Alterations in the levels of heterotrimeric G protein subunits induced by psychostimulants, opiates, barbiturates, and ethanol: Implications for drug dependence, tolerance, and withdrawal

Kitanaka, Nobue; Kitanaka, Junichi; Hall, F. Scott; Tatsuta, Tomohiro; Morita, Yoshio; Takemura, Masashi; Wang, Xiao-Bing; Uhl, George R.

doi:10.1002/syn.20543

Cited by 18 publications

(11 citation statements)

References 87 publications

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“…Polymorphisms of PI3K p85 α (Desrivieres et al, 2008) and NF-κB1 (Edenberg et al, 2008) affect the risk for alcoholism in humans and adaptations of the NF-κB system have been observed in human alcoholics (Okvist et al, 2007). Recruitment of the PDEs pathway by alcohol in a K-ras dependent manner is consistent with alcohol targeting diverse GPCR signaling systems such as dopamine, adenosine, and metabotropic glutamate receptors (Cozzoli et al, 2009; Heilig and Egli, 2006; Kitanaka et al, 2008; Mailliard and Diamond, 2004). The PDEs pathway – which included the cAMP selective PDE, PDE8, among the differentially expressed genes – is critical in signaling by cAMP-PKA, a known target of alcohol (Asyyed et al, 2006; Pandey et al, 2003; Repunte-Canonigo et al, 2007).…”

Section: Discussionsupporting

confidence: 63%

Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

et al. 2010

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Adaptations in the anterior cingulate cortex (ACC) have been implicated in alcohol and drug addiction. To identify genes that may contribute to excessive drinking, here we performed microarray analyses in laser microdissected rat ACC after a single or repeated administration of an intoxicating dose of alcohol (3g/kg). Expression of the small G protein K-ras was reduced following both single and repeated alcohol administration. We also observed that voluntary alcohol intake in K-ras heterozygous null mice (K-ras +/− ) did not increased after withdrawal from repeated cycles of intermittent ethanol vapor exposure, unlike in their wild-type littermates. To identify K-ras regulated pathways, we then profiled gene expression in the ACC of K-ras +/− , heterozygous null mice for the K-ras negative regulator Nf1 (Nf1 +/− ) and wild-type mice following repeated administration of an intoxicating dose of alcohol. Pathway analysis showed that alcohol differentially affected various pathways in a K-ras dependent manner -some of which previously shown to be regulated by alcohol -including the insulin/PI3K pathway, the NF-kB, the phosphodiesterases (PDEs) pathway, the Jak/Stat and the adipokine signaling pathways. Altogether, the data implicate K-ras-regulated pathways in the regulation of excessive alcohol drinking after a history of dependence.

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Section: Discussionsupporting

confidence: 63%

Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

et al. 2010

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“…The molecular targets for ethanol are multiple and the effect of ethanol on the G-protein signaling is heterologous (Gordon et al, 1986; Kitanaka N, 2008; Richelson et al, 1986; Tabakoff et al, 1995). The GABA A receptor complex (Sundstrom-Poromaa I, 2002) and G-protein-coupled inwardly rectifying potassium channels (GIRKs) (Lewohl JM, 1992) are among a few of the GPCRs shown to be targeted by ethanol.…”

Section: Discussionmentioning

confidence: 99%

N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation

Rashid

Kim

2016

Neuropharmacology

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Previous studies demonstrated that prenatal exposure to ethanol interferes with embryonic and fetal development, and causes abnormal neurodevelopment. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid highly enriched in the brain, was shown to be essential for proper brain development and function. Recently, we found that N-docosahexenoyethanolamine (synaptamide), an endogenous metabolite of DHA, is a potent PKA-dependent neurogenic factor for neural stem cell (NSC) differentiation. In this study, we demonstrate that ethanol at pharmacologically relevant concentrations down regulates cAMP signaling in NSC and impairs neurogenic differentiation. In contrast, synaptamide reverses ethanol-impaired NSC neurogenic differentiation through counter-acting on the cAMP production system. NSC exposure to ethanol (25-50 mM) for 4 days dose-dependently decreased the number of Tuj-1 positive neurons and PKA/CREB phosphorylation with a concomitant reduction of cellular cAMP. Ethanol-induced cAMP reduction was accompanied by the inhibition of G-protein activation and expression of adenylyl cyclase (AC) 7 and AC8, as well as PDE4 upregulation. In contrast to ethanol, synaptamide increased cAMP production, GTPγS binding, and expression of AC7 and AC8 isoforms in a cAMP-dependent manner, offsetting the ethanol-induced impairment in neurogenic differentiation. These results indicate that synaptamide can reduce ethanol-induced impairment of neuronal differentiation by counter-affecting shared targets in G-protein coupled receptor (GPCR)/cAMP signaling. The synaptamide-mediated mechanism observed in this study may offer a possible avenue for ameliorating the adverse impact of fetal alcohol exposure on neurodevelopment.

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“…In this focused qRT‐PCR study, gene selection was critical. We initially defined a system of interest based on previous CeA alcohol studies including GABA A (Bajo et al., ; Nie et al., ), NMDA (McCool et al., ; Obara et al., ; Roberto et al., , ), GPCR subunits including Grm5, Crhr1, Oprm1, Cckbr, Gnb4, and genes related to GPCR function like Ace, Ace2, Agtrap, and Ren (Cruz et al., ; Kitanaka et al., ). This list was expanded to include associated regulatory elements including Rgs (Ho et al., ; Liu et al., ) and receptor trafficking proteins (Obara et al., ), downstream signaling components (Bajo et al., ; Sanna et al., ), TFs (Pandey, ; Radwanska et al., ; Vilpoux et al., ), and inducible targets (McBride et al., ) as shown in a schematic in Fig.…”

Section: Methodsmentioning

confidence: 99%

Coordinated Dynamic Gene Expression Changes in the Central Nucleus of the Amygdala During Alcohol Withdrawal

Freeman

Staehle

Vadigepalli

et al. 2012

Alcoholism Clin & Exp Res

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Background Chronic alcohol use causes widespread changes in the cellular biology of the amygdala's central nucleus (CeA), a GABAergic center that integrates autonomic physiology with the emotional aspects of motivation and learning. While alcohol-induced neurochemical changes play a role in dependence and drinking behavior, little is known about the CeA's dynamic changes during withdrawal, a period of emotional and physiologic disturbance. Methods We used a qRT-PCR platform to measure 139 transcripts in 92 rat CeA samples from control (N = 33), chronically alcohol exposed (N = 26), and withdrawn rats (t = 4, 8, 18, 32, and 48 hours; N = 5, 10, 7, 6, 5). This focused transcript set allowed us to identify significant dynamic expression patterns during the first 48 hours of withdrawal and propose potential regulatory mechanisms. Results Chronic alcohol exposure causes a limited number of small magnitude expression changes. In contrast, withdrawal results in a greater number of large changes within 4 hours of removal of the alcohol diet. Sixty-five of the 139 measured transcripts (47%) showed differential regulation during withdrawal. Over the 48-hour period, dynamic changes in the expression of γ-aminobutyric acid type A (GABAA), ionotropic glutamate and neuropeptide system–related G-protein-coupled receptor subunits, and the Ras/Raf signaling pathway were seen as well as downstream transcription factors (TFs) and epigenetic regulators. Four temporally correlated gene clusters were identified with shared functional roles including NMDA receptors, MAPKKK and chemokine signaling cascades, and mediators of long-term potentiation, among others. Cluster promoter regions shared overrepresented binding sites for multiple TFs including Cebp, Usf-1, Smad3, Ap-2, and c-Ets, suggesting a potential regulatory role. Conclusions During alcohol withdrawal, the CeA experiences rapid changes in mRNA expression of these functionally related transcripts that were not predicted by measurement during chronic exposure. This study provides new insight into dynamic expression changes during alcohol withdrawal and suggests novel regulatory relationships that potentially impact the aspects of emotional modulation.

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Alterations in the levels of heterotrimeric G protein subunits induced by psychostimulants, opiates, barbiturates, and ethanol: Implications for drug dependence, tolerance, and withdrawal

Cited by 18 publications

References 87 publications

Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation

Coordinated Dynamic Gene Expression Changes in the Central Nucleus of the Amygdala During Alcohol Withdrawal

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