title: Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise.
abstract: Serotonergic neurons of the raphe nucleus regulate sleep, mood, endocrine function, and other processes that mature during adolescence. Alcohol abuse and binge drinking are common during human adolescence. We tested the novel hypothesis that adolescent intermittent ethanol exposure would alter the serotonergic system that would persist into adulthood. Using a Wistar rat model of adolescent intermittent ethanol (AIE; 5.0g/kg, i.g., 2-day on/2-day off from postnatal day [P]25 to P55), we found a loss of dorsal raphe nucleus (DRN) serotonin (5-HT)-immunoreactive (+IR) neurons that persisted from late adolescence (P56) into adulthood (P220). Hypothalamic and amygdalar DRN serotonergic projections were reduced following AIE. Tryptophan hydroxylase 2, the rate-limiting 5-HT synthesizing enzyme, and vesicular monoamine transporter 2, which packages 5-HT into synaptic vesicles, were also reduced in the young adult midbrain following AIE treatment. Adolescent intermittent ethanol treatment increased expression of phosphorylated (activated) NF-κB p65 as well as markers of microglial activation (i.e., Iba-1 and CD11b) in the adult DRN. Administration of lipopolysaccharide to mimic AIE-induced innate immune activation reduced 5-HT+IR and increased phosphorylated NF-κB p65+IR similar to AIE treatment. Voluntary exercise during adolescence through young adulthood blunted microglial marker and phosphorylated NF-κB p65+IR, and prevented the AIE-induced loss of 5-HT+IR neurons in the DRN. Together, these novel data reveal that AIE reduces 5-HT+IR neurons in the adult DRN, possibly through an innate immune mechanism, which might impact adult cognition, arousal, or reward sensitivity. Further, exercise prevents the deleterious effects of AIE on the serotonergic system.
authors.affiliation: The Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: rvetreno@email.unc.edu.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Vetreno
authors.affiliation: The Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yesha
authors.initials: Y
authors.lastname: Patel
authors.affiliation: The Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Urvi
authors.initials: U
authors.lastname: Patel
authors.affiliation: The Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: T Jordan
authors.initials: TJ
authors.lastname: Walter
authors.affiliation: The Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Fulton T
authors.initials: FT
authors.lastname: Crews
mesh_terms: D000437:Alcoholism / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009474:Neurons / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D012701:Serotonin; D000431:Ethanol
keywords: Adolescence; Alcohol; Binge drinking; Development; Microglia; Serotonin