Vladana Vukojevic's research group
Experimental alcohol- and drug dependence research
Substance dependence/abuse is a complex neuropsychiatric disorder of multifaceted etiology, where biological and environmental factors play a significant role. Our research focuses on two important biological factors underlying the development of substance dependence/abuse, the genetic background and signal transduction in the Central Nervous System (CNS).
Genetic predisposition remains the single most important risk factor for many neuropsychiatric disorders. To study the role of genetic and epigenetic backgrounds in the development of neuropsychiatric disorders, we have gathered relevant information and material from two large patient cohorts diagnosed with schizophrenia and with alcoholism. Patient material in the HUBIN project is also pooled with material from populations in and outside of Scandinavia to reach a sufficient statistical significance for genotyping. Patient records and material from about 300 sibling pairs diagnosed with alcoholism is assembled in the Genes and Alcohol biobank and presently used to study the interplay of genetic and epigenetic mechanisms in alcohol abuse/dependence.
Signal transduction is crucial for understanding the development of substance dependence/abuse. Alcohol/drug-induced changes in cell surface receptor function are among the first steps in a cascade of events that ultimately leads to remodeling of cellular signaling in the brain and the neuroendocrine system. Qualitative differences in signaling dynamics at the organism level are being reflected through qualitative changes in the behavior of an individual, such as transition from voluntary to compulsory alcohol/drugs seeking and use.
Our studies at the cellular level focus on G-protein coupled receptors (GPCRs), and opioid receptor function in particular. In order to understand how opioid receptor-mediated signaling is perturbed by substances of abuse, we use functional Fluorescence Microscopy Imaging (fFMI), a multiplexed approach by high-resolution fluorescence microscopy imaging and fluorescence correlation spectroscopy. This approach allows us to visualize in live cells sparse fluorescently-tagged opioid receptors, measure their local surface density and quantitatively characterize the kinetics of their interactions with other molecules with single-molecule sensitivity.
To understand the complex hierarchical organization of opioid signaling pathways and their integration at the organism level in the Hypothalamus-Pituitary-Adrenal (HPA) axis, we develop stoichiometric models of this dynamical network that is the main regulator of the neuroendocrine system function. We use mathematical modeling to emulate changes in the concentration of steroid and peptide hormones that comprise the HPA axis and use approaches from dynamical systems theory to analyze how alcohol/substances of abuse affect the dynamics of this regulatory network. Using dynamical systems theory approach to neuropsychiatric diseases, our goal is to understand how qualitative changes in the neuroendocrine system dynamics occur under the effect of alcohol/drugs and how such changes, when persistent, lead to the disruption of dynamical control mechanisms and eventually to the development of common neuropsychiatric diseases, such as alcohol/drug dependence/abuse.
- Genetic risk factors for schizophrenia and addiction
- Functional fluorescence imaging of molecular dynamics in the living cell
- Dynamic nanotechnology for the study of cells and biosurfaces
- Understanding chronic pain and new druggable targets: Focus on glial-opioid receptor interface
- Mathematical Modeling of Neuroendocrine Signaling Network Dynamics
- Molecular imaging in the pathology of Alzheimer’s disease
Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat-Experimental observations and mathematical modeling.
Abulseoud OA, Ho MC, Choi DS, Stanojević A, Čupić Ž, Kolar-Anić L, et al
PLoS ONE 2017 ;12(5):e0177551
The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations.
Čupić Ž, Stanojević A, Marković VM, Kolar-Anić L, Terenius L, Vukojević V
Addict Biol 2017 Nov;22(6):1486-1500
Nanoscale effects of ethanol and naltrexone on protein organization in the plasma membrane studied by photoactivated localization microscopy (PALM).
Tobin SJ, Cacao EE, Hong DW, Terenius L, Vukojevic V, Jovanovic-Talisman T
PLoS ONE 2014 ;9(2):e87225
Ethanol alters opioid regulation of Ca(2+) influx through L-type Ca(2+) channels in PC12 cells.
Gruol DL, Nelson TE, Hao C, Michael S, Vukojevic V, Ming Y, et al
Alcohol. Clin. Exp. Res. 2012 Mar;36(3):443-56
Quantitative single-molecule imaging by confocal laser scanning microscopy.
Vukojevic V, Heidkamp M, Ming Y, Johansson B, Terenius L, Rigler R
Proc. Natl. Acad. Sci. U.S.A. 2008 Nov;105(47):18176-81
Mu-opioid receptor activation in live cells.
Vukojević V, Ming Y, D'Addario C, Hansen M, Langel U, Schulz R, et al
FASEB J. 2008 Oct;22(10):3537-48
Ethanol/naltrexone interactions at the mu-opioid receptor. CLSM/FCS study in live cells.
Vukojević V, Ming Y, D'Addario C, Rigler R, Johansson B, Terenius L
PLoS ONE 2008 ;3(12):e4008