TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment

Montesinos, Jorge; Pascual, Marı́a; Pla, Antoni; Maldonado, Carmen; Rodrı́guez-Arias, Marta; Miñarro, José; Guerri, Consuelo

doi:10.1016/j.bbi.2014.11.015

Cited by 122 publications

(179 citation statements)

References 75 publications

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“…Guerri’s lab has multiple reports finding that anti-inflammatory drugs (Pascual et al, 2007) or mice lacking the neuroimmune Toll-like receptor 4 do not respond to ethanol activation of glia, ethanol stimulated NAc DA release and changes in adult ethanol behavioral responses (Alfonso-Loeches et al, 2010; Pascual et al, 2009, 2011). Adolescent alcohol exposure induction of brain neuroimmune genes and pathology does not occur in transgenic mice lacking TLR4 receptors (Pascual et al, 2014) including loss of ethanol activation of kinases and mobilization of HMGB1 from nuclear to cytosolic fractions (Montesinos et al, 2015). Although the mechanisms of adolescent alcohol treatment induced blunting of PFC c-Fos responses is not clear, alterations in histone acetylation and neuroimmune gene induction persist after adolescent ethanol treatment and are likely to contribute to the long-lasting changes in adult brain PFC responses.…”

Section: Discussionmentioning

confidence: 99%

Adolescent Intermittent ethanol exposure enhances ethanol activation of the nucleus accumbens while blunting the prefrontal cortex responses in adult rat

Liu

Crews

2015

Neuroscience

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The brain continues to develop through adolescence when excessive alcohol consumption is prevalent in humans. We hypothesized that binge drinking doses of ethanol during adolescence will cause changes in brain ethanol responses that persist into adulthood. To test this hypothesis Wistar rats were treated with an adolescent intermittent ethanol (AIE; 5 g/kg, i.g. 2 days on–2 days off; P25–P54) model of underage drinking followed by 25 days of abstinence during maturation to young adulthood (P80). Using markers of neuronal activation c-Fos, EGR1, and phophorylated extracellar signal regulated kinase (pERK1/2), adult responses to a moderate and binge drinking ethanol challenge, e.g., 2 or 4 g/kg, were determined. Adult rats showed dose dependent increases in neuronal activation markers in multiple brain regions during ethanol challenge. Brain regional responses correlated are consistent with anatomical connections. AIE led to marked decreases in adult ethanol PFC (prefrontal cortex) and blunted responses in the amygdala. Binge drinking doses led to the nucleus accumbens (NAc) activation that correlated with the ventral tegmental area (VTA) activation. In contrast to other brain regions, AIE enhanced the adult NAc response to binge drinking doses. These studies suggest that adolescent alcohol exposure causes long-lasting changes in brain responses to alcohol that persist into adulthood.

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Section: Discussionmentioning

confidence: 99%

Adolescent Intermittent ethanol exposure enhances ethanol activation of the nucleus accumbens while blunting the prefrontal cortex responses in adult rat

Liu

Crews

2015

Neuroscience

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“…The following behaviors were scored: sum of the total time (t, seconds) exploring the two stones in T1, sum of the time exploring the stone and the toy in T2, and difference between the time exploring the stone and the toy in T2. The basic measure of memory acquisition in the object recognition test was the discrimination index (DI), calculated as: [DI = (tnovel—tfamiliar)/(tnovel + tfamiliar) × 100%] [40]. …”

Section: Methodsmentioning

confidence: 99%

Adolescent but not adult ethanol binge drinking modulates cocaine withdrawal symptoms in mice

