Role of Metal Ion Transporter ZIP8 in Alcohol-Related Behaviors

• INCLUSION CRITERIA:

  1. Male and female participants between 21-60 years of age. [Based on: identification provided to Clinical Center Admissions office].
  2. Non-smokers with no history of smoking in the past year and not a daily smoker for more than 1 month in their lifetime. [Based on: smoking history questionnaire, Additional History Form]
  3. Participants of European ancestry: the minor T allele of rs13107325, has a frequency of 0.08 in European ancestry, but is almost absent in Asian and African populations (http://www.ensembl.org). Due to the rare occurrence of the T allele and to avoid populations stratification in this small sample-sized study, only participants with self-reported White racial category (European ancestry) will be enrolled in this study.
  4. Inclusion criteria for persons of childbearing potential: Use of adequate method of birth control during the study, if participant is sexually active and is not surgically sterilized. Adequate methods of contraception include abstinence, 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 same-sex sexual partner(s). Justification: To minimize the risk of administering alcohol to pregnant persons of childbearing potential, given the known effects of alcohol exposure on fetuses. [Based on: medical history].
  5. Ability to understand the written consent form and willing to sign it. [Based on: consent quiz].

EXCLUSION CRITERIA:

1. Current history (past 12 months) of major medical illness, including CNS, cardiovascular, respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders, or positive hepatitis (A, B antigen, or C), or HIV test. Justification: Many illnesses may alter the neuropsychological effects of alcohol as well as MRI measures. Hepatitis can alter liver function and alcohol pharmacokinetics. HIV infection can alter brain function. [Based on: clinically significant findings on medical history and physical exam, ECG, laboratory tests].
2. Current history of psychiatric disorders, including depressive disorder, bipolar disorder, or anxiety disorders. Justification: Concurrent psychopathology can alter brain function and alcohol response. [Based on: SCID interview]
3. Lifetime history of psychotic disorders, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), or eating disorder. Justification: These disorders can have long-term effects on brain function and alcohol response. [Based on: SCID interview]
4. Current or lifetime diagnosis of alcohol or substance use disorder. Past mild AUD or past mild SUD with no current symptoms for at least 2 years will not be exclusionary. Justification: History of moderate to severe alcohol or substance use disorder will impact brain function and alcohol response We do not anticipate past mild AUD or SUD in remission for 2+ years would have such impact on brain function and alcohol response. We will examine this in an exploratory analysis. We will also do a follow-up telephone/telehealth visit with these participants to assess any changes in alcohol or substance use or problems related to their participation in the study. [Based on: SCID interview].
5. 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. [Based on: medical history]
6. Non-drinkers (alcohol-naive 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. [Based on: medical history].
7. 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. [Based on: alcohol flushing questionnaire].
8. 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. [Based on: laboratory tests and breathalyzer test].
9. 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 criterion. Additionally, withdrawal symptoms would be a major safety concern for participants, and a major confound in the assessment of alcohol response and brain function. [Based on: CIWA assessment].

10. Medication exclusion criteria: [Based on Medical history and physical exam, Additional History Form].

    • Use of prescription or OTC medication known to interact with alcohol 2 weeks prior to screening or screening update visit. 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 (more than once a week) or prescribed use of antihistamines, pain medicines, and anti-inflammatories such as aspirin, ibuprofen, acetaminophen, celecoxib, and naproxen, and unable to refrain from these medications for 48 hours prior to study visits.NOTE: Seasonal use of antihistamines is not-exclusionary unless participants are unable to refrain from these medications for

      48 hours prior to study visits.

    • Use of medications known to inhibit or induce enzymes that metabolize alcohol for 4 weeks prior to screening or screening update visit. These include chlorzoxazone, isoniazid, metronidazole, and disulfiram.
    • Use of drugs known to affect hemodynamic response 2 weeks prior to screening or screening update visit. These include antihypertensives, insulin, and thyroid medications.

11. Exclusion criteria for MRI:

    • Left-handedness (Edinburgh Handedness Scale). Justification: To avoid lateralized effects on brain function measures and reduce potential variance in MRI signals.
    • 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).
    • Fear of enclosed spaces. Justification: To minimize risk and discomfort.
    • Inability to lie comfortably on back for up to 2 hours in the MRI scanner. Justification: To minimize risk and discomfort.

    [Based on: MRI Safety Screening Questionnaire, Additional History Form]

12. Exclusion criteria for persons of childbearing potential:

Justification: To minimize the risk of administering alcohol to pregnant or nursing persons, given the known effects of alcohol exposure on fetuses and infants.

• Pregnant [Based on: urine beta-hCG test at screening]. Persons of childbearing potential must also test negative on urine beta-hCG test at the start of every study visit.
• Breast-feeding [Based on: Medical history and physical exam].