Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood

Abstract

Binge drinking is common during adolescence and can lead to the development of psychiatric disorders, including alcoholism in adulthood. Here, the role and persistent effects of histone modifications during adolescent intermittent ethanol (AIE) exposure in the development of anxiety and alcoholism in adulthood were investigated. Rats received intermittent ethanol exposure during post-natal days 28-41, and anxiety-like behaviors were measured after 1 and 24 hrs of the last AIE. The effects of AIE on anxiety-like and alcohol-drinking behaviors in adulthood were measured with or without treatment with the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). Amygdaloid brain regions were collected to measure HDAC activity, global and gene-specific histone H3 acetylation, expression of brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated (Arc) protein and dendritic spine density (DSD). Adolescent rats displayed anxiety-like behaviors after 24 hrs, but not 1 hr, of last AIE with a concomitant increase in nuclear and cytosolic amygdaloid HDAC activity and HDAC2 and HDAC4 levels leading to deficits in histone (H3-K9) acetylation in the central (CeA) and medial (MeA), but not in basolateral nucleus of amygdala (BLA). Interestingly, some of AIE-induced epigenetic changes such as, increased nuclear HDAC activity, HDAC2 expression, decreased global histone acetylation persisted in adulthood. In addition, AIE decreased BDNF exon I, IV and Arc promoter specific histone H3 acetylation that was associated with decreased BDNF, Arc expression and DSD in the CeA and MeA during adulthood. AIE also induced anxiety-like behaviors and enhanced ethanol intake in adulthood, which was attenuated by TSA treatment via normalization of deficits in histone H3 acetylation of BDNF and Arc genes. These novel results indicate that AIE induces long-lasting effects on histone modifications and deficits in synaptic events in the amygdala, which are associated with anxiety-like and alcohol drinking behaviors in adulthood.

A Critical Role of Brain-Derived Neurotrophic Factor in Alcohol Consumption

“…Interestingly, infusion of HDAC2 siRNA in the CeA of alcohol-preferring rats was able to correct the deficits in BDNF levels and attenuated excessive alcohol drinking behaviors. Together, these studies support the notion that BDNF gates alcohol drinking behaviors (1, 3–6, 9, 10). …”

“…The epigenetic regulation of BDNF also plays a crucial role in early life adversity, such as adolescent alcohol exposure, which produces a persistent decrease in the expression of BDNF and Arc and dendritic spines in the CeA and MeA due to HDAC2-mediated deficits in histone acetylation in adulthood. These changes are associated with adolescent alcohol exposure-induced anxiety and alcohol drinking behaviors in adulthood that are attenuated by HDAC inhibitor treatment (10). As discussed by Warnault et al (1), low blood levels of BDNF have been associated with the severity of alcoholism in clinical populations.…”

The effects of gonadectomy and binge-like ethanol exposure during adolescence on open field behaviour in adult male rats

“…The open field activity scores for most of the tests were significantly altered with early binge drinking in the Intact rats,GX-TP and GX rats, and our results supported studies showing an alcohol-induced increase in anxiety-like behaviours in male rats. Similar results have also shown,in the LDB and EPM behavioural tests, that adolescent intermittent ethanol induced anxiety-like behaviours in adulthood [29]. These results indicated that binge drinking produced anxiety-like behaviours during adolescence that persisted into adulthood.…”

Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure

“…Intermittent access to drugs of abuse results in altered behavioral responses in comparison to continued administration (Marec et al, 2011), and intermittent exposure administration procedures are commonly used to study alcohol effects (Pandey et al, 2015; Risher et al, 2015). Having assessed adaptations in cytokine responses that occur with repeated once-daily exposure to ethanol, we next examined whether the schedule of ethanol exposure would impact cytokine expression patterns in the CNS.…”