Toll-like receptor 3 dynamics in female C57BL/6J mice: Regulation of alcohol intake

Warden, Anna S.; Azzam, Moatasem M.; DaCosta, Adriana; Mason, Sonia; Blednov, Yuri A.; Messing, Robert O.; Mayfield, R. Dayne

doi:10.1016/j.bbi.2018.12.006

Cited by 32 publications

(45 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is consistent with our previous findings that inhibiting downstream TRIF‐signaling components reduces 2 BC ‐EOD drinking in C57BL/6J male mice 8 . Our current findings are also consistent with increased 2BC‐EOD ethanol consumption in wild‐type male, but not female, C57BL/6J mice after chronic activation of TLR3 with poly(I:C) 10,26 . We observed changes in ethanol consumption only during 2BC‐EOD drinking, and we have reported that different ethanol drinking procedures produce distinct effects on brain gene expression, with the 2BC‐EOD procedure evoking the strongest neuroimmune‐related response in mice 27 .…”

Section: Discussionsupporting

confidence: 92%

“…Except for LORR in Myd88 −/− mice, alterations in ethanol‐induced behaviors in Tlr3 −/− and Myd88 −/− males were not present in Tlr3 −/− and Myd88 −/− females (Table 1). Although there are examples of sex‐specific effects on ethanol behaviors in other knockout mouse models, 25,26,36 the current findings are notable because the acute behavioral responses to ethanol in Tlr3 −/− male mice are consistent with the reduction in voluntary ethanol consumption observed only in males. We note that males and females differ in their TLR3‐dependent neuroimmune responses when TLR3 is activated by poly(I:C).…”

Section: Discussionsupporting

confidence: 60%

See 1 more Smart Citation

Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

Pharmacological studies implicate toll‐like receptor 3 (TLR3) signaling in alcohol drinking. We examined the role of TLR3 in behavioral responses to alcohol and GABAergic drugs by studying Tlr3 −/− mice. Because of opposing signaling between TLR3 and MyD88 pathways, we also evaluated Myd88 −/− mice. Ethanol consumption and preference decreased in male but not in female Tlr3 −/− mice during two‐bottle choice every‐other‐day (2BC‐EOD) drinking. There were no genotype differences in either sex during continuous or limited‐access drinking. Null mutations in Tlr3 or Myd88 did not alter conditioned taste aversion to alcohol and had small or no effects on conditioned place preference. The Tlr3 null mutation did not alter acute alcohol withdrawal. Male, but not female, Tlr3 −/− mice took longer than wild‐type littermates to recover from ataxia by ethanol or diazepam and longer to recover from sedative‐hypnotic effects of ethanol or gaboxadol, indicating regulation of GABAergic signaling by TLR3. Acute functional tolerance (AFT) to alcohol‐induced ataxia was decreased in Tlr3 −/− mice but was increased in Myd88 −/− mice. Thus, MyD88 and TLR3 pathways coordinately regulate alcohol consumption and tolerance to intoxicating doses of alcohol and GABAergic drugs. Despite similar alcohol metabolism and similar amounts of total alcohol consumed during 2BC and 2BC‐EOD procedures in C57BL/6J mice, only 2BC‐EOD drinking induced tolerance to alcohol‐induced ataxia. Ataxia recovery was inversely correlated with level of drinking in wild‐type and Tlr3 −/− littermates. Thus, deleting Tlr3 reduces alcohol consumption by reducing AFT to alcohol and not by altering tolerance induced by 2BC‐EOD drinking.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 60%

Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similarly, female B6N mice clear bacterial infections faster than their female B6J female counterparts (Ulland et al, 2016), suggesting that there is not a sex-specific effect between substrains for baseline drinking or immune response. However, poly(I:C) does have a sex-specific effect, only male B6J mice escalate EtOH intake after TLR3 activation (Warden et al, 2019a;Warden et al, 2019b). This is due to differences in immune response time course between sexes in B6J mice, with longer-lasting changes occurring in female B6J mice (Warden et al, 2019a;Warden et al, 2019b).…”

Section: Discussionmentioning

confidence: 99%

“…However, poly(I:C) does have a sex-specific effect, only male B6J mice escalate EtOH intake after TLR3 activation (Warden et al, 2019a;Warden et al, 2019b). This is due to differences in immune response time course between sexes in B6J mice, with longer-lasting changes occurring in female B6J mice (Warden et al, 2019a;Warden et al, 2019b). Therefore, the role of substrain in neuroimmune-induced escalation in EtOH consumption could only be tested in males.…”

Section: Discussionmentioning

confidence: 99%

Inbred Substrain Differences Influence Neuroimmune Response and Drinking Behavior

Warden

DaCosta

Mason

et al. 2020

Alcoholism Clin & Exp Res

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…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, ).…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

Toll-like receptor 3 dynamics in female C57BL/6J mice: Regulation of alcohol intake

Cited by 32 publications

References 83 publications

Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice

Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice

Inbred Substrain Differences Influence Neuroimmune Response and Drinking Behavior

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

Contact Info

Product

Resources

About