Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents

Harris, R. Adron; Bajo, Michal; Bell, Richard L.; Blednov, Yuri A.; Varodayan, Florence P.; Truitt, Jay; Guglielmo, Giordano de; Lasek, Amy W.; Logrip, Marian L.; Vendruscolo, Leandro F.; Roberts, Amanda J.; Roberts, Edward; George, Olivier; Mayfield, Jody; Billiar, Timothy R.; Hackam, David J.; Mayfield, R. Dayne; Koob, George F.; Roberto, Marisa; Homanics, Gregg E.

doi:10.1523/jneurosci.2002-16.2016

Cited by 73 publications

(63 citation statements)

References 76 publications

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“…Despite these findings suggesting a prominent role of TLR4 in alcohol-induced behaviors, a recent report provides evidence that TLR4 is not involved in alcohol consumption. In this report, both pharmacological and genetic manipulations of TLR4 fail to significantly alter excessive alcohol consumption utilizing a two-bottle choice paradigm, drinking-in-the-dark procedure and a chronic intermittent exposure procedure (Harris et al, 2016). These findings suggest that the alcohol-induced immune activation of microglia contribute to alcohol drinking and the subjective effects of alcohol administration, although the role of TLR4 remains unclear.…”

Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 96%

Glial and neuroinflammatory targets for treating substance use disorders

Bachtell

Jones

Heinzerling

et al. 2017

Drug and Alcohol Dependence

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Background The plenary session at the 2016 Behavior, Biology and Chemistry: Translational Research in Addiction Conference focused on glia as potential players in the development, persistence and treatment of substance use disorders. Glia partake in various functions that are important for healthy brain activity. Drugs of abuse alter glial cell activity producing several perturbations in brain function that are thought to contribute to behavioral changes associated with substance use disorders. Consequently, drug-induced changes in glia-driven processes in the brain represent potential targets for pharmacotherapeutics treating substance use disorders. Methods Four speakers presented preclinical and clinical research illustrating the effects that glial modulators have on abuse-related behavioral effects of psychostimulants and opioids. This review highlights some of these findings and expands its focus to include other research focused on drug-induced glia abnormalities and glia-focused treatment approaches in substance use disorders. Results Preclinical findings show that drugs of abuse induce neuroinflammatory signals and disrupt glutamate homeostasis through their interaction with microglia and astrocytes. Preclinical and clinical studies testing the effects of glial modulators show general effectiveness in reducing behaviors associated with substance use disorders. Conclusions The contribution of drug-induced glial activity continues to emerge as an intriguing target for substance use disorder treatments. Clinical investigations of glial modulators have yielded promising results on substance use measures and indicate that they are generally safe and well-tolerated. However, results have not been entirely positive and more questions remain for continued exploration in the development and testing of glial-directed treatments for substance use disorders.

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Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 96%

Glial and neuroinflammatory targets for treating substance use disorders

Bachtell

Jones

Heinzerling

et al. 2017

Drug and Alcohol Dependence

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“…Indeed, alcohol self‐administration increases expression of the TLR4 protein in the VTA of alcohol‐preferring rats (June et al ., ). Mice lacking the TLR4 protein or the TLR4 adaptor protein, MyD88, display lower sensitivity to the sedative and motor‐impairing effects of alcohol compared to wild‐type mice (Wu et al ., ; Harris et al ., ), whereas MYD88 knockout increases ethanol consumption (Blednov et al ., ). TLR4 activation in the VTA and central amygdala, in particular, may be an important signal for binge alcohol consumption, as site‐selective knockdown of TLR4 in these regions using siRNA reduces binge drinking in alcohol‐preferring rats (Liu et al ., ; June et al ., ).…”

Section: Glial Mechanisms Underlying Behavioral Changes After Drug Exmentioning

confidence: 99%

“…Furthermore, genetic knockout of TLR2 or CD14, suppresses ethanol intake . In contrast, some have reported no effect of pharmacological or genetic manipulation of TLR4 on excessive alcohol consumption in the two-bottle choice, drinking-in-the-dark, or chronic intermittent access paradigms Harris et al, 2017). Blednov et al (2017) demonstrated that TLR4 mutant mice have unaltered alcohol consumption behavior.…”