et al. 2017

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BackgroundEthanol (EtOH) binge drinking is an increasingly common behavior among teenagers that induces long-lasting neurobehavioral alterations in adulthood. An early history of EtOH abuse during adolescence is highly correlated with cocaine addiction in adulthood. Abstinence of cocaine abuse can cause psychiatric symptoms, such as anxiety, psychosis, depression, and cognitive impairments. This study assessed the consequences of adolescent exposure to EtOH on the behavioral alterations promoted by cocaine withdrawal in adulthood.MethodsWe pretreated juvenile (34–47 days old) or adult (68–81 days old) mice with EtOH (1.25 g/kg) following a binge-drinking pattern. Then, after a three-week period without drug delivery, they were subjected to a chronic cocaine treatment in adulthood and tested under cocaine withdrawal by the ensuing paradigms: open field, elevated plus maze, prepulse inhibition, tail suspension test, and object recognition. Another set of mice were treated with the same EtOH binge-drinking procedure during adolescence and were tested immediately afterwards under the same behavioral paradigms.ResultsAdolescent EtOH pretreatment undermined the anxiogenic effects observed after cocaine abstinence, reduced prepulse inhibition, and increased immobility scores in the tail suspension test following cocaine withdrawal. Moreover, the memory deficits evoked by these substances when given separately were enhanced in cocaine-withdrawn mice exposed to EtOH during adolescence. EtOH binge drinking during adolescence also induced anxiety, depressive symptoms, and memory impairments when measured immediately afterwards. In contrast, neither EtOH nor cocaine alone or in combination altered any of these behaviors when given in adulthood.ConclusionsEtOH binge drinking induces short- and long-term behavioral alterations and modulates cocaine withdrawal symptoms when given in adolescent mice.

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“…Hence, it is not surprising that alcohol exposure during adolescence induces lasting increases in expression of neuroimmune genes, including a variety of proinflammatory signaling molecules, along with activation of the innate immune system receptor, Toll-like receptor 4 (TLR4) (see Crews & Vetreno, 2014, for review). Activation of TLR4 receptors by EtOH triggers transcription factors such as NFκB and AP-1 to induce cytokine production and mediators of inflammation that are thought to lead to the brain damage produced by EtOH (see Montesinos et al, 2015b). Evidence supports the suggestion that immune activation via TLR4 may be critical for the production of certain neural and behavioral consequences of EtOH exposure during adolescence.…”

Section: Alcoholmentioning

confidence: 99%

“…Induction of TRL4 activation with an agonist (lipopolysaccharide) was found to induce lasting reductions in neurogenesis similar to that observed after adolescent EtOH administration (Vetreno & Crews, 2015). Conversely, TLR-4 deficient (TLR4-KO) mice exposed to EtOH during adolescence did not show the inflammatory response nor cognitive and behavioral alterations characteristic of adolescent EtOH exposure (Montesinos et al, 2015a,b). Likewise, administration of an anti-inflammatory agent (indomethacin) was found to block the pattern of cell death and behavioral deficits associated with EtOH exposure during adolescence (Pascual et al, 2007).…”

Section: Alcoholmentioning

confidence: 99%

Consequences of adolescent use of alcohol and other drugs: Studies using rodent models

Spear

2016

Neuroscience & Biobehavioral Reviews

136

112

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Studies using animal models of adolescent exposure to alcohol, nicotine, cannabinoids, and the stimulants cocaine, 3,4-Methylenedioxymethampethamine and methamphetamine have revealed a variety of persisting neural and behavioral consequences. Affected brain regions often include mesolimbic and prefrontal regions undergoing notable ontogenetic change during adolescence, although it is unclear whether this represents areas of specific vulnerability or particular scrutiny to date. Persisting alterations in forebrain systems critical for modulating reward, socioemotional processing and cognition have emerged, including apparent induction of a hyper-dopaminergic state with some drugs and/or attenuations in neurons expressing cholinergic markers. Disruptions in cognitive functions such as working memory, alterations in affect including increases in social anxiety, and mixed evidence for increases in later drug self-administration have also been reported. When consequences of adolescent and adult exposure were compared, adolescents were generally found to be more vulnerable to alcohol, nicotine, and cannabinoids, but generally not to stimulants. More work is needed to determine how adolescent drug exposure influences sculpting of the adolescent brain, and provide approaches to prevent/reverse these effects.

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TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment

Cited by 122 publications

References 75 publications

Adolescent Intermittent ethanol exposure enhances ethanol activation of the nucleus accumbens while blunting the prefrontal cortex responses in adult rat

Adolescent Intermittent ethanol exposure enhances ethanol activation of the nucleus accumbens while blunting the prefrontal cortex responses in adult rat

Adolescent but not adult ethanol binge drinking modulates cocaine withdrawal symptoms in mice

Consequences of adolescent use of alcohol and other drugs: Studies using rodent models

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