The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations

• Published in: Addiction biology Vol. 22; no. 6; pp. 1486 - 1500
• Main Authors: Čupić, Željko, Stanojević, Ana, Marković, Vladimir M., Kolar‐Anić, Ljiljana, Terenius, Lars, Vukojević, Vladana
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-11-2017
• Subjects: Alcohol or ethanol; Alcohol use; Blood levels; blunted HPA axis response; Central Nervous System Depressants - pharmacology; Cholesterol; Cholesterol - metabolism; Computer Simulation; corticotropin‐releasing factor or corticotropin‐releasing hormone; Cortisol; Drug abuse; dynamical systems theory; Ethanol; Ethanol - pharmacology; Gonadal Steroid Hormones - metabolism; HPA axis; Humans; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - drug effects; Hypothalamus; Mathematical models; Medicin och hälsovetenskap; Models, Biological; opioid surfeit; Oscillations; Peptide Hormones - drug effects; Peptide Hormones - metabolism; Pituitary; Pituitary-Adrenal System - drug effects; Steroid hormones; stress; Stress response; opioid surfeit; stress; dynamical systems theory; blunted HPA axis response; HPA axis; corticotropin-releasing factor or corticotropin-releasing hormone; Alcohol or ethanol
• ISSN: 1355-6215; 1369-1600; 1369-1600
• DOI: 10.1111/adb.12409

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.
A stoichiometric model is developed to succinctly describe ethanol effects on neurochemical transformations underlying the hypothalamic‐pituitary‐adrenal (HPA) axis. This enables the investigation of ethanol effects on HPA axis activity with high temporal resolution, where experimental data are scarce. Mathematical modelling shows that ethanol effects on HPA axis activity are complex and dependent on ethanol dose, timing and administration strategy; it enables us to shed light on so far inconclusive experimental results and may help to design further experiments.