The Role of Dopaminergic and Glutamatergic Neurotransmission for Dysfunctional Learning in Alcohol Use Disorders (LeADP5)

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

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).

Study Overview

• Status: Completed
• Conditions: Alcohol Use Disorder
• Intervention / Treatment: Other: Alcohol detoxification

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 Type: Observational
• Enrollment (Actual): 60

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Charité - Universitätsmedizin Berlin
  • Berlin, Germany, 10115
    • Charité Berlin, Division of Neuroimaging

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Detoxified alcohol- dependent patients and age- and gender matched healthy controls living in Germany

Description

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 Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
striatal-prefrontal connectivity (fMRI)	striatal-prefrontal connectivity (see other LeAD-projects) in the probabilistic reversal learning task	first assessment time point (alc. dependent pat. up to 21 days after detoxification)

Collaborators and Investigators

• Sponsor: Technische Universität Dresden
• Collaborators: Charite University, Berlin, Germany
• Investigators: Principal Investigator: Jürgen Gallinat, Prof MD, Charite University, Berlin, Germany

Publications and helpful links

Helpful Links

• Official study group website
• English study description

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2012
• Primary Completion (Actual): April 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: March 20, 2014
• First Submitted That Met QC Criteria: March 20, 2014
• First Posted (Estimate): March 21, 2014

Study Record Updates

• Last Update Posted (Actual): July 30, 2020
• Last Update Submitted That Met QC Criteria: July 28, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Glutamate; Positron emission tomography (PET); Magnetic resonance spectroscopy (MRS); Pavlovian-to-instrumental transfer; Relapse Risk; Reward- based learning; Dopamine receptor availability
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism; Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Central Nervous System Depressants; Ethanol
• Other Study ID Numbers: GA707/6-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO