Role of Metal Ion Transporter ZIP8 in Alcohol-Related Behaviors

Phase 1

Recruiting

• Conditions: Healthy Volunteer
• Interventions: Drug: Ethanol

• Registration Number: NCT06819189
• Lead Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Brief Summary

Background:

Alcohol use disorder (AUD) can damage people s health, work, and family. Researchers want to know more about why some people are more vulnerable to AUD than others. The ZIP8 gene may be linked to an increased risk of AUD. Researchers want to find out how different forms of the ZIP8 gene affect how healthy people drink alcohol and how alcohol affects their brain.

Objective:

To study how genes may affect how people drink alcohol and how it affects their brain.

Eligibility:

Healthy people aged 21 to 60 years. They must not smoke, and they must have no history of AUD. They must have European ancestry and be enrolled in Natural History Protocol (14-AA-0181).

Design:

Participants will have 2 study visits.

At the first visit, participants will be given alcohol; it will be infused through a tube attached to a needle inserted into a vein. They may self-administer each dose by pressing a button. Over time, they will have to press the button an increasing number of times to receive more alcohol. The infusion period will last 2.5 hours.

Participants will have blood samples taken and breath measurments, and they will do computer tasks and complete questionnaires during and after the infusion. After the infusion, they will remain in the clinic until their breath alcohol levels drop to a safe level.

At the second visit, participants will have an imaging scan of their brain. They will do tasks and play games on a computer screen during the scan.

Some participants may have an extra visit for screening. A mid-study visit may also be needed if more than 6 months pass between the 2 study visits....

Detailed Description

Study Description:

Genome-wide association studies of alcohol use disorder and alcohol consumption phenotypes have consistently identified significant associations with the metal ion transporter ZIP8 gene, specifically a single nucleotide polymorphism SLC39A8. The goal of this study is to examine the effect of SLC39A8 variation on alcohol-related phenotypes using an integrated translational pharmacogenetics approach. Alcohol-seeking and consumption will be evaluated using a human lab model of alcohol self-administration in a sample of 50 male and female non-AUD drinkers, classified into 2 groups based on their SLC39A8 genotype (rs13107325): 1) T-allele carriers (TT or CT genotype), and 2) CC-allele homozygotes (CC genotype). Participants will also undergo resting-state functional MRI scanning to assess functional connectivity in brain networks such as the salience network, and task-based functional MRI scans to assess activation in brain regions associated with reward processing and decision making, for association with SLC39A8 SNP genotype. The hypotheses guiding this project are that SLC39A8 variation would be associated with altered alcohol self-administration phenotypes of alcohol seeking and consumption, as well as with brain activation in brain regions associated with reward and decision making that are also associated with alcohol s effects.

Objectives:

Primary Objective:

To examine the effect of SLC39A8 genetic variation on IV alcohol self-administration phenotypes in non-AUD drinkers.

Secondary Objective:

To examine the effect of SLC39A8 genetic variation on brain activation and responses using functional magnetic resonance imaging in non-AUD drinkers.

Endpoints:

Primary Endpoints:

IV alcohol self-administration measures - Peak breath alcohol concentration (BrAC), number of alcohol infusions received.

Secondary endpoints:

brain activation (fMRI BOLD signal change) associated with reward during the monetary incentive delay (MID) task. Brain activation (fMRI BOLD signal change) associated with decision making during the risk task. Brain regions of interest include striatum, insula, cingulate cortex and prefrontal cortex.

Study Timeline

• Study First Submitted: 2025-02-08
• Study First Submitted QC: 2025-02-10
• Study First Posted: 2025-02-11
• Status Verified: 2025-04-29
• Last Update Submitted: 2025-05-20
• Last Update Posted: 2025-05-21
• Study Start: 2025-05-26
• Primary Completion: 2027-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
IV Ethanol	Ethanol	IV Ethanol

Primary Outcome Measures

Name	Time	Method
Primary Endpoints: IV alcohol self-administration measures Peak breath alcohol concentration (BrAC), number of alcohol infusions received.	2 YEARS	The Peak BrAC and number of infusions are direct measures of alcohol exposure and amount consumed during the laboratory session.

Trial Locations

Locations (1)

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States