Section: Manipulations Of Tlr4 Function Modulate Drug-associated Behamentioning

confidence: 99%

Glial mechanisms underlying substance use disorders

Linker

Cross

Leslie

2018

Eur J of Neuroscience

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Addiction is a devastating disorder that produces persistent maladaptive changes to the central nervous system, including glial cells. Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive. Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of processes beyond inflammation and immune surveillance, and may represent a promising therapeutic target. Indeed, glia actively modulate neurotransmission, synaptic connectivity and neural circuit function, and are critically poised to contribute to addictive‐like brain states and behaviors. In this review, we argue that glia influence the cellular, molecular, and synaptic changes that occur in neurons following drug exposure, and that this cellular relationship is critically modified following drug exposure. We discuss direct actions of abused drugs on glial function through immune receptors, such as Toll‐like receptor 4, as well as other mechanisms. We highlight how drugs of abuse affect glia‐neural communication, and the profound effects that glial‐derived factors have on neuronal excitability, structure, and function. Recent research demonstrates that glia have brain region‐specific functions, and glia in different brain regions have distinct contributions to drug‐associated behaviors. We will also evaluate the evidence demonstrating that glial activation is essential for drug reward and drug‐induced dopamine release, and highlight clinical evidence showing that glial mechanisms contribute to drug abuse liability. In this review, we synthesize the extensive evidence that glia have a unique, pivotal, and underappreciated role in the development and maintenance of addiction.

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“…Although it still remains unclear whether immune receptors, TLRs, are involved in alcohol drinking in adult animals (Harris et al, ), recent studies have shown that blocking the TLR4 response using selective inhibitor 5342126 decreases ethanol drinking in both ethanol‐dependent and nondependent mice (Bajo et al, ). Adult TLR4‐deficient adolescent female mice exposed to alcohol in adolescence appear to be protected against escalation in alcohol preference (Montesinos, Pascual, et al, ).…”

Section: Impact Of Immune System Activation On Alcohol‐induced Brain mentioning

confidence: 99%

Role of the innate immune system in the neuropathological consequences induced by adolescent binge drinking

Pascual

Montesinos

2017

J of Neuroscience Research

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Adolescence is a critical stage of brain maturation in which important plastic and dynamic processes take place in different brain regions, leading to development of the adult brain. Ethanol drinking in adolescence disrupts brain plasticity and causes structural and functional changes in immature brain areas (prefrontal cortex, limbic system) that result in cognitive and behavioral deficits. These changes, along with secretion of sexual and stress-related hormones in adolescence, may impact self-control, decision making, and risk-taking behaviors that contribute to anxiety and initiation of alcohol consumption. New data support the participation of the neuroimmune system in the effects of ethanol on the developing and adult brain. This article reviews the potential pathological bases that underlie the effects of alcohol on the adolescent brain, such as the contribution of genetic background, the perturbation of epigenetic programming, and the influence of the neuroimmune response. Special emphasis is given to the actions of ethanol in the innate immune receptor toll-like receptor 4 (TLR4), since recent studies have demonstrated that by activating the inflammatory TLR4/NFκB signaling response in glial cells, binge drinking of ethanol triggers the release of cytokines/chemokines and free radicals, which exacerbate the immune response that causes neuroinflammation/neural damage as well as short- and long-term neurophysiological, cognitive, and behavioral dysfunction. Finally, potential treatments that target the neuroimmune response to treat the neuropathological and behavioral consequences of adolescent alcohol abuse are discussed.

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Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents

Cited by 73 publications

References 76 publications

Glial and neuroinflammatory targets for treating substance use disorders

Glial and neuroinflammatory targets for treating substance use disorders

Glial mechanisms underlying substance use disorders

Role of the innate immune system in the neuropathological consequences induced by adolescent binge drinking

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