Projects

Worldwide two billion people drink regularly alcohol. A major health consequence is alcohol addiction that is characterized by chronic relapses. Preventing relapse is the main Treatment goal. Current pharmacological treatments have limited effectiveness and there is a large heterogeneity in the treatment response. Better treatments and prediction approaches that can be easily translated into the clinical situation are warranted. In our e:Med funded SysMedAlcoholism consortium we have identified early warning signs and drinking profiles that predict future relapse behavior and treatment response of clinically used anti-relapse medications. We have also identified in a multi-omics approach alterations in the oxytocin (OXY) system in alcoholic patients suggesting OXY as a candidate medication to reduce relapse. Here our Goals are (i) to demonstrate the clinical applicability of OXY and (ii) to computationally predict elapse and identify treatment responsive individuals. For the demonstration of the clinical applicability of OXY, we propose a new module in the drug development process, namely a preclinical multicenter placebo controlled trial in rats with a step-wise translation into a naturalistic pilot trial with ambulatory assessment in alcoholic patients. As a comparator, we will use datasets from previous trials where we tested placebo vs acamprosate – which is a clinically effective medication. These data will be contrasted with a 3-arm design in male and female alcohol addicted rats where two doses of intranasally applied OXY will be tested against placebo in a well-validated rat model for alcohol addiction. From this preclinical trial we will obtain intensive longitudinal data (ILD) sets on drinking and activity. Using new in silico approaches we will then be able to identify early warnings signs and drinking clusters for relapse and OXY treatment responsive individuals. This preclinical work will guide our naturalistic Trial with ambulatory assessment in alcoholic patients.

Drug-associated conditioned stimuli (CS) can induce craving and precipitate relapse behavior. Therefore, disruption of these learned associations may reduce the subsequent risk of relapse. Within the context of SFB636 we are interested in extinction and reconsolidation processes of these CS-drug memories and have conducted in the 2nd funding period of SFB636 several extinction studies demonstrating the importance of glutamate receptors in extinguishing CS-drug associations and subsequent relapse behavior. However, the clinical efficacy of extinction-based therapies in drug addicts or alcohol-dependent patients might be limited due to the fact that a persistent weakening of a CS-drug association seems hardly to be achieved. Although some patients do benefit, many relapse due to cue-, drug priming-, or stress-induced reinstatement of previous drug-seeking behavior. Alternatively, disruption of reconsolidation processes can be used to interfere with CS-drug associations. In the process of reconsolidation, a retrieved memory transiently returns into a labile state and requires new protein synthesis to persist further. During this labile state, the memory is amenable to enhancement or disruption. We have now shown for the first time that pharmacological disruption of reconsolidation of alcohol-associated memories can be achieved by use of protein synthesis inhibitors and by N-methyl-D-aspartate (NMDA-) antagonists and may thus provide a potential new therapeutic strategy for the prevention of relapse in alcohol addiction. In the new funding period we will systematically examine the neuronal ensembles mediating the reconsolidation of alcohol-associated memories in rats by using a novel method ermed “Daun02 inactivation”. This is, to the best of our knowledge, the only method that allows selective silencing of activated neuronal ensembles mediating a particular learned behavior. In a first set of experiments we will anatomically map the brain sites and neuronal ensembles involved in the reconsolidation of CS-alcohol memories. In a second set of experiments we will probe with the prodrug Daun02 the functional relevance of the morphologically identified neuronal ensembles. In summary, these experiments will provide a better neurobiological understanding of reconsolidation process. Since NMDA receptors are crucial for the reconsolidation process of cue-alcohol associated memories we will further define in a preclinical setting the cue/context and temporal parameters that lead to the most pronounced disruption of the reconsolidation process of alcohol-associated memories by NMDA receptor blockade. Two NMDA receptor antagonists will be studied: memantine and the noble gas xenon - as both substances are already approved in Germany for different indications with a limited side effect profile. In the case that we achieve a successful disruption of alcohol-related memories in alcohol-addicted rats with either one of these compounds we will propose an experimental medicine study in alcohol dependent patients.