The Role of Dopaminergic and Glutamatergic Neurotransmission for Dysfunctional Learning in Alcohol Use Disorders

Study Overview
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Brief Summary
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The aim of this project is to assess reward- based learning behavior and its association with alterations in dopaminergic and glutamatergic transmission in detoxified alcohol-dependent patients and matched controls. The investigators will explore how these alterations interact with clinical and psychosocial factors which can modify the relapse risk and learning deficits. Patients will be detoxified in an inpatient setting. Clinical assessments, behavioral paradigms of learning and brain imaging will be carried out within at least 4 half- lives after any psychotropic medication. The investigators will implement and apply functional imaging paradigms assessing Pavlovian-to-instrumental transfer and reversal learning tasks and associate model parameters of learning with alcohol craving, intake and prospective relapse risk. In this project, the impact of the dopamine x glutamate interaction on learning deficits and consecutive relapse probability is targeted with [18F]fallypride PET and the measurement of absolute concentrations of glutamate with magnetic resonance spectroscopy (MRS).

Detailed Description
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Alcohol consumption despite negative consequences may rely on impaired flexibility in adapting the behavior to environmental changes, i.e. learning in response to reward contingencies. This learning deficit is of clinical relevance particularly during therapy and for the psychosocial outcome. The reduced availability of central dopamine D2-receptors in detoxified alcohol dependent patients observed in PET investigations and their hypothetical effects on reward-related learning are in line with evidence for learning deficits in hypodopaminergic states, particularly for avoidance learning in non-dependent samples. Growing evidence indicates that the learning-related striatal dopamine signals are modulated by higher executive functions involving, e.g., the prefrontal cortex. Here, broad glutamatergic outputs of the prefrontal cortex are crucial for subcortical learning mechanisms and match with recent models of interactive dopamine-glutamate dysfunctions and models of neurotrophic signaling in alcohol dependence.

Official Title
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The Role of Dopaminergic and Glutamatergic Neurotransmission for Dysfunctional Learning in Alcohol Use Disorders (LeAD P5)

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Other: Alcohol detoxification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Alcohol dependence according to DSM-IV Minimum of 72 hours of abstinence, maximum of 21 days of abstinence Minimum of three years of alcohol dependence Low severity of withdrawal symptoms Ability to provide fully informed consent and to use self- rating scales Exclusion Criteria: Lifetime history of DSM- IV bipolar or psychotic disorder Current threshold DSM-IV diagnosis of any following disorders: current major - depressive disorder, generalized anxiety disorder, PTSD, borderline personality disorder or obsessive- compulsive disorder History of substance dependence other than alcohol or nicotine dependence

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Controls, highrisk for AD<br>Community-based ad-hoc participants, high risk for alcohol dependence, matched to inpatients by sociodemographics | |
| Controls, low risk for AD<br>Community-based ad-hoc participants, low risk for alcohol dependence, matched to inpatients by sociodemographics | |
| Alcohol detoxification<br>Inpatients with alcohol dependence from local psychiatric hospital wards (18-65 years old) | Other: Alcohol detoxification<br>* Detoxified alcohol- dependent patients in an inpatient setting<br>* Other names: Alcohol- dependent patients;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Striatal D2-receptor availability (PET) and prefrontal glutamate concentration (MRS) | reduction in striatal D2-receptor availability and a increase in prefrontal glutamate concentration in alcohol-dependent patients compared to healthy controls | first assessment time point (alc. dependent pat. up to 21 days after detoxification) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| behavioral data in reward-habit-learning paradigms | Reduced learning speed and PIT withdrawal score in the probabilistic reversal learning task | first assessment time point (alc. dependent pat. up to 21 days after detoxification) | 
| Treatment response | test the predictive effects of striatal D2-receptor availability and prefrontal glutamate availability for treatment outcome (relapse vs abstinence) in alcohol-dependent patients | 12-month follow-up period beginning after first assessment timepoint | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reward- based learning, Pavlovian-to-instrumental transfer, Relapse Risk, Positron emission tomography (PET), Magnetic resonance spectroscopy (MRS), Dopamine receptor availability, Glutamate