Students
Aleksandr Petrov
MSc Molecular Biophysics / Saint Petersburg State University
PharMetrX Research+ Program
PhD student year: 2024
University of PhD: University of Potsdam
Supervisor: Prof. Wilhelm Huisinga
Co-Supervisor: Prof. Charlotte Kloft
Mentoring I-Partner: Merck
PhD Project
Mathematical modelling of cognition & behavior in the context of therapeutic intervention in addiction
One of the major risk factors for global mortality and disability is the use of alcohol, tobacco, and illicit drugs. Despite the growing understanding of individual factors contributing to the initiation and maintenance of substance use disorders, the disease trajectories of losing and regaining control over drug intake (ReCoDe) remain insufficiently described. My research is conducted in collaboration with the cognitive science department at the University of Potsdam, who are part of the ReCoDe consortium, which aims to: (i) identify triggers and modifying factors that modulate the trajectories of losing and regaining control over drug consumption under real-life conditions; (ii) study the underlying behavioral, cognitive, and neurobiological mechanisms; and (iii) implicate mechanism-based interventions.
My PhD project focuses on studying the trajectories of losing and regaining control in individuals with alcohol use disorder (AUD). As part of this research, various behavioral data were collected over a year in a clinical study from participants with AUD in Germany, including changes in mood, alcohol cravings, stress levels, and ultimately the amount of alcohol consumed. The goal of my research is to link alcohol intake and pharmacokinetics with behavioral changes via also modelling relevant biomarkers like dopamine in the central nervous system (CNS), the primary site of alcohol/ethanol action.
Project 1 focuses on alcohol and its distribution within CNS. When alcohol is consumed, ethanol is distributed throughout the body, penetrating various parts of the nervous system, such as brain tissue and cerebrospinal fluid. Once ethanol enters the brain tissue, it affects human cognitive and behavioral functions at certain dosages. In this project, I aim to describe changes in the active concentration of ethanol in brain tissue and link it to biomarkers of behavioral and cognitive changes. To achieve this, I will use mechanistic modeling approaches, specifically Physiologically Based Pharmacokinetic (PBPK) modeling, with a focus on the detailed distribution of ethanol in different parts of the CNS. The use of PBPK modeling in this project provides an opportunity to mechanistically account for active metabolites of ethanol, as well as the influence of the type of alcoholic beverage consumed (such as beer, wine, whiskey, etc.) on ethanol distribution. Furthermore, the developed PBPK framework can later be used to study the distribution of other substances of abuse, such as nicotine and caffeine.
Project 2 will focus on cognitive and behavioral biomarkers influenced by ethanol action. In this study, dopamine levels will be considered as a surrogate for mood. It is known that ethanol increases extracellular dopamine concentrations in the ventral tegmental area (VTA) of the brain, and that this dopamine increase is associated with heightened arousal and corresponding mood changes. A mathematical model describing the effect of ethanol on dopamine is therefore necessary. Thus, in this project, I plan to complement the PBPK CNS ethanol model developed in Project 1 with a description of the dopaminergic cycle and establish the relationship between ethanol in the brain and extracellular dopamine in the VTA. As a result, this project will produce a Quantitative Systems Pharmacology (QSP) model describing changes in extracellular dopamine concentrations in the VTA in response to alcohol consumption.
Finally, Project 3 aims to establish a link between the developed PBPK/QSP model and the behavioral data collected in the study of AUD within the ReCoDe consortium. As noted above, the trajectories of losing and regaining control over drug intake remain poorly understood. To enable the PBPK/QSP model to shed light on these trajectories, various social factors associated with changes in alcohol consumption, as well as processes accompanying the development of addiction, must be accounted for. Based on the developed model, a reward-mediated learning model for addiction will be developed, which will allow not only to describe the development of addiction within the ReCoDe study but also to predict various new scenarios of addiction development. This could significantly aid in understanding the behavioral, cognitive, and neurobiological mechanisms of addiction.
Publications
Please see the list of all publications and PhD theses.
Education
- 03/2024: Entering PharMetrX
- 08/2021-07/2023: Pharmacometrician at GEROPHARM R&D Center, Saint Petersburg, Russia
- 09/2020–06/2021: One-year training program: Algorithmic Bioinformatics at Bioinformatics Institute, Russia
- 09/2019–06/2021: M.Sc. Molecular Biophysics at Saint Petersburg State University, Russia
- 09/2014–06/2019: B.Sc. Physics at Saint Petersburg State University, Russia