A R subtypes, most abundant synaptic GABA A Rs are essentially insensitive to ethanol concentrations that occur during social ethanol consumption (<30 mM). However, extrasynaptic δ and β3 subunit-containing GABA A Rs, associated in the brain with α4or α6 subunits, are sensitive to low millimolar ethanol concentrations, as produced by drinking half a glass of wine. Additionally, we found that a mutation in the cerebellar α6 subunit (α6R100Q), initially reported in rats selectively bred for increased alcohol sensitivity, is sufficient to produce increased alcohol-induced motor impairment and further increases of alcohol sensitivity in recombinant α6β3δ receptors. Furthermore, the behavioral alcohol antagonist Ro15-4513 blocks the low dose alcohol enhancement on α4/6/β3δ receptors, without reducing GABA-induced currents. In binding assays α4β3δ GABA A Rs bind [ 3 H] Ro15-4513 with high affinity, and this binding is inhibited, in an apparently competitive fashion, by low ethanol concentrations, as well as analogs of Ro15-4513 that are active to antagonize ethanol or Ro15-4513's block of ethanol. We conclude that most low to moderate dose alcohol effects are mediated by alcohol actions on alcohol/Ro15-4513 binding sites on GABA A R subtypes.

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“…For model Zih_1, category 'zinc ion homeostasis' was again overrepresented and evaluated with the highest z-score (e.g. 43.00 and 70.26, respectively) consisting of Mt1 and Mt2 genes ( Table 3). This analysis also identified a new target gene, Synaptojanin 1 (Synj1), for module Zih_1 in the 'intracellular-signaling cascade' category and the gene tryptophan hydroxylase 1 (Tph1) in 'metal ion binding' category.…”

Section: Zinc Ion Homeostasismentioning

confidence: 99%

“…On the other hand, CREB is known to control gene expression for a variety of functions in the central nervous system. 43 Exposure to ethanol causes changes in basal and receptor-stimulated cAMP production, CREB phosphorylation and CRE-mediated gene expression in brain cell lines. [44][45][46] Previous studies have suggested that CREB might be associated with both anxiety and alcohol preference.…”

Section: Zinc Ion Homeostasismentioning

confidence: 99%

“…47,48 Haplodeficiency of the CREB gene and ethanol-induced decreases in CREB function have been shown to be associated with increased alcohol drinking in mice. 43 Thus, it is very likely that changes in CREB expression via ethanol may affect the functioning of the CRM modules Zih_1 and the after effect will likely be seen not only in metal ion homeostasis but also in ethanol response pathways.…”

Section: Zinc Ion Homeostasismentioning

confidence: 99%

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Ethanol-responsive genes: identification of transcription factors and their role in metabolomics

Uddin

Singh

2006

Pharmacogenomics J

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Transcription factors (TFs) and their combinatorial control on cis-regulatory elements play critical role in the co-expression of genes. This affects the interaction of genes in the transcriptome and thus may affect signals that cascade through cellular pathways. Using a combination of bioinformatic approaches, we sought to identify such common combinations of TFs in a set of ethanol-responsive (ER) genes and assess the role of ethanol in affecting multiple pathways through their co-regulation. Our results show that the metallothionein genes are regulated by TF motifs cAMP responsive element binding protein (CREB) and metal-activated transcription factor 1 and primarily involved in zinc ion homeostasis. We have also identified new target genes, Synaptojanin 1 and tryptophan hydroxylase 1, potentially regulated by this module. Altered arrangement of TF-binding sites in the module may direct the action of these and other target genes in intracellular signaling cascades, cell growth and/or maintenance. In addition to CREB, other key TFs identified are ecotropic viral integration site-1 and SP1. These modulate the contribution of the target ER genes in cell cycle regulation and apoptosis or programmed cell death. Multiple lines of evidence confirm the above findings and indicate that different groups of ER genes are involved in different biological processes and their co-regulation most likely results from different sets of regulatory modules. These findings associate the role of the ER genes studied and their potential TF modules with alcohol response pathways and phenotypes.

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CREB Gene Transcription Factors: Role in Molecular Mechanisms of Alcohol and Drug Addiction

Cited by 55 publications

References 79 publications

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Low dose acute alcohol effects on GABAA receptor subtypes

Ethanol-responsive genes: identification of transcription factors and their role in metabolomics

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