Adolescent intermittent ethanol (AIE) produces lasting, sex-specific changes in rat body fat independent of changes in white blood cell composition

Early initiation of alcohol use during adolescence, and adolescent binge drinking are risk factors for the development of alcohol use disorder later in life. Adolescence is a time of rapid sex-dependent neural, physiological, and behavioral changes as well as a period of heightened vulnerability to many effects of alcohol. The goal of the present studies was to determine age-related changes in blood (leukocyte populations) and body composition across adolescence and early adulthood, and to investigate whether adolescent intermittent ethanol (AIE) exposure would alter the trajectory of adolescent development on these broad physiological parameters. We observed significant ontogenetic changes in leukocyte populations that were mirrored by an age-related increase in cytokine expression among mixed populations of circulating leukocytes. Despite these developmental changes, AIE did not significantly alter overall leukocyte numbers or cytokine gene expression. However, AIE led to sex-specific changes in body fat mass and fat percentage, with AIE-exposed male rats showing significantly decreased fat levels and female rats showing significantly increased fat levels relative to controls. These changes suggest that while AIE may not alter overall leukocyte levels, more complex phenotypic changes in leukocyte populations could underlie previously reported differences in cytokine expression. Coupled with long-term shifts in adipocyte levels, this could have long-lasting effects on innate immunity and the capacity of individuals to respond to later immunological and physiological threats

Highlight Article: Conditioning the neuroimmune response to ethanol using taste and environmental cues in adolescent and adult rats

© 2019 by the Society for Experimental Biology and Medicine. Our work in adult Sprague-Dawley rats has shown elevation of the cytokine Interleukin (IL)-6 in the hippocampus and amygdala following acute and repeated binge-like doses of ethanol during intoxication. Previously, we have shown that in adults, the central IL-6 response to a sub-threshold dose of ethanol was sensitized by repeated pairings of ethanol as an unconditioned stimulus (US) with an odor conditioned stimulus (CS).In the present studies, acute ethanol exposure (4 g/kg intraperitoneal) was paired with a combined odor and taste cue using a single trial learning procedure, after which rats were tested for conditioned effects of the CS on neuroimmune gene expression. We found that IL-6 was significantly elevated in the amygdala based on exposure to the CS after just one CS–US pairing in young adolescent rats (age P32–40), an effect that was more modest in young adults (P72–80). These data indicate that, despite a normal disposition toward a blunted neuroimmune response to ethanol, adolescents were more sensitive than adults to forming learned associations between ethanol’s neuroimmune effects and conditioned stimuli. Given the emergent role of the immune system in alcoholism, such as regulating ethanol intake, these ethanol-induced conditioned effects on cytokine levels may contribute to our understanding of the unique attributes that make adolescence a time period of vulnerability in the development of later alcohol abuse behaviors. Impact statement: A combined odor and taste cue was paired with a binge-like ethanol exposure (4 g/kg intraperitoneal) using a single-trial learning paradigm. Re-exposure to the CS alone was sufficient to evoke a conditioned Interleukin (IL)-6 elevation in the amygdala in adolescents, an effect that was not observed in young adults. This demonstrates a particular sensitivity of adolescents to alcohol-associated cues and neuroimmune learning, whereas prior work indicated that adults require multiple pairings of ethanol to the CS in order to achieve a conditioned amygdala IL-6 response. While the role of immune conditioning has been studied in other drugs of abuse, these findings highlight a previously unknown aspect of alcohol-related learning. Given the emergent importance of the neuroimmune system in alcohol abuse, these findings may be important for understanding cue-induced reinstatement of alcohol intake among problem drinkers

Conditioning the neuroimmune response to ethanol using taste and environmental cues in adolescent and adult rats

Our work in adult Sprague-Dawley rats has shown elevation of the cytokine Interleukin (IL)-6 in the hippocampus and amygdala following acute and repeated binge-like doses of ethanol during intoxication. Previously, we have shown that in adults, the central IL-6 response to a sub-threshold dose of ethanol was sensitized by repeated pairings of ethanol as an unconditioned stimulus (US) with an odor conditioned stimulus (CS).In the present studies, acute ethanol exposure (4 g/kg intraperitoneal) was paired with a combined odor and taste cue using a single trial learning procedure, after which rats were tested for conditioned effects of the CS on neuroimmune gene expression. We found that IL-6 was significantly elevated in the amygdala based on exposure to the CS after just one CS–US pairing in young adolescent rats (age P32–40), an effect that was more modest in young adults (P72–80). These data indicate that, despite a normal disposition toward a blunted neuroimmune response to ethanol, adolescents were more sensitive than adults to forming learned associations between ethanol’s neuroimmune effects and conditioned stimuli. Given the emergent role of the immune system in alcoholism, such as regulating ethanol intake, these ethanol-induced conditioned effects on cytokine levels may contribute to our understanding of the unique attributes that make adolescence a time period of vulnerability in the development of later alcohol abuse behaviors. Impact statement: A combined odor and taste cue was paired with a binge-like ethanol exposure (4 g/kg intraperitoneal) using a single-trial learning paradigm. Re-exposure to the CS alone was sufficient to evoke a conditioned Interleukin (IL)-6 elevation in the amygdala in adolescents, an effect that was not observed in young adults. This demonstrates a particular sensitivity of adolescents to alcohol-associated cues and neuroimmune learning, whereas prior work indicated that adults require multiple pairings of ethanol to the CS in order to achieve a conditioned amygdala IL-6 response. While the role of immune conditioning has been studied in other drugs of abuse, these findings highlight a previously unknown aspect of alcohol-related learning. Given the emergent importance of the neuroimmune system in alcohol abuse, these findings may be important for understanding cue-induced reinstatement of alcohol intake among problem drinkers.Fil: Gano, Anny. University Of Binghamton. Departament Of Psychology; Estados UnidosFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Doremus-Fitzwater, Tamara L.. University Of Binghamton. Departament Of Psychology; Estados UnidosFil: Barney, Thaddeus M.. University Of Binghamton. Departament Of Psychology; Estados UnidosFil: Vore, Andrew S.. University Of Binghamton. Departament Of Psychology; Estados UnidosFil: Deak, Terrence. University Of Binghamton. Departament Of Psychology; Estados Unido

Presentation1_Adolescent intermittent ethanol (AIE) produces lasting, sex-specific changes in rat body fat independent of changes in white blood cell composition.PPTX

Early initiation of alcohol use during adolescence, and adolescent binge drinking are risk factors for the development of alcohol use disorder later in life. Adolescence is a time of rapid sex-dependent neural, physiological, and behavioral changes as well as a period of heightened vulnerability to many effects of alcohol. The goal of the present studies was to determine age-related changes in blood (leukocyte populations) and body composition across adolescence and early adulthood, and to investigate whether adolescent intermittent ethanol (AIE) exposure would alter the trajectory of adolescent development on these broad physiological parameters. We observed significant ontogenetic changes in leukocyte populations that were mirrored by an age-related increase in cytokine expression among mixed populations of circulating leukocytes. Despite these developmental changes, AIE did not significantly alter overall leukocyte numbers or cytokine gene expression. However, AIE led to sex-specific changes in body fat mass and fat percentage, with AIE-exposed male rats showing significantly decreased fat levels and female rats showing significantly increased fat levels relative to controls. These changes suggest that while AIE may not alter overall leukocyte levels, more complex phenotypic changes in leukocyte populations could underlie previously reported differences in cytokine expression. Coupled with long-term shifts in adipocyte levels, this could have long-lasting effects on innate immunity and the capacity of individuals to respond to later immunological and physiological threats.</p

Table1_Adolescent intermittent ethanol (AIE) produces lasting, sex-specific changes in rat body fat independent of changes in white blood cell composition.DOCX

Early initiation of alcohol use during adolescence, and adolescent binge drinking are risk factors for the development of alcohol use disorder later in life. Adolescence is a time of rapid sex-dependent neural, physiological, and behavioral changes as well as a period of heightened vulnerability to many effects of alcohol. The goal of the present studies was to determine age-related changes in blood (leukocyte populations) and body composition across adolescence and early adulthood, and to investigate whether adolescent intermittent ethanol (AIE) exposure would alter the trajectory of adolescent development on these broad physiological parameters. We observed significant ontogenetic changes in leukocyte populations that were mirrored by an age-related increase in cytokine expression among mixed populations of circulating leukocytes. Despite these developmental changes, AIE did not significantly alter overall leukocyte numbers or cytokine gene expression. However, AIE led to sex-specific changes in body fat mass and fat percentage, with AIE-exposed male rats showing significantly decreased fat levels and female rats showing significantly increased fat levels relative to controls. These changes suggest that while AIE may not alter overall leukocyte levels, more complex phenotypic changes in leukocyte populations could underlie previously reported differences in cytokine expression. Coupled with long-term shifts in adipocyte levels, this could have long-lasting effects on innate immunity and the capacity of individuals to respond to later immunological and physiological threats.</p