IMAGe-Stress: Investigation of the importance of stress-induced sensitization of striatal dopamine release for the development of cue-induced alcohol craving and relapse in patients with alcohol dependence

• Applicants: Professor Dr. Patrick Bach; Professor Dr. Gerhard Gründer
• Subject Area: Biological Psychiatry ; Human Cognitive and Systems Neuroscience
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547225916

Studies pointed to stress as a key factor in the development of an alcohol dependence with evidence pointing towards a stress-induced sensitization of the response to alcohol cues, which was associated with increased alcohol craving and relapse risk. Preclinical data suggest that the effects of stress on dependent behavior are mediated via altered dopamine activity in the mesolimbic reward system and that stress leads to a sensitization of the striatal dopamine system. The potential effect of stress on striatal dopamine activity appears to be of particular importance with respect to addictive disorders, as the action of dopamine in the mesolimbic reward system has been identified as a key process in the development and maintenance of addiction. However, the neurobiological basis of the effects of stress in alcohol dependent patients and the associations with clinical parameters, such as risk of relapse, have not been investigated yet. An investigation of these relationships in alcohol-dependent patients is highly relevant to determine the neurobiological basis of the interaction of stress and alcohol cue-exposure on the development of alcohol craving and to new treatment targets. Combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) is the only in vivo method that allows the simultaneous measurement of dopamine receptor binding (PET) and coupled changes in the hemodynamic responses (fMRI) to map dynamic changes in the dopamine system with unprecedented temporal resolution. Therefore, the aim of the proposed project is to demonstrate stress-induced enhancement of dynamic striatal dopamine activity as the neurobiological basis of the interaction between stress and alcohol-cue exposure on dependent behavior in alcohol-dependent patients. To this end, N=42 subjects with alcohol dependence, aged between 18 and 65 years, will be enrolled in a randomized controlled crossover study with a follow-up period of 90 days. The participants will undergo two assessments in randomized order (7 days apart), which consist of either a stress induction or a control intervention using validated methods. Simultaneous combined PET/MRI during stress induction and control intervention will be used to investigate the effect of psychosocial stress on the [18F]-Desmethoxyfallypride binding potential (using PET), as a parameter for dopamine D2/D3 activity in the mesolimbic reward system, and mesolimbic cue-reactivity (using MRI). In parallel, repeated measurements of alcohol craving and cortisol plasma levels will be performed to investigate stress effects on clinical symptoms and biological markers. In addition, the associations of neural cue-reactivity and dopamine activity in the mesolimbic reward system with cortisol levels, subjective alcohol craving and relapse risk during follow-up period will be examined, in order to determine the significance of stress effects on clinical symptoms and treatment outcome.

• DFG Programme: Research Grants