Nicotinic Receptor Genetic Variation and Alcohol Reward

• ClinicalTrials.gov Identifier: NCT03294460
• Recruitment Status: Recruiting
• First Posted: September 27, 2017
• Last Update Posted: January 13, 2021
• Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )

Study Description

Brief Summary:

Background:

People with the brain disease AUD (alcohol use disorder) have a serious problem with drinking. Researchers want to study how different people react to alcohol, and how genes affect this. They will focus on a nicotine receptor gene that may increase a person s AUD risk.

Objectives:

To see if people with variations of a nicotine receptor gene take alcohol differently and have different brain responses to alcohol cues.

Eligibility:

Healthy adults ages 21 - 60. This study includes smokers and non-smokers.

Design:

Participants will be screened under another protocol.

Participants will have three 9-hour visits. They must have no alcohol or non-prescription drugs before all visits and no food or drink before 2 visits.

At every visit, participants will:

• Get a light meal
• Have breath and urine tests
• Get taxi rides there and back

At visits 1 and 3, participants will:

• Have a thin plastic tube inserted in an arm and connected to a pump for alcohol infusion.
• Have sensors on their chest to monitor heart rate.
• Sit in a chair for 2.5 hours and get alcohol by pushing a button. Their breath alcohol level will be monitored.
• Answer questions about mood and effects of alcohol
• Give blood samples
• Relax at the clinic while their breath alcohol level drops

At visit 2, participants will:

• Answer questions and do computer tests
• Have an alcoholic drink and a snack
• Have a magnetic resonance imaging (MRI) scan. They will lie in a machine that takes pictures of the brain. They will do computer tasks.
• Have another drink and snack
• Relax until their alcohol level drops

Participants will have a follow-up call after each visit.

Condition or disease	Intervention/treatment	Phase
Alcohol Drinking	Drug: Alcohol (Oral); Drug: Alcohol (IV); Drug: Alcohol (Ethanol)	Phase 1

Detailed Description:

Objectives:

Alcohol use disorder (AUD) is a chronic disease that has a tremendously negative impact on individuals and their families and a substantial burden on society. Research on quantitative endophenotypes such as alcohol response, and their genetic and environmental determinants, is critical to understanding the risk for AUD. There has been a great interest in examining variation in target genes that may play a mechanistic role in the expression of these endophenotypes, such the missense single-nucleotide polymorphism (SNP) in the gene encoding the 5 subunit of the nicotinic acetylcholine receptor (CHRNA5) - rs16969968. Studies have shown that CHRNA5 A-allele carriers are at greater risk for nicotine addiction and smoking-related consequences. However, little work has been done to examine the effect of this SNP on alcohol use, dependence, or alcohol response. Given the high prevalence of nicotinic receptors on dopamine (DA) neurons in brain reward regions, and the high co-use and abuse of alcohol and nicotine, these receptors may play a critical role in modulating incentive salience and reward responses to alcohol. Thus, the goal of this project is to examine the influence of CHRNA5 variation and smoking status (smokers and non-smokers) on alcohol-related phenotypes, including intravenous alcohol self-administration (IV-ASA) behavior and neuroimaging responses to cues signaling alcohol rewards.

Study Population:

This study will include 128 male and female, non-dependent drinkers, 21-60 years of age. Participants will be stratified into equally-sized groups based on their smoking status (smokers and non-smokers) and rs16969968 genotype: 1). A-allele carriers (AA or AG genotype), and 2). G-allele homozygotes (GG genotype). The study will be open to all racial and ethnic groups, as long as the individual meets the genotype criteria. Participants will be in good health as determined by medical history, physical exam, ECG, and lab tests.

Design:

Following screening, participants will undergo three study visits. The first visit will include an IV alcohol self-administration (IV-ASA) session using the Computer-Assisted Infusion System (CAIS), which employs a physiologically-based pharmacokinetic (PBPK) model-based algorithm that allows participants free access to standardized alcohol infusions. During this session, breath alcohol concentrations (BrAC) and subjective responses will be measured as markers of the rewarding effects of alcohol. In another visit, participants will undergo a second IV-ASA session where they will have free-access to alcohol infusions along with the ability to control the rate of each individual self-administered infusion. This will provide an operant measure of sensitivity to rate of change of BrAC as an additional marker of the rewarding effect of alcohol. Finally, participants will undergo a magnetic resonance imaging (MRI) session where they will be scanned while performing the Alcohol-Food Incentive Delay (AFID) task, which assesses neural processing while responding to cues signaling alcohol reward. Additional fMRI task-based scans and a resting-state scan will also be obtained.

Outcome Measures:

The following measures will be examined as a function of smoking status (smokers and non-smokers) and CHRNA5 genotype. The influence of sex, age, and recent drinking history will be examined as covariates. Primary outcome measures include: (1a) BrAC exposure (peak BrAC, number of infusions, time to binge-level BrAC) during the free-access IV-ASA; (1b) BOLD response during the AFID task in neural regions associated with alcohol reward processing, including ventral striatum, amygdala, and insula. Secondary outcome measures include: (2a) resting state functional connectivity (rsFC) between the regions associated with the salience network, including dorsal anterior cingulate cortex, ventral striatum, and extended amygdala; (2b) preferred rate of self-infusion during the second IV-ASA session.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 128 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Nicotinic Receptor Genetic Variation and Alcohol Reward
• Actual Study Start Date: June 10, 2019
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; Alcohol self-administration (IV ethanol for sessions 1 and 3, oral for session 2)	Drug: Alcohol (Oral); Oral Self-administration; Drug: Alcohol (IV); IV Self-administration; Drug: Alcohol (Ethanol); IV and Oral Self-administration

Outcome Measures

Primary Outcome Measures :

1. To examine the effect of CHRNA5 (rs16969968) genetic variation on neural correlates of incentive salience for alcohol, as measured by BOLD response during the Alcohol-Food Incentive Delay (AFID) task using fMRI. [ Time Frame: 3 hours ]
   The following measures will be examined as a function of smoking status (smokers and non-smokers) and CHRNA5 genotype. The influence of sex, age, and recent drinking history will be examined as covariates. Primary outcome measures include: (1a) BrAC exposure (peak BrAC, number of infusions, time to binge-level BrAC) during the free-access IV-ASA; (1b) BOLD response during the AFID task in neural regions associated with alcohol reward processing, including ventral striatum, amygdala, and insula. Secondary outcome measures include: (2a) resting state functional connectivity (rsFC) between the regions associated with the salience network, including dorsal anterior cingulate cortex, ventral striatum, and extended amygdala; (2b) preferred rate of self-infusion during the second IV-ASA session.
2. To examine the effect of CHRNA5 (rs16969968) genetic variation on IV alcohol self-administration, as measured by BrAC exposure (peak BrAC, number of infusions, time to binge-level) in non-smoking, non-dependent drinkers. [ Time Frame: 3 hours ]
   The following measures will be examined as a function of smoking status (smokers and non-smokers) and CHRNA5 genotype. The influence of sex, age, and recent drinking history will be examined as covariates. Primary outcome measures include: (1a) BrAC exposure (peak BrAC, number of infusions, time to binge-level BrAC) during the free-access IV-ASA; (1b) BOLD response during the AFID task in neural regions associated with alcohol reward processing, including ventral striatum, amygdala, and insula. Secondary outcome measures include: (2a) resting state functional connectivity (rsFC) between the regions associated with the salience network, including dorsal anterior cingulate cortex, ventral striatum, and extended amygdala; (2b) preferred rate of self-infusion during the second IV-ASA session.

Secondary Outcome Measures :

1. To examine the effect of CHRNA5 (rs16969968) genetic variation on resting-state functional connectivity (rsFC) among brain regions associated with the salience network, including dorsal anterior cingulate cortex, ventral striatum and extended am... [ Time Frame: 3 hours ]
   associated with the salience network, including dorsal anterior cingulate cortex, ventral striatum and extended amygdala in non-smoking non-dependent drinkers.
2. To examine the effect of CHRNA5 (rs16969968) genetic variation on the rate of IV alcohol self-administration, as measured by the preferred rate during the second IV-ASA session in non-smoking, non-dependent drinkers. [ Time Frame: 3 hours ]
3. To examine the relationship between fMRI measures (BOLD response during AFID and rsFC measures) and IV alcohol self-administration, and any differences in the degree of association among these measures by CHRNA5 genotype. [ Time Frame: 3 hours ]

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

• INCLUSION CRITERIA:
• Male and female participants between 21-60 years of age. (assessment: identification provided to Clinical Center Admissions office)

• Smoking status:

  1. Smokers will have a history of at least 1 year of daily smoking, defined as individuals who smoke more than 20 uses of nicotinic products/week on average, and a cotinine level, measured by the NicAlert test, of greater than or equal to 4. (assessment: Smoking history questionnaire, Additional medical history, Nic Alert test)
  2. Non-smokers with no history of smoking in the past year and less than 20 uses of nicotinic products lifetime.(assessment: smoking history questionnaire, Additional medical history)
• Inclusion criteria for women: Use of adequate method of birth control during the study, if female is sexually active and is not surgically sterilized. Adequate methods of contraception include: use of oral contraceptives; use of barrier method of contraceptive; use of an approved IUD or other long-acting reversible contraceptive (LARC); have a male sexual partner who is surgically sterilized; or have exclusively female sexual partner(s). Justification: To minimize the risk of administering alcohol to pregnant women, given the known effects of alcohol exposure on fetuses. (assessment: medical history)

EXCLUSION CRITERIA:

• Current or prior history of major medical illness, including CNS, cardiovascular, respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders. Justification: Many illnesses may alter the neuropsychological effects of alcohol as well as MRI measures. (assessment: clinically significant findings on medical history and physical exam, ECG, laboratory tests)
• Positive hepatitis (A, B antigen, or C), or HIV test at screening. Justification: Hepatitis can alter liver function and alcohol pharmacokinetics. HIV infection can alter brain function. (assessment: laboratory tests)
• Current (past 12 months) history of psychiatric disorders, including depressive disorder, bipolar disorder, or anxiety disorders. Justification: Concurrent psychopathology can alter brain function and alcohol response. (assessment: SCID interview)
• Lifetime history of psychotic disorders, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), or eating disorder. Justification: These disorders can have long-term effects on brain function and alcohol response. (assessment: SCID interview)
• Current or lifetime diagnosis of alcohol or substance use disorder. Justification: History of alcohol or substance use disorder will impact brain function and alcohol response. (assessment: SCID interview)
• Currently seeking treatment for alcohol use disorders. Justification: It would be unethical to administer alcohol to individuals seeking treatment for alcohol problems. Also, this study does not provide treatment for individuals with alcohol use disorder. (assessment: medical history)
• History of significant withdrawal symptoms or presence of clinically significant withdrawal symptoms (Clinical Institute Withdrawal Assessment (CIWA) score > 8) at screening. Justification: Withdrawal symptoms would be indicative of alcohol use disorder, which is already an exclusion criteria. Additionally, withdrawal symptoms would be a major safety concern for participants, and a major confound in the assessment of alcohol response and brain function. (assessment: CIWA assessment)
• Non-drinkers (alcohol-na(SqrRoot) ve individuals or current abstainers) or individuals with no experience drinking 5 or more drinks on one occasion in their lifetime. Justification: It would be unethical to administer alcohol to individuals that do not drink alcohol. (assessment: medical history)
• Positive result on urine drug screen or positive breathalyzer during screening visit. Positive urine drug screen or breathalyzer reading during more than 1 study visit will result in participant withdrawal from the study. Justification: Current or recent exposure to alcohol or drugs of abuse could impact brain function and alcohol response. (assessment: laboratory tests and breathalyzer test performed at screening or update visit under 14-AA-0181 most proximal to enrollment)
• Current or prior history of alcohol-induced flushing reactions, including rapid reddening of the face, rapid heart rate and breathing, and nausea after 1 or 2 drinks. Justification: It would not be safe to administer alcohol to individuals with the highly aversive flushing response to alcohol. (assessment: alcohol flushing questionnaire)

• Medication exclusion criteria:

  1. Use of prescription or OTC medications known to interact with alcohol within 2 weeks of the study. These include, but may not be limited to: isosorbide; nitroglycerine; benzodiazepines; warfarin; anti-depressants such as amitriptyline, clomipramine and nefazodone; anti-diabetes medications such as glyburide, metformin and tolbutamide; H2-antagonists for heartburn such as famotidine, cimetidine and ranitidine; muscle relaxants; anti-epileptics including phenytoin and phenobarbital; codeine and opioid analgesics including Darvocet, Percocet and hydrocodone; regular or prescribed use of anti-histamines, pain medicines, and anti-inflammatories such as aspirin, ibuprofen, acetaminophen, celecoxib, and naproxen.
  2. Use of medications known to inhibit or induce enzymes that metabolize alcohol for 4 weeks prior to the study. These include chlorzoxazone, isoniazid, metronidazole, and disulfiram.
  3. Use of drugs known to affect hemodynamic response. These include antihypertensives, insulin, and thyroid medications.

Note that any discontinuation of medications will only be done at the recommendation of a physician.

(assessment: medical history and physical exam)

• Exclusion criteria for MRI:

  1. Left-handedness (Edinburgh Handedness Scale). Justification: To avoid lateralized effects on brain function measures and reduce potential variance in MRI signals.
  2. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head (including but not limited to pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted delivery pump, or shrapnel fragments).
  3. Fear of enclosed spaces. Justification: To minimize risk and discomfort.
  4. Inability to lie comfortable on back for up to 2 hours in the MRI scanner. Justification: To minimize risk and discomfort. (assessment: NIAAA MRI Safety Screening Questionnaire)

• Exclusion criteria for women: Justification: To minimize the risk of administering alcohol to pregnant or nursing women, given the known effects of alcohol exposure on fetuses and infants.

  1. Pregnant (assessment: urine beta-hCG test at screening). Women must also test negative on urine beta-hCG test at the start of every study visit.
  2. Breast-feeding (assessment: medical history and physical exam).

Contacts and Locations

Contacts

Contact: Vijay A Ramchandani, Ph.D.; (301) 402-8527; vijayr@mail.nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov

Sponsors and Collaborators

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: Vijay A Ramchandani, Ph.D.; National Institute on Alcohol Abuse and Alcoholism (NIAAA)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• ClinicalTrials.gov Identifier: NCT03294460
• Other Study ID Numbers: 170171; 17-AA-0171
• First Posted: September 27, 2017
• Last Update Posted: January 13, 2021
• Last Verified: June 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) ):

Functional Magnetic Resonance Imaging (fMRI); Alcohol Use; Polymorphism, Genetic; Magnetic Resonance Imaging (MRI)

Additional relevant MeSH terms:

Alcohol Drinking; Drinking Behavior; Ethanol; Anti-Infective Agents, Local; Anti-Infective Agents; Central Nervous System Depressants; Physiological Effects of Drugs