Mechanisms of Persistent Neurobiological Changes Following Adolescent Alcohol Exposure: NADIA Consortium Findings

Abstract

The Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium has focused on the impact of adolescent binge drinking on brain development, particularly on effects that persist into adulthood. Adolescent binge drinking is common, and while many factors contribute to human brain development and alcohol use during adolescence, animal models are critical for understanding the specific consequences of alcohol exposure during this developmental period and the underlying mechanisms. Using adolescent intermittent ethanol (AIE) exposure models, NADIA investigators identified long‐lasting AIE‐induced changes in adult behavior that are consistent with observations in humans, such as increased alcohol drinking, increased anxiety (particularly social anxiety), increased impulsivity, reduced behavioral flexibility, impaired memory, disrupted sleep, and altered responses to alcohol. These behavioral changes are associated with multiple molecular, cellular, and physiological alterations in the brain that persist long after AIE exposure. At the molecular level, AIE results in long‐lasting changes in neuroimmune/trophic factor balance and epigenetic–microRNA (miRNA) signaling across glia and neurons. At the cellular level, AIE history is associated in adulthood with reduced expression of cholinergic, serotonergic, and dopaminergic neuron markers, attenuated cortical thickness, decreased neurogenesis, and altered dendritic spine and glial morphology. This constellation of molecular and cellular adaptations to AIE likely contributes to observed alterations in neurophysiology, measured by synaptic physiology, EEG patterns, and functional connectivity. Many of these AIE‐induced brain changes replicate findings seen in postmortem brains of humans with alcohol use disorder (AUD). NADIA researchers are now elucidating mechanisms of these adaptations. Emerging data demonstrate that exercise, antiinflammatory drugs, anticholinesterases, histone deacetylase inhibitors, and other pharmacological compounds are able to prevent (administered during AIE) and/or reverse (given after AIE) AIE‐induced pathology in adulthood. These studies support hypotheses that adolescent binge drinking increases risk of adult hazardous drinking and influences brain development, and may provide insight into novel therapeutic targets for AIE‐induced neuropathology and AUDs.

Time Course of Blood and Brain Cytokine/Chemokine Levels Following Adolescent Alcohol Exposure and Withdrawal in Rats

“…Alcohol use and binge drinking among adolescents are associated with increased health risks (Miller et al, ), and enhanced propensity for the development of alcohol use disorders (AUDs) in later life (Dawson et al, ; Ehlers et al, ; Hingson et al, ; Johnston et al, ). Adolescence is a critical period for the onset of binge drinking, and alcohol exposure during this time has been demonstrated to produce persistent alterations in neural development, behavior, and drinking levels in adulthood in several rodent models (Alaux‐Cantin et al, ; Crews et al, ; Crews et al, ; Maldonado‐Devincci et al, ; Spear, ; Spear, ; Spear and Swartzwelder, ).…”

Adolescent intermittent ethanol exposure induces sex-dependent divergent changes in ethanol drinking and motor activity in adulthood in C57BL/6J mice

“…In previous rodent studies, the impact of adolescent intermittent ethanol (AIE) exposure on adult drinking patterns and behaviors has varied. AIE has regularly been shown to increase alcohol drinking, social anxiety, and loss of behavioral flexibility in adulthood in rats (Crews et al 2019;Gilpin, ALCOHOL, ADOLESCENCE, SEX DIFFERENCES, CONSUMPTION 5 Karanikas, and Richardson 2012; Maldonado-Devincci et al 2010;Maldonado-Devincci, Badanich, and Kirstein 2010), while others have found no change in alcohol consumption following adolescent ethanol exposure (Nentwig et al, 2019;Slawecki and Betancourt, 2002).…”

“…Several models of AIE exposure have been used in both rats and mice, including voluntary consumption in geneticallybred mouse and rat strains, forced gavage exposure, intermittent intraperitoneal injections, forced ethanol consumption with only one bottle of ethanol presented, drinking in the dark, etc. (Acheson et al, 2013;Crews et al, 2019;Gilpin et al, 2012;Maldonado-Devincci et al, 2010a;Miller et al, 2017;Slawecki and Betancourt, 2002;Thiele and Navarro, 2014).…”

Adolescent Intermittent Ethanol Increases the Sensitivity to the Reinforcing Properties of Ethanol and the Expression of Select Cholinergic and Dopaminergic Genes within the Posterior Ventral Tegmental Area

“…Adolescent alcohol exposure can disrupt this normal remodeling of cortical and limbic regions (Spear, ). Replicable effects of adolescent alcohol consumption on the adult brain include a hyperdopaminergic response to stimuli, reduction in choline acetyltransferase (ChAT), alterations in neuroimmune function, and nonspecific modulation of epigenetic factors (Crews et al., ; Mulholland et al., ; Spear and Swartzwelder, ).…”

“…The consistent findings that AIE exposure results in persistent reduction in ChAT in multiple brain regions (cf. Crews et al., ) would suggest an up‐regulation in cholinergic receptors to maintain functional homeostasis. Up‐regulation of cholinergic receptors would enhance the propensity of DA neurons to respond to EtOH and other drugs of abuse that act on those receptors.…”