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Background: Multiple ethanol binge drinking‐like exposures during adolescence in the rat induce neuroinflammation, loss of neurogenesis, and cognitive deficits in adulthood. Interestingly, the first ethanol binge drinking‐like exposure during adolescence also induces short‐ term impairments in cognition and synaptic plasticity in the hippocampus though the cellular mechanisms of these effects are unclear. Here, we sought to determine which of the cellular effects of ethanol might play a role in the disturbances in cognition and synaptic plasticity observed in the adolescent male rat after two binge‐like ethanol exposures. Methods: Using immunochemistry, we measured neurogenesis, neuronal loss, astrogliosis, neuroinflammation, and synaptogenesis in the hippocampus of adolescent rats 48 h after two binge‐like ethanol exposures (3 g/kg, i.p., 9 h apart). We used flow cytometry to analyze activated microglia and identify the TLR4‐expressing cell types. Results: We detected increased hippocampal doublecortin immunoreactivity in the subgranular zone (SGZ) of the dentate gyrus (DG), astrogliosis in the SGZ, and a reduced number of mature neurons in the DG and in CA3, suggesting compensatory neurogenesis. Synaptic density decreased in the stratum oriens of CA1 revealing structural plasticity. There was no change in microglial TLR4 expression or in the number of activated microglia, suggesting a lack of neuroinflammatory processes, although neuronal TLR4 was decreased in CA1 and DG. Conclusions: Our findings demonstrate that the cognitive deficits associated with hippocampal synaptic plasticity alterations that we previously characterized 48 h after the first binge‐like ethanol exposures are associated with hippocampal structural plasticity, astrogliosis, and decreased neuronal TLR4 expression, but not with microglia reactivity. [ABSTRACT FROM AUTHOR]

Ethanol (EtOH) induces cognitive impairment through modulation of synaptic plasticity notably in the hippocampus. The cellular mechanism(s) of these EtOH effects may range from synaptic signaling modulation to alterations of the epigenome. Previously, we reported that two binge-like exposures to EtOH (3 g/kg, ip, 9 h apart) in adolescent rats abolished long-term synaptic depression (LTD) in hippocampus slices, induced learning deficits, and increased N-methyl-d-aspartate (NMDA) receptor signaling through its GluN2B subunit after 48 hours. Here, we tested the hypothesis of EtOH-induced epigenetic alterations leading to modulation of GluN2B and GluN2A NMDA receptor subunits. Forty-two days old rats were treated with EtOH or the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB, 600 mg/kg, ip) injected alone or 30 minutes before EtOH. After 48 hours, learning was tested with novel object recognition while synaptic plasticity and the role of GluN2A and GluN2B subunits in NMDA-fEPSP were measured in CA1 field of hippocampus slices. LTD and memory were impaired 48 hours after EtOH and NMDA-fEPSP analysis unraveled changes in the GluN2A/GluN2B balance. These results were associated with an increase in histone deacetylase (HDAC) activity and HDAC2 mRNA and protein while Ac-H4K12 labelling was decreased. EtOH increases expression of HDAC2 and mRNA level for GluN2B subunit (but not GluN2A), while HDAC2 modulates the promoter of the gene encoding GluN2B. Interestingly, NaB pretreatment prevented all the cellular and memory-impairing effects of EtOH. In conclusion, the memory-impairing effects of two binge-like EtOH exposure involve NMDA receptor-dependent LTD deficits due to a GluN2A/GluN2B imbalance resulting from changes in GluN2B expression induced by HDAC2. [ABSTRACT FROM AUTHOR]

As the contribution of cannabinoid (CB1) receptors in the neuroadaptations following chronic alcohol exposure is unknown, we investigated the neuroadaptations induced by chronic alcohol exposure on both NMDA and GABAA receptors in CB1−/− mice. Our results show that basal levels of hippocampal [3H]MK-801 ((1)-5-methyl-10,11-dihydro-5Hdibenzo[ a,d]cyclohepten-5,10-imine) binding sites were decreased in CB1−/− mice and that these mice were also less sensitive to the locomotor effects of MK-801. Basal level of both hippocampal and cerebellar [3H]muscimol binding was lower and sensitivity to the hypothermic effects of diazepam and pentobarbital was increased in CB1−/− mice. GABAAα1, β2, and γ2 and NMDA receptor (NR) 1 and 2B subunit mRNA levels were altered in striatum of CB1−/− mice. Our results also showed that [3H]MK-801 binding sites were increased in cerebral cortex and hippocampus after chronic ethanol ingestion only in wild-type mice. Chronic ethanol ingestion did not modify the sensitivity to the locomotor effects of MK-801 in both genotypes. Similarly, chronic ethanol ingestion reduced the number of [3H]muscimol binding sites in cerebral cortex, but not in cerebellum, only in CB1+/+ mice. We conclude that lifelong deletion of CB1 receptors impairs neuroadaptations of both NMDA and GABAA receptors after chronic ethanol exposure and that the endocannabinoid/CB1 receptor system is involved in alcohol dependence. [ABSTRACT FROM AUTHOR]

Binge drinking (BD) in young adults/adolescents can lead to cognitive deficits in the adult probably through neuroinflammation and epigenetic. However, the mode of action of alcohol during the initial exposure is less known while it may be the origin of the deficits seen in adults. Recent studies in adolescent rat hippocampus revealed that loss of memory occurred since the very first exposure to BD with similar mechanisms than those highlighted for longer alcohol exposure. Thus, initiation to BD in the young is responsible for cognitive deficits that will be probably entertained by repeated BD behavior. These kind of data may serve to reinforce the prevention campaigns towards the young population who practice BD., (© 2023 médecine/sciences – Inserm.)

Alcohol use disorder is a devastating illness with a profound health impact, and its development is dependent on both genetic and environmental factors. This disease occurs over time and requires changes in brain gene expression. There is converging evidence suggesting that the epigenetic processes may play a role in the alcohol-induced gene regulations and behavior such as the intervention of DNA methylation and histone acetylation. Histone acetylation, like histone methylation, is a highly dynamic process regulated by two classes of enzymes: histone acetyltransferases and histone deacetylases (HDACs). To date, 18 human HDAC isoforms have been characterized, and based on their sequence homologies and cofactor dependencies, they have been phylogenetically categorized into 4 main classes: classes I, II (a and b), III, and IV. In the brain, expression of the different classes of HDACs varies between cell types and also in their subcellular localization (nucleus and/or cytosol). Furthermore, we recently showed that a single ethanol exposure inhibits HDAC activity and increases both H3 and H4 histone acetylation within the amygdala of rats. In the brain of alcoholic patients, ethanol has been shown to induce histone-related and DNA methylation epigenetic changes in several reward regions involved in reward processes such as hippocampus, prefrontal cortex, and amygdala. We recently demonstrated alteration of histone H3 acetylation levels in several brain regions from the reward circuit of rats made dependent to alcohol after chronic and intermittent exposure to ethanol vapor. In neuronal cell line culture, ethanol was shown to induce HDAC expression. In mouse and rat brain, numerous studies reported epigenetic alterations following ethanol exposure. We also demonstrated that both the expression of genes and the activity of enzymes involved in epigenetic mechanisms are changed after repeated administrations of ethanol in mice sensitized to the motor stimulant effect of ethanol (a model of drug-induced neuroplasticity). Numerous studies have shown that HDAC inhibitors are able to counter ethanol-induced behaviors and the ethanol-induced changes in the levels of HDAC and/or levels of acetylated HDAC. For example, trichostatin A (TSA) treatment caused the reversal of ethanol-induced tolerance, anxiety, and ethanol drinking by inhibiting HDAC activity, thereby increasing histone acetylation in the amygdala of rats. Another study demonstrated that TSA prevented the development of ethanol withdrawal induced anxiety in rats by rescuing deficits in histone acetylation induced by increased HDAC activity in the amygdala. We have demonstrated that treatment with the HDAC inhibitor sodium butyrate blocks both the development and the expression of ethanol-induced behavioral sensitization in mice. In this context, converging evidence indicates that HDAC inhibitors could be useful in counteracting ethanol-induced gene regulations via epigenetic mechanisms, that is, HDAC inhibitors could affect different acetylation sites and may also alter the expression of different genes that could in turn counteract the effect of ethanol. Recent work in rodents has shown that systemic administration of pan HDAC class I and II inhibitors, TSA and N-hydroxy-N-phenyl-octanediamide [SuberoylAnilide Hydroxamic Acid] (SAHA), and of the more selective inhibitor (mainly HDAC1 and HDAC9) MS-275, decrease binge-like alcohol drinking in mice. SAHA selectively reduced ethanol operant self-administration and seeking in rats. Our previous study revealed that MS-275 strongly decreased operant ethanol self-administration in alcohol-dependent rats when administered 30 minutes before the session at the second day of injection. We also demonstrated that intra-cerebro-ventricular infusion of MS-275 increases acetylation of Histone 4 within the nucleus accumbens and the dorsolateral striatum, associated to a decrease in ethanol self-administration by about 75%. MS-275 also diminished both the motivation to consume ethanol (25% decrease), relapse (by about 50%) and postponed reacquisition after abstinence. Both literature and several of our studies strongly support the potential therapeutic interest of targeting epigenetic mechanisms in excessive alcohol drinking and strengthen theinterest of focusing on specific isoforms of histone deacetylases., (© Société de Biologie, 2017.)

A few clinical studies have shown that dual antidepressants (serotonergic (5-HT) and noradrenergic (NE) transporter inhibitors, SNRIs) may be effective in alcoholism treatment. We studied the effect of the dual antidepressant milnacipran on ethanol operant self-administration in acutely withdrawn ethanol-dependent and in -non-dependent Wistar rats, and used fluoxetine and desipramine to dissect both 5-HT and NE components, respectively, in the effect of milnacipran. Milnacipran was also tested for relapse after protracted abstinence and on ethanol-induced (1.0 g/kg) conditioned place preference in control rats and ethanol-induced locomotor sensitization in DBA/2J female mice. Milnacipran dose dependently (5-40 mg/kg) attenuated the increased ethanol self-administration observed during early withdrawal and was more potent in preventing reinstatement in dependent rats after protracted abstinence as compared with non-dependent rats. Desipramine and fluoxetine (10 mg/kg) blocked ethanol self-administration during early withdrawal, and recovery was delayed in dependent animals, indicating a potent effect. Ethanol self-administration was also reduced 1 day after treatment with desipramine and fluoxetine but not with milnacipran. Finally, milnacipran prevented ethanol-induced place preference in ethanol-naive rats and reduced the magnitude of ethanol-induced sensitization associated with a delayed induction in mice. Desipramine (20 mg/kg) countered sensitization development and reduced its expression at 1 week after treatment; fluoxetine (10 mg/kg) reduced sensitization expression. Thus, 5-HT and NE transmissions during sensitization expression may mediate the effect of milnacipran on sensitization induction. These results support that SNRIs may have a potential use in alcoholism treatment.