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

Completed

• Conditions: Alcohol Use Disorder
• Interventions: Other: Alcohol detoxification

• Registration Number: NCT02094196
• Lead Sponsor: Technische Universität Dresden

Brief Summary

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

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.

Study Timeline

• Study Start: 2012-12
• Study First Submitted: 2014-03-20
• Study First Submitted QC: 2014-03-20
• Study First Posted: 2014-03-21
• Primary Completion: 2018-04
• Study Completion: 2018-12
• Status Verified: 2020-07
• Last Update Submitted: 2020-07-28
• Last Update Posted: 2020-07-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

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

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Alcohol detoxification	Alcohol detoxification	Inpatients with alcohol dependence from local psychiatric hospital wards (18-65 years old)

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Charité Berlin, Division of Neuroimaging; 🇩🇪 Berlin, Germany

Charité - Universitätsmedizin Berlin; 🇩🇪 Berlin, Germany