Adolescent Alcohol Exposure: Burden of Epigenetic Reprogramming, Synaptic Remodeling, and Adult Psychopathology

Abstract

Adolescence represents a crucial phase of synaptic maturation characterized by molecular changes in the developing brain that shape normal behavioral patterns. Epigenetic mechanisms play an important role in these neuromaturation processes. Perturbations of normal epigenetic programming during adolescence by ethanol can disrupt these molecular events, leading to synaptic remodeling and abnormal adult behaviors. Repeated exposure to binge levels of alcohol increases the risk for alcohol use disorder (AUD) and comorbid psychopathology including anxiety in adulthood. Recent studies in the field clearly suggest that adolescent alcohol exposure causes widespread and persistent changes in epigenetic, neurotrophic, and neuroimmune pathways in the brain. These changes are manifested by altered synaptic remodeling and neurogenesis in key brain regions leading to adult psychopathology such as anxiety and alcoholism. This review details the molecular mechanisms underlying adolescent alcohol exposure-induced changes in synaptic plasticity and the development of alcohol addiction-related phenotypes in adulthood.

Keywords: adolescence; anxiety; binge drinking; dendritic spines; epigenetics; neurogenesis; neuroinflammation.

Figure 1

Alcohol use disorder is characterized by the classical pattern of addiction, namely a cycle from a state of euphoria during alcohol intoxication to that of dysphoria during alcohol withdrawal to one of craving in the absence of acute intoxication. Craving, with or without withdrawal symptoms, is characterized by preoccupation with obtaining alcohol and anticipation of alcohol use, leading to relapse and a return to the intoxicated state. Certain individual clinical characteristics or psychosocial factors can exacerbate this cycle, driving alcohol use and addiction. For example, impulsivity renders an individual more sensitive to the immediate, rewarding effects of alcohol intake, with minimization of any longer term negative consequences, driving alcohol intake. Adolescence alone is characterized by an increased sensitivity to the rewarding effects of alcohol with a protection from the negative effects relative to aged counterparts, driving alcohol intake for this group. Adolescence is often characterized by impulsivity and together these characteristics facilitate alcohol intake. Also they require higher doses of ethanol to produce anxiolysis and sedation. Withdrawal from alcohol can both induce anxiety or depression symptoms and be worsened by comorbid mood disorders. Anxiety or depression can separately be exacerbated by other stressors, acute or chronic, and has been shown to be increased over the long term by environmental insults during development (early adversity). Stress and/or mood decompensation can also, in the absence of withdrawal dysphoria, directly stimulate craving and relapse, driving the cycle of addiction at either stage.

Figure 2

Hypothetical model of epigenetic reprogramming by alcohol during adolescence. Adolescence is characterized by widespread changes in the developing brain. These changes are underpinned by molecular processes such as epigenetic programming, which turn specific genetic programs on to mediate cell fate determination, axonal outgrowth, dendrite formation and neuronal maturation. These processes, in turn, affect synaptic plasticity and neurocircuit function to shape normal behaviors. However, developmental perturbation by early life and/or binge alcohol exposure during this critical period can produce persistent effects on chromatin remodeling, synaptic plasticity, and brain function in adulthood, leading to alcohol use disorders (AUDs) and comorbid psychopathology including anxiety and depression. Adult exposure of alcohol can also disturb chromatin remodeling and plasticity, but some of these effects may not be long-lasting.

Figure 3

Molecular and cellular signaling mechanisms in the brain leading to altered synaptic plasticity in adulthood after adolescent alcohol exposure. Adolescent binge alcohol exposure exerts effects in the brain long after alcohol has left the system. For example, adolescent alcohol causes a long-lasting decrease in key synaptic plasticity-related genes including cyclic AMP response element binding protein (CREB) pathway (CREB binding protein), brain-derived neurotrophic factor (BDNF), and activity-regulated cytoskeleton-associated protein (Arc). At the same time, adolescent binge alcohol exposure increases neuroimmune mediators including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), high mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4). The increase in neuroimmune factors and decrease in neurotrophic factors may be responsible for molecular imbalance in the adult brain that is mediated by increased microglial activation and decreased synaptic plasticity, leading to an increased risk for alcohol use disorders (AUDs) and related psychopathology such as anxiety.