Nicotinic Receptor Genetic Variation and Alcohol Reward

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 4 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:

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

2)Smoking status:

1. Smokers will have a history of at least 2 years1 year of daily smoking, defined
as individuals who smoke more than 20 cigarettes/week on average, and a cotinine
level, measured by the NicAlert test, of greater than or equal to 4. (assessment:
Smoking history questionnaire, Nic Alert test)

2. Non-smokers with no history of smoking in the past year and less than 20
cigarettes lifetime.(assessment: smoking history questionnaire)

4) 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:

1. 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)

2. Positive hepatitis (A, B, 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)

3. 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)

4. 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)

5. 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)

6. 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)

7. 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)

8. 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)

9. 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)

10. 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)

11. 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)

12. 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)

13. 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).