The Toll‐Like Receptor 3 Agonist Poly(I:C) Induces Rapid and Lasting Changes in Gene Expression Related to Glutamatergic Function and Increases Ethanol Self‐Administration in Rats

Randall, Patrick A.; Vetreno, Ryan P.; Makhijani, Viren H.; Crews, Fulton T.; Besheer, Joyce

doi:10.1111/acer.13919

Cited by 36 publications

(35 citation statements)

References 71 publications

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“…The results showed a reduction in the expression of choline acetyltransferase (ChAT), which is involved in acetylcholine biosynthesis [98,99]. Several studies showed that reduction of ChAT is correlated with memory and cognitive impairments in patients with AD and other neurodegenerative diseases [100,101]. A critical role of the TLR4 response was confirmed by observation of microglia activation and neuroinflammatory damage induced by ethanol, and by microglia activation (CD11b + cells) in cerebral cortex of TLR4 +/+ mice, but not in TLR4deficient mice after acute ethanol administration.…”

Section: High Wine Consumptionmentioning

confidence: 99%

Relationship of Wine Consumption with Alzheimer’s Disease

et al. 2020

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Background: Alzheimer’s disease (AD), the most threatening neurodegenerative disease, is characterized by the loss of memory and language function, an unbalanced perception of space, and other cognitive and physical manifestations. The pathology of AD is characterized by neuronal loss and the extensive distribution of senile plaques and neurofibrillary tangles (NFTs). The role of environment and the diet in AD is being actively studied, and nutrition is one of the main factors playing a prominent role in the prevention of neurodegenerative diseases. In this context, the relationship between dementia and wine use/abuse has received increased research interest, with varying and often conflicting results. Scope and Approach: With this review, we aimed to critically summarize the main relevant studies to clarify the relationship between wine drinking and AD, as well as how frequency and/or amount of drinking may influence the effects. Key Findings and Conclusions: Overall, based on the interpretation of various studies, no definitive results highlight if light to moderate alcohol drinking is detrimental to cognition and dementia, or if alcohol intake could reduce risk of developing AD.

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Section: High Wine Consumptionmentioning

confidence: 99%

Relationship of Wine Consumption with Alzheimer’s Disease

et al. 2020

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“…and then euthanized mice at 3 and 24 hours post-injection before qRT-PCR analysis. The 5mg/kg dose has been shown to have a peak immune response between 3 and 8 hours after injection, minimizes sickness response, and prevents any adverse effect on drinking behavior (Qin and Crews, 2012;Randall et al, 2019;Warden et al, 2019a).…”

Section: Drug Preparation and Administrationmentioning

confidence: 99%

“…Here, we compared male B6N and B6J mice for response to TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)) and escalation of EtOH consumption, a known model of neuroimmune-related drinking behaviors (Randall et al, 2019;Warden et al, 2019a). B6N mice had a more robust but shorter inflammatory response to poly(I:C).…”

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confidence: 99%

Inbred Substrain Differences Influence Neuroimmune Response and Drinking Behavior

Warden

DaCosta

Mason

et al. 2020

Alcoholism Clin & Exp Res

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Background The inbred mouse strain C57BL/6 is widely used in both models of addiction and immunological disease. However, there are pronounced phenotypic differences in ethanol (EtOH) consumption and innate immune response between C57BL/6 substrains. The focus of this study was to examine the effects of substrain on innate immune response and neuroimmune‐induced escalation of voluntary EtOH consumption. The main goal was to identify whether substrain differences in immune response can account for differences in EtOH behavior. Methods We compared acute innate immune response with a viral dsRNA mimic, polyinosinic:polycytidylic acid (poly(I:C)), in brain using qRT‐PCR in both C57BL/6N and C57BL/6J mice. Next, we used a neuroimmune model of escalation using poly(I:C) to compare drinking behavior between substrains. Finally, we compared brain neuroimmune response with both EtOH and repeated poly(I:C) in both substrains as a way to account for differences in EtOH behavior. Results We found that C57BL/6 substrains have differing immune response and drinking behaviors. C57BL/6N mice have a shorter but more robust inflammatory response to acute poly(I:C). In contrast, C57BL/6J mice have a smaller but longer‐lasting acute immune response to poly(I:C). In our neuroimmune‐induced escalation model, C57BL/6J mice but not C57BL/6N mice escalate EtOH intake after poly(I:C). Finally, only C57BL/6J mice show enhanced proinflammatory transcript abundance after poly(I:C) and EtOH, suggesting that longer‐lasting immune responses are critical to neuroimmune drinking phenotypes. Conclusions Altogether, this work has elucidated additional influences that substrain has on both innate immune response and drinking phenotypes. Our observations highlight the importance of considering and reporting the source and background used for production of transgenic and knockout mice. These data provide further evidence that genetic background must be carefully considered when investigating the role of neuroimmune signaling in EtOH abuse.

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“…Studies in animal models showed that manipulation of various immune pathways could reduce alcohol consumption in mice (Blednov et al, ). The reverse has also been demonstrated where inducing systemic inflammation, via peripheral injection of the bacterial wall component lipopolysaccharide (LPS) or with the TLR3 ligand poly(I:C), increased alcohol consumption in mice (Blednov et al, ; Randall et al, ; Warden et al, ). Interestingly, studies in human patients correlate alcohol craving severity with increased markers of systemic inflammation, including cytokines (Leclercq et al, ).…”

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confidence: 99%

Inhibition of the Inflammasome Signaling Cascade Reduces Alcohol Consumption in Female But Not Male Mice

Lowe

Cho

Tornai

et al. 2020

Alcoholism Clin & Exp Res

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Background: Alcohol use disorder is a significant societal and medical burden that is associated with both organ pathology and addiction. Excessive alcohol use results in neuroinflammation characterized by activation of the inflammasome, a multiprotein complex, and IL-1b increase in the brain. Recent studies suggest that inflammation could contribute to alcohol addiction. Here, we targeted components of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome cascade, which senses and responds to immunologic stimuli, to determine whether NLRP3 inhibition modulates alcohol consumption.Methods: C57BL/6J male and female mice were provided a 2-bottle choice of alcohol at increasing concentrations (3, 6, 9, and 12%, 4 days each) or water, and some were treated with daily injections of an NLRP3 inhibitor (MCC950), a caspase-1 inhibitor (VX765), IL-1 receptor antagonist (IL-1ra; anakinra), or vehicle injection.Results: Treatment with VX765, MCC950, and IL-1ra significantly reduced alcohol consumption and preference in female mice (p < 0.05). Treatment with MCC950 and IL-1ra reduced alcohol consumption, while IL-1ra reduced alcohol preference in male mice (p < 0.05). VX765 did not affect alcohol consumption or preference in male mice.Conclusions: These findings highlight gender differences in alcohol preference and demonstrate that inhibition of different steps in inflammasome signaling can reduce alcohol consumption in females. Inhibition of NLRP3 inflammasome activation and the inflammasome-IL-1b cascade opens novel insights into the development of new therapies to address alcohol use disorder in an era of targeted and precision medicine.

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The Toll‐Like Receptor 3 Agonist Poly(I:C) Induces Rapid and Lasting Changes in Gene Expression Related to Glutamatergic Function and Increases Ethanol Self‐Administration in Rats

Cited by 36 publications

References 71 publications

Relationship of Wine Consumption with Alzheimer’s Disease

Relationship of Wine Consumption with Alzheimer’s Disease

Inbred Substrain Differences Influence Neuroimmune Response and Drinking Behavior

Inhibition of the Inflammasome Signaling Cascade Reduces Alcohol Consumption in Female But Not Male Mice

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