title: The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations.
abstract: Stress and alcohol use are interrelated-stress contributes to the initiation and upholding of alcohol use and alcohol use alters the way we perceive and respond to stress. Intricate mechanisms through which ethanol alters the organism's response to stress remain elusive. We have developed a stoichiometric network model to succinctly describe neurochemical transformations underlying the stress response axis and use numerical simulations to model ethanol effects on complex daily changes of blood levels of cholesterol, 6 peptide and 8 steroid hormones. Modelling suggests that ethanol alters the dynamical regulation of hypothalamic-pituitary-adrenal (HPA) axis activity by affecting the amplitude of ultradian oscillations of HPA axis hormones, which defines the threshold with respect to which the response to stress is being set. These effects are complex-low/moderate acute ethanol challenge (<8 mM) may reduce, leave unaltered or increase the amplitude of ultradian cortisol (CORT) oscillations, giving rise to an intricate response at the organism level, offering also a potential explanation as to why apparently discordant results were observed in experimental studies. In contrast, high-dose acute ethanol challenge (>8 mM) increases instantaneous CORT levels and the amplitude of ultradian CORT oscillations in a dose-dependent manner, affecting the HPA axis activity also during the following day(s). Chronic exposure to ethanol qualitatively changes the HPA axis dynamics, whereas ethanol at intoxicating levels shuts down this dynamic regulation mechanism. Mathematical modelling gives a quantitative biology-based framework that can be used for predicting how the integral HPA axis response is perturbed by alcohol.
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, University of Belgrade, Belgrade, Serbia.
authors.forename: Željko
authors.initials: Ž
authors.lastname: Čupić
authors.affiliation: Faculty of Physical Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Stanojević
authors.affiliation: Faculty of Physical Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Marković
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, University of Belgrade, Belgrade, Serbia.|Faculty of Physical Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Kolar-Anić
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Terenius
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vladana
authors.initials: V
authors.lastname: Vukojević
mesh_terms: D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D003198:Computer Simulation; D000431:Ethanol / Q000494:pharmacology*; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008954:Models, Biological; D036361:Peptide Hormones / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects*
chemical_list: D002492:Central Nervous System Depressants; D012739:Gonadal Steroid Hormones; D036361:Peptide Hormones; D000431:Ethanol; D002784:Cholesterol
keywords: Alcohol or ethanol; HPA axis; blunted HPA axis response; corticotropin-releasing factor or corticotropin-releasing hormone; dynamical systems theory; opioid surfeit; stress