The Role of NFkB in Drug Addiction: Beyond Inflammation

Nennig, Sadie E.; Schank, Jesse R.

doi:10.1093/alcalc/agw098

Cited by 174 publications

(110 citation statements)

References 101 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…Here, we assessed NFkB activation 48 hours after the last IEA session or final gavage treatment. It is also important to highlight that the gene targets and effects of NFkB are extremely diverse (Nennig and Schank, ). As such, NFkB could influence the expression of different genes in different brain regions or cell types, which may have variable effects on the behavioral responses to alcohol.…”

Section: Discussionmentioning

confidence: 99%

“…To examine a cellular mechanism that could underlie the relationship between alcohol exposure and stress sensitivity, we assessed the effects of alcohol exposure on activation of the transcription factor nuclear factor light chain enhancer of activated B cells (NFkB). Under baseline conditions, NFkB subunit dimers are bound in the cytosol by inhibitor of NFkB (IkB) (Nennig and Schank, ). A protein kinase known as IkB kinase (IKK) phosphorylates IkB, tagging it for proteasomal degradation and releasing the NFkB subunit dimers to translocate to the nucleus where they act as a transcription factor for a variety of genes involved in inflammation and various other processes (Nennig and Schank, ).…”

mentioning

confidence: 99%

“…Under baseline conditions, NFkB subunit dimers are bound in the cytosol by inhibitor of NFkB (IkB) (Nennig and Schank, ). A protein kinase known as IkB kinase (IKK) phosphorylates IkB, tagging it for proteasomal degradation and releasing the NFkB subunit dimers to translocate to the nucleus where they act as a transcription factor for a variety of genes involved in inflammation and various other processes (Nennig and Schank, ). Several studies have examined the influence of the NFkB pathway on alcohol‐related behaviors including continuous 2BC (Truitt et al, ), drinking in the dark (Truitt et al, ), and conditioned place preference (Nennig et al, ), as well as the immune‐related effects following long‐term EtOH self‐administration (Helms et al, ).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Intermittent Ethanol Access Increases Sensitivity to Social Defeat Stress

Nennig

Fulenwider

Eskew

et al. 2020

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background Comorbidity between alcoholism and depression is extremely common. Recent evidence supports a relationship between alcohol exposure and stress sensitivity, an underlying factor in the development of depression. Our laboratory has recently shown that chronic alcohol gavage increases sensitivity to social defeat stress (SDS). However, the effects of voluntary alcohol consumption, resulting from protocols such as intermittent ethanol access (IEA), on defeat stress sensitivity have yet to be elucidated. Methods We first assessed the effects of 4 weeks of IEA to 20% alcohol on sensitivity to subthreshold SDS exposure. Next, to examine neuroinflammatory mechanisms, we analyzed gene expression of inhibitor of NFkB (IkB) following IEA or chronic alcohol exposure (10 days of 3.0 g/kg alcohol via intragastric gavage). Then, we quantified NFkB activation via β‐galactosidase immunohistochemistry following IEA or chronic alcohol gavage in NFkB‐LacZ mice. Results IEA‐exposed mice displayed an increase in sensitivity to subthreshold SDS compared to water‐drinking controls. We also found that IkB gene expression was decreased in the nucleus accumbens (NAC) and amygdala (AMY) following IEA but was not altered following chronic alcohol gavage. Finally, we observed increased NFkB activity in the central amygdala (CEA), basolateral amygdala (BLA), and medial amygdala (MEA) after IEA, and increased NFkB activity solely in the CEA following chronic alcohol gavage. Conclusions These findings further corroborate that prior alcohol exposure, in this case intermittent voluntary consumption, can impact development of depressive‐like behavior by altering stress sensitivity. Furthermore, our results suggest the CEA as a potential mediator of alcohol's effects on stress sensitivity, as NFkB was activated in this region following both IEA and chronic alcohol gavage. Thus, this study provides novel insight on alterations in the NFkB pathway and identifies specific regions to target in future experiments assessing the functional role of NFkB in these processes.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Intermittent Ethanol Access Increases Sensitivity to Social Defeat Stress

Nennig

Fulenwider

Eskew

et al. 2020

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

show abstract

“…In particular, the ethanol-induced upregulation of iNOS, COX 2 , and IL-1β occurs via the stimulation of RhoE, as well as IRAK and MAP kinases, such as ERK1/2, p-38, and JNK, which trigger the downstream activation of oxidant-sensitive transcription factors NF-κB and AP-1 (Valles et al, 2004; Guasch et al, 2007). Alterations in the expression of pro-inflammatory immune genes occur in postmortem brain from alcoholics and animals exposed to alcohol, whereas molecules known to reduce inflammation have shown to ameliorate alcohol-mediated behaviors in animal models (Mayfield et al, 2013; Cui et al, 2014; Truitt et al, 2016; Nennig and Schank, 2017). Increased free radical production and low antioxidant levels are major features of alcohol-induced brain damage (Crews et al, 2000).…”

Section: Astrocytes and Microglia: Primary Targets Of Alcohol Abusementioning

confidence: 99%

New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

Orellana

Cerpa

Carvajal

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Alcohol dependence causes physical, social, and moral harms and currently represents an important public health concern. According to the World Health Organization (WHO), alcoholism is the third leading cause of death worldwide, after tobacco consumption and hypertension. Recent epidemiologic studies have shown a growing trend in alcohol abuse among adolescents, characterized by the consumption of large doses of alcohol over a short time period. Since brain development is an ongoing process during adolescence, short- and long-term brain damage associated with drinking behavior could lead to serious consequences for health and wellbeing. Accumulating evidence indicates that alcohol impairs the function of different components of the melanocortin system, a major player involved in the consolidation of addictive behaviors during adolescence and adulthood. Here, we hypothesize the possible implications of melanocortins and glial cells in the onset and progression of alcohol addiction. In particular, we propose that alcohol-induced decrease in α-MSH levels may trigger a cascade of glial inflammatory pathways that culminate in altered gliotransmission in the ventral tegmental area and nucleus accumbens (NAc). The latter might potentiate dopaminergic drive in the NAc, contributing to increase the vulnerability to alcohol dependence and addiction in the adolescence and adulthood.

show abstract

“…Currently, we lack sufficient knowledge of the following relationships that challenge the development of successful treatment strategies: (i) mechanisms underlying the interactions among the affected neural circuits, molecular mechanisms, synaptic plasticity, and their relation to the functioning of the rest of the CNS and behavioral changes; (ii) causal relationships between neurobiological changes in the brain and their effects on the peripheral systems and vice versa (e.g., the interaction between the hormone ghrelin release in the gastrointestinal system and its effect on the CNS in alcohol craving and between the peripheral and central inflammatory systems in depression and addiction) (12)(13)(14)(15); and (iii) the extent to which social connections and environmental factors alter neurobiological mechanisms in brain circuitries in patients with SUDs. These challenges are fundamental knowledge gaps that require continued funding for relevant interdisciplinary research that can foster innovative approaches and discoveries by the engaged scientific communities.…”

mentioning

confidence: 99%