Nicotinic Receptor Genetic Variation and Alcohol Reward
Nicotinic Receptor Genetic Variation and Alcohol Reward
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.
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.
-  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 NarcoCheck PreDosage Nicotine Test (PNT)
 test, of >= 2. [assessment: Smoking history questionnaire, Additional medical
 history, PreDosage Nicotine 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).