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Exploring Regulation and Function of Dopamine D3 Receptors in Alcohol Use Disorders: A [11C]-(+)-PHNO Study

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ClinicalTrials.gov Identifier: NCT03037060
Recruitment Status : Recruiting
First Posted : January 31, 2017
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Bernard Le Foll, Centre for Addiction and Mental Health

Brief Summary:
There is a need to better understand the mechanisms underlying alcohol use and dependence in order to advance the clinical treatment of alcohol dependence. Here, the investigators will use Positron Emission Tomography to determine if there is an up-regulation of D3 receptors in the brains of subjects with alcohol use disorders. The investigators will also investigate the relationship between D3 binding and major phenotypes associated with alcohol use disorders, namely: alcohol cue induced craving and motivation to self-administer alcohol in the laboratory.

Condition or disease Intervention/treatment Phase
Alcohol Use Disorder Other: [11C]-(+)-PHNO PET scan Other: Alcohol Self-Administration Other: Craving Task Other: MRI scan Other: Neuropsychological Assessment Not Applicable

Detailed Description:

Alcohol dependence is a devastating illness with social and medical costs estimated to be 180 billion dollars annually in the US. In the clinical treatment of alcoholism, reducing alcohol consumption in heavy drinkers is a major clinical challenge. As such, there has been much emphasis in both clinical and preclinical research to identify the substrates that mediate craving, excessive drinking and addiction. Identifying the neurobiological mechanisms of alcohol dependence may lead to the development of new and better treatment strategies. Preclinical studies indicate that the D3 receptor is involved in alcohol-cue response and in the motivation to drink alcohol. However, there is currently no data available in human subjects exploring the relationship between D3 and those behavioral responses in subjects with alcohol use disorders.

Aim #1: To measure the [11C]-(+)-PHNO PET binding levels in the brains of subjects with alcohol use disorders.

Aim #2: To determine the relationship between D3 receptor binding and alcohol cue induced craving and motivation to self-administer alcohol in the laboratory.

To achieve designated goals, the investigators will recruit 25 male and female subjects who are non-treatment seekers. After a period of abstinence from alcohol, participants will come to the Centre for Addiction of Mental Health for a [11C]-(+)-PHNO PET scan. Participants will also have additional sessions during which other alcohol-related measures will be assessed (i.e. alcohol cue induced craving and motivation to self-administer alcohol in the laboratory).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Exploring Regulation and Function of Dopamine D3 Receptors in Alcohol Use Disorders: A [11C]-(+)-PHNO Study
Study Start Date : December 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Alcohol

Arm Intervention/treatment
Experimental: Experimental

5 experimental sessions per participant:

(1) [11C]-(+)-PHNO PET scan, (2), Alcohol Self-Administration, (3) Craving Task, (4) MRI scan and (5) Neuropsychological Assessment.

Other: [11C]-(+)-PHNO PET scan
PET scan

Other: Alcohol Self-Administration
Session for assessing motivation for consuming alcohol.

Other: Craving Task
Cue exposure paradigm

Other: MRI scan
MRI scan scan to analyze the PET data will be administered.

Other: Neuropsychological Assessment
Cognitive questionnaires administered over course of study.




Primary Outcome Measures :
  1. Dopamine D2/D3 receptor occupancy [ Time Frame: One PET scan after 2-7 days of abstinence from alcohol; ~2 hours in duration. ]
    Dopamine D2/D3 receptor occupancy in the brains of individuals with Alcohol Use Disorders will be quantified using [11C]-(+)-PHNO Positron Emission Tomography (PET). [11C]-(+)-PHNO binding levels will be used to infer receptor occupancy.


Secondary Outcome Measures :
  1. Alcohol craving ratings [ Time Frame: Cue paradigm session is expected to take ~1 hour and will occur on the PET day. ]
    Participants' ratings for alcohol craving acquired during the validated Cue-Induced Craving Paradigm (using the Alcohol Urge Questionnaire: 8 items on a 11-point Likert scale) will be correlated to dopamine receptor occupancy (outcome 1).

  2. Effort to obtain alcohol [ Time Frame: Single self-administration session will occur on its own day with a time commitment of ~6 hours. ]
    Laboratory alcohol self-administration paradigm in which participants press a button to intravenously self-administer small doses of alcohol will be used to assess amount of effort expended to obtain alcohol ("break point"). The # of button presses required to obtain the alcohol will increase as per the Progressive Ratio schedule. Regression analysis between effort and [11C]-(+)-PHNO binding (outcome 1) will be applied.



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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects will meet diagnostic criteria for alcohol use disorder (mild through severe).
  • Willing to abstain from drugs and alcohol prior to study visits
  • A negative urine screen for illicit psychoactive drug use
  • Willing and capable to provide written informed consent
  • Willing to participate in cue exposure and intravenous alcohol administration sessions
  • Male and female adults (at least 19 years old)

Exclusion Criteria:

  • DSM diagnosis of drug dependence other than alcohol
  • Any severe Axis I disorder aside from alcohol use disorder
  • Any medical condition requiring immediate investigation
  • History of seizures, past or current neurological illness or serious head trauma
  • Suicidal ideation
  • Pregnancy tested by urine or blood screen or lactation
  • Current past or anticipated exposure to radiation exceeding permissible limits as set by the CAMH PET Centre
  • Metal implants or paramagnetic objects within the body which may interfere with the MRI
  • Claustrophobia or a history of panic attacks
  • Any other problem that, in the investigators' opinion, would preclude participation in trial (i.e., complicated withdrawal).
  • Currently seeking treatment or attempting to reduce/quit drinking
  • History of negative responses to venipuncture procedures (e.g., fainting/vasovagal response)
  • Medications or medical disorders for which alcohol consumption is contraindicated

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03037060


Contacts
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Contact: Bernard Le Foll, MD PhD 416-535-8501 bernard.lefoll@camh.ca
Contact: Saima Malik, PhD 416-535-8501 saima.malik@camh.ca

Locations
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Canada, Ontario
Centre for Addiction and Mental Health Recruiting
Toronto, Ontario, Canada, M5S2S1
Contact: Saima Malik, PhD    416-535-8501    saima.malik@camh.ca   
Sponsors and Collaborators
Centre for Addiction and Mental Health
Investigators
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Principal Investigator: Bernard Le Foll, MD, PhD Centre for Addiction and Mental Health

Additional Information:
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Responsible Party: Bernard Le Foll, Principal Investigator, MD, PhD, CCFP, Centre for Addiction and Mental Health
ClinicalTrials.gov Identifier: NCT03037060     History of Changes
Other Study ID Numbers: 052/2016
First Posted: January 31, 2017    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Bernard Le Foll, Centre for Addiction and Mental Health:
Alcohol use, problem

Additional relevant MeSH terms:
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Disease
Alcohol Drinking
Alcoholism
Pathologic Processes
Drinking Behavior
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Ethanol
Dopamine
Anti-Infective Agents, Local
Anti-Infective Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents