Role of Proinflammatory Signaling in Alcohol Craving

• INCLUSION CRITERIA:

  1. Diagnostic and Statistical Manual (DSM)-IV diagnosis of alcohol dependence on Structured Clinical Interview for DSM Diagnosis (SCID) alcohol problