The title of my talk: Paradox antidepressant effects of alcohol and mechanisms of alcohol instrumentalization

Abstract: Alcohol is a major psychoactive drug in western societies involved in many cultural activities. It was shown that alcohol can be instrumentalized, i.e. used to achieve goals that would be impossible to achieve or require more work load without alcohol use. Alcohol use can serve numerous instrumentalization goals, one of the most important goals being the self-medication for innate or induced psychiatric problems, like for depression and/or anxiety disorders. There is a high comorbidity of depression and alcohol use disorder with bi-directional trajectories. While the neuropharmacology of alcohol is well known, neurobiological mechanisms for alcohol instrumentalization are poorly understood. Together with cholesterol and glycerophospholipids, sphingolipids are the most common lipids in brain membranes. Sphingolipids form lipid rafts and signaling platforms, which are membrane compartments enriched in G-protein-coupled receptors. Acid sphingomyelinase (ASM) hydrolyses sphingomyelin to ceramide and phosphorylcholine and, thus, represents a major regulator of sphingolipid metabolism, which was shown to be involved in emotional behaviour. While a temporary decline in brain ASM activity and ceramide levels are associated with the effective extinction of no longer rewarded behaviour in rats, ASM overexpression of ASM in mice (tgASM) induces depression-like behaviour. We found that it also enhanced consumption of alcohol and the alcohol-deprivation-effects after repeated withdrawal in a free-choice drinking paradigm. ASM hyperactivity facilitates the establishment of the rewarding effects of alcohol. Furthermore, we found that free-choice alcohol drinking, but not forced alcohol exposure, reduces depression-like behaviour selectively in depressed animals by normalization of ASM activity. Using SolariX MALDI-MS slice imaging, we showed that ASM hyperactivity induces sphingolipid and subsequent monoamine transmitter allostasis in the nucleus accumbens. Alcohol drinking restores sphingolipid and monoamine homeostasis selectively in depressed mice. These findings provide the first biological evidence for the instrumentalization of the paradox antidepressant effects of alcohol with the goal to self-medicate and ameliorate behavioural symptoms of a genetically-induced innate depression. We show that alcohol drinking normalises ASM function and re-establishes sphingolipid- and monoamine homeostasis in the nucleus accumbens of depressed mice. Thus, sphingolipid homeostasis emerges as a new mechanism to control depression-alcohol addiction comorbidity.

Bio:

1999-   Diploma in Psychologie, Heinrich-Heine-Universität Düsseldorf

2003-  Dr. rer. nat.; Heinrich-Heine-Universität Düsseldorf

2006- Habilitation and Venia Legendi in Psychologie, Heinrich-Heine-Universität Düsseldorf

1999-2003- Research assistant, Institute of Physiological Psychology/ University of Düsseldorf/ Germany (Prof. J.P. Huston)

2002- Guest scientist;   Department of Psychiatry/ State University of New York/ Syracuse/ USA (Prof. R.J. Carey)

2003 – 2007- Research scientist; Institute of Physiological Psychology/ University of Düsseldorf/ Germany (Prof. J.P. Huston)

2003/2005- Guest scientist;   Primate center/ University of Brasilia/ Brazil (Prof. C. Tomaz)

2007 – 2010- Senior Lecturer in Addiction and Behavioral Neuroscience/ MRC SGDP-Center/ Institute of Psychiatry/ King’s College London/ UK

2010 – Professor of Addiction Medicine (W2), Department of Psychiatry and Psychotherapy, University Clinic/ Erlangen/ Germany

 Main Research Areas

  • Functional genetic of alcohol- and drug-addiction
  • Role of the serotonergic and dopaminergic systems in pathological behaviour
  • Role of monoaminergic systems in pharmacotherapeutic action
  • In-vivo neurochemistry of behaviour
  • Sphingolipids in normal and disturbed behaviour
  • New addictive drugs – Kratom/Mitragynine