The influence of central interleukin-6 on behavioral changes associated with acute alcohol intoxication in adult male rats

Barney, Thaddeus M.; Vore, Andrew S.; Gano, Anny; Mondello, Jamie E.; Deak, Terrence

doi:10.1016/j.alcohol.2018.11.004

Cited by 16 publications

(11 citation statements)

References 57 publications

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“…It is important to note here that few of the proposed mediating stimulus effects have been directly tested and the failure of specific toxins to induce aversions still needs to be explained (see [ 31 ] for an explanation of failure of several rodenticides and toxins). Further, over the past 20 years, a wide range of neuroactive compounds as well as neurochemicals involved in the modulation of normal neuronal function (and behaviorally active) are not effective in inducing CTAs, failures that challenge a simple homeostatic disruption as mediating aversion learning, e.g., interleukin-1B [ 225 ], interleukin-6 [ 226 ], leptin [ 227 ], GHR-R antagonist JMV 2959 [ 228 , 229 ], L-tryptophan [ 230 ], N-acylphosphatidylethanolamine [ 231 ], and oleoylethanolamide [ 232 ].…”

Section: Nature Of the Aversive Effects Of Drugsmentioning

confidence: 99%

Impact of the Aversive Effects of Drugs on Their Use and Abuse

Riley

Manke

Huang

2022

Behavioural Neurology

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Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential.

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Section: Nature Of the Aversive Effects Of Drugsmentioning

confidence: 99%

Impact of the Aversive Effects of Drugs on Their Use and Abuse

Riley

Manke

Huang

2022

Behavioural Neurology

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“…One of the top statistically significant DEGs was interleukin 6 receptor ( Il6r ) ( Figure 1 B). This receptor is part of the pro-inflammatory cytokine IL-6 pathway that has been involved in the neuroimmune response to alcohol and may play a critical role in alcohol dependence [ 61 , 62 , 63 ].…”

Section: Resultsmentioning

confidence: 99%

Alcohol Dependence in Rats Is Associated with Global Changes in Gene Expression in the Central Amygdala

et al. 2021

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Alcohol dependence is associated with adverse consequences of alcohol (ethanol) use and is evident in most severe cases of alcohol use disorder (AUD). The central nucleus of the amygdala (CeA) plays a critical role in the development of alcohol dependence and escalation of alcohol consumption in dependent subjects. Molecular mechanisms underlying the CeA-driven behavioral changes are not well understood. Here, we examined the effects of alcohol on global gene expression in the CeA using a chronic intermittent ethanol (CIE) vapor model in rats and RNA sequencing (RNA-Seq). The CIE procedure resulted in robust changes in CeA gene expression during intoxication, as the number of differentially expressed genes (DEGs) was significantly greater than those expected by chance. Over-representation analysis of cell types, functional groups and molecular pathways revealed biological categories potentially important for the development of alcohol dependence in our model. Genes specific for astrocytes, myelinating oligodendrocytes, and endothelial cells were over-represented in the DEG category, suggesting that these cell types were particularly affected by the CIE procedure. The majority of the over-represented functional groups and molecular pathways were directly related to the functions of glial and endothelial cells, including extracellular matrix (ECM) organization, myelination, and the regulation of innate immune response. A coordinated regulation of several ECM metalloproteinases (e.g., Mmp2; Mmp14), their substrates (e.g., multiple collagen genes and myelin basic protein; Mbp), and a metalloproteinase inhibitor, Reck, suggests a specific mechanism for ECM re-organization in response to chronic alcohol, which may modulate neuronal activity and result in behavioral changes, such as an escalation of alcohol drinking. Our results highlight the importance of glial and endothelial cells in the effects of chronic alcohol exposure on the CeA, and demonstrate further insight into the molecular mechanisms of alcohol dependence in rats. These molecular targets may be used in future studies to develop therapeutics to treat AUD.

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“…Previous work has shown that high dose (3.5–4 g/kg) acute ethanol produces rapid induction of brain cytokine expression ( Doremus-Fitzwater et al, 2014 ; Gano et al, 2017 ; Gano et al, 2019 ), loss of righting reflex ( Barney et al, 2019 ), and withdrawal-induced hypolocomotion ( Buck et al, 2011 ). These doses produce BECs achieved during heavy drinking episodes in humans (300–400 mg/dl) ( Usala et al, 2015 ; Vore et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Acute Ethanol Challenge Differentially Regulates Expression of Growth Factors and miRNA Expression Profile of Whole Tissue of the Dorsal Hippocampus

Barney

Vore²,

Deak³

2022

Front. Neurosci.

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Acute ethanol exposure produces rapid alterations in neuroimmune gene expression that are both time- and cytokine-dependent. Interestingly, adolescent rats, who often consume binge-like quantities of alcohol, displayed reduced neuroimmune responses to acute ethanol challenge. However, it is not known whether growth factors, a related group of signaling factors, respond to ethanol similarly in adults and adolescents. Therefore, Experiment 1 aimed to assess the growth factor response to ethanol in both adolescents and adults. To test this, adolescent (P29–P34) and adult (P70–P80) Sprague Dawley rats of both sexes were injected with either ethanol (3.5 g/kg) or saline, and brains were harvested 3 h post-injection for assessment of growth factor, cytokine, or miRNA expression. As expected, acute ethanol challenge significantly increased IL-6 and IκBα expression in the hippocampus and amygdala, replicating our prior findings. Acute ethanol significantly decreased BDNF and increased FGF2 regardless of age condition. PDGF was unresponsive to ethanol, but showed heightened expression among adolescent males. Because recent work has focused on the PDE4 inhibitor ibudilast for treatment in alcohol use disorder, Experiment 2 tested whether ibudilast would alter ethanol-evoked gene expression changes in cytokines and growth factors in the CNS. Ibudilast (9.0 mg/kg s.c.) administration 1 h prior to ethanol had no effect on ethanol-induced changes in cytokine or growth factor changes in the hippocampus or amygdala. To further explore molecular alterations evoked by acute ethanol challenge in the adult rat hippocampus, Experiment 3 tested whether acute ethanol would change the miRNA expression profile of the dorsal hippocampus using RNASeq, which revealed a rapid suppression of 12 miRNA species 3 h after acute ethanol challenge. Of the miRNA affected by ethanol, the majority were related to inflammation or cell survival and proliferation factors, including FGF2, MAPK, NFκB, and VEGF. Overall, these findings suggest that ethanol-induced, rapid alterations in neuroimmune gene expression were (i) muted among adolescents; (ii) independent of PDE4 signaling; and (iii) accompanied by changes in several growth factors (increased FGF2, decreased BDNF). In addition, ethanol decreased expression of multiple miRNA species, suggesting a dynamic molecular profile of changes in the hippocampus within a few short hours after acute ethanol challenge. Together, these findings may provide important insight into the molecular consequences of heavy drinking in humans.

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The influence of central interleukin-6 on behavioral changes associated with acute alcohol intoxication in adult male rats

Cited by 16 publications

References 57 publications

Impact of the Aversive Effects of Drugs on Their Use and Abuse

Impact of the Aversive Effects of Drugs on Their Use and Abuse

Alcohol Dependence in Rats Is Associated with Global Changes in Gene Expression in the Central Amygdala

Acute Ethanol Challenge Differentially Regulates Expression of Growth Factors and miRNA Expression Profile of Whole Tissue of the Dorsal Hippocampus

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