Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice

Karlsson, Camilla; Schank, Jesse R.; Rehman, Faazal; Stojakovic, Andrea; Björk, Karl; Barbier, Estelle; Solomon, Matthew G.; Tapocik, Jenica D.; Engblom, David; Thorsell, Annika; Heilig, Markus

doi:10.1111/adb.12416

Cited by 31 publications

(18 citation statements)

References 43 publications

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“…Interestingly, this is consistent with studies finding innate immune signaling contributes to the development of AUD (Crews et al., 2017; de Timary et al., 2017). Innate immune signaling cytokines alter EtOH consumption (Marshall et al., 2017, 2017), and cytokine receptors contribute to stress‐induced EtOH consumption (Karlsson et al., 2017). Further, immune signaling molecules are increased in postmortem human alcoholic brain (Crews et al., 2017) and regulate preference for alcohol drinking in animal studies (Mayfield et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

“…However, reducing endotoxin release with antibiotics, probiotics, and drugs resulted in a loss of the stress hormone response, suggesting stress‐induced changes in blood endotoxin contribute to stress hormone responses (Ait‐Belgnaoui et al., 2012). Innate immune signaling cytokines also alter EtOH consumption (Marshall et al., 2016, 2017), and the cytokine receptors IL1R1 and TNFR1 contribute to stress‐induced EtOH consumption (Karlsson et al., 2017), suggesting the neuroimmune system may contribute to addiction. Cytokines also enhance stressful emotional states following alcohol withdrawal (Breese et al., 2008).…”

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confidence: 99%

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Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Walter

Vetreno

Crews

2017

Alcoholism Clin & Exp Res

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BackgroundCycles of alcohol and stress are hypothesized to contribute to alcohol use disorders. How this occurs is poorly understood, although both alcohol and stress activate the neuroimmune system—the immune molecules and cells that interact with the nervous system. The effects of alcohol and stress on the neuroimmune system are mediated in part by peripheral signaling molecules. Alcohol and stress both enhance immunomodulatory molecules such as corticosterone and endotoxin to impact neuroimmune cells, such as microglia, and may subsequently impact neurons. In this study, we therefore examined the effects of acute and chronic ethanol (EtOH) on the corticosterone, endotoxin, and microglial and neuronal response to acute stress.MethodsMale Wistar rats were treated intragastrically with acute EtOH and acutely stressed with restraint/water immersion. Another group of rats was treated intragastrically with chronic intermittent EtOH and acutely stressed following prolonged abstinence. Plasma corticosterone and endotoxin were measured, and immunohistochemical stains for the microglial marker CD11b and neuronal activation marker c‐Fos were performed.ResultsAcute EtOH and acute stress interacted to increase plasma endotoxin and microglial CD11b, but not plasma corticosterone or neuronal c‐Fos. Chronic EtOH caused a lasting sensitization of stress‐induced plasma endotoxin, but not plasma corticosterone. Chronic EtOH also caused a lasting sensitization of stress‐induced microglial CD11b, but not neuronal c‐Fos.ConclusionsThese results find acute EtOH combined with acute stress enhanced plasma endotoxin, as well as microglial CD11b in many brain regions. Chronic EtOH followed by acute stress also increased plasma endotoxin and microglial CD11b, suggesting a lasting sensitization to acute stress. Overall, these data suggest alcohol and stress interact to increase plasma endotoxin, resulting in enhanced microglial activation that could contribute to disease progression.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Walter

Vetreno

Crews

2017

Alcoholism Clin & Exp Res

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“…In preclinical models of male social defeat stress, B6 or Swiss-derived outbred male mice exposed to repeated attacks from a dominant male resident later consume significantly more alcohol than non-defeated controls ( Fig. 1 ; Albrechet-Souza et al, 2017 ; Hwa et al, 2016a ; Karlsson et al, 2017 ; Kudryavtseva et al, 2006 ; Kudryavtseva et al, 1991 ; Nelson et al, 2018 ; Newman et al, 2018 ; Norman et al, 2015 ). Recently, we developed a model of social stress that promotes inter-female aggression to evaluate the effects of social defeat stress on alcohol consumption in female B6 mice (Newman et al in prep).…”

Section: Animal Models Of Social Stress and Pathological Patterns Of mentioning

confidence: 99%

Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF

Newman

Leonard

Arena

et al. 2018

Neurobiology of Stress

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Both the ostensibly aversive effects of unpredictable episodes of social stress and the intensely rewarding effects of drugs of abuse activate the mesocorticolimbic dopamine systems. Significant neuroadaptations in interacting stress and reward neurocircuitry may underlie the striking connection between stress and substance use disorders. In rodent models, recurring intermittent exposure to social defeat stress appears to produce a distinct profile of neuroadaptations that translates most readily to the repercussions of social stress in humans. In the present review, preclinical rodent models of social defeat stress and subsequent alcohol, cocaine or opioid consumption are discussed with regard to: (1) the temporal pattern of social defeat stress, (2) male and female protocols of social stress-escalated drug consumption, and (3) the neuroplastic effects of social stress, which may contribute to escalated drug-taking. Neuroadaptations in corticotropin-releasing factor (CRF) and CRF modulation of monoamines in the ventral tegmental area and the bed nucleus of the stria terminalis are highlighted as potential mechanisms underlying stress-escalated drug consumption. However, the specific mechanisms that drive CRF-mediated increases in dopamine require additional investigation as do the stress-induced neuroadaptations that may contribute to the development of compulsive patterns of drug-taking.

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“…In addition to the classical proinflammatory and potentially neurotoxic activation phenotype, microglia are now recognized to exhibit several alternative phenotypes related to motility, phagocytosis, repair, and anti-inflammatory responses, which are associated with the formation and proper function of neuronal circuits (Frost and Schafer, 2016;Sousa et al, 2017) with microglia-derived neurotrophic factors playing a key role (Parkhurst et al, 2013). The involvement of neuroimmune responses has been implicated in the pathophysiology of alcohol use disorders (Blednov et al, 2012;Karlsson et al, 2017). Various in vitro and animal studies have reported a spectrum of microglial phenotypes in responses to EtOH, ranging from classical proinflammatory (Pascual et al, 2011;Qin and Crews, 2012a;Qin and Crews, 2012b) to noninflammatory phenotypes (Bell-Temin et al, 2015;Bell-Temin et al, 2013;Guergues et al, 2020;Marshall et al, 2013) and a mix of both (Peng et al, 2017).…”

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confidence: 99%

Chronic Voluntary Binge Ethanol Consumption Causes Sex‐Specific Differences in Microglial Signaling Pathways and Withdrawal‐associated Behaviors in Mice

Rath

Guergues

Pinho

et al. 2020

Alcoholism Clin & Exp Res

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Background Microglia are the resident immune cells in the brain where they play essential roles in the development and maintenance of physiological functions of this organ. Aberrant activation of microglia is speculated to be involved in the pathogenesis of a variety of neurological disorders, including alcohol use disorders. Repeated binge ethanol (EtOH) consumption can have a profound impact on the function and integrity of the brain resulting in changes in behaviors such as withdrawal and reward. However, the microglial molecular and cellular pathways associated with EtOH binge consumption remain poorly understood. Method In this study, adult C57BL/6J male and female mice were subjected daily to a gelatin‐based drinking‐in‐the‐dark voluntary EtOH consumption paradigm (3 h/d for 4 months) to characterize EtOH consumption and withdrawal‐associated and anxiety‐like behaviors. Brain microglia were isolated at the end and analyzed for protein expression profile changes using unbiased mass spectrometry‐based proteomic analysis. Results Both male and female mice consistently consumed binge quantities of EtOH daily, resulting in blood EtOH levels > 80 mg/dl measured at the end of the 3‐hour daily consumption period. Although female mice consumed a significantly greater amount of EtOH than male mice, EtOH withdrawal‐associated anxiety‐like behaviors measured by marble‐burying, light‐dark box, and elevated plus maze tests were predominantly observed in male mice. Proteomic analysis of microglia isolated from the brains of animals at the end of the 4‐month binge EtOH consumption identified 117 and 37 proteins that were significantly up‐ or downregulated in EtOH‐exposed male and female mice, respectively, compared to their pair‐fed controls. Protein expression profile‐based pathway analysis identified several cellular pathways that may underlie the sex‐specific and EtOH withdrawal‐associated behavioral abnormalities. Conclusion Taken together, our findings revealed sex‐specific changes in EtOH withdrawal‐associated behaviors and signaling pathways in the mouse brain microglia and may help advance our understanding of the molecular, cellular, and behavioral changes related to human binge EtOH consumption.

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Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice

Cited by 31 publications

References 43 publications

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF

Chronic Voluntary Binge Ethanol Consumption Causes Sex‐Specific Differences in Microglial Signaling Pathways and Withdrawal‐associated Behaviors in Mice

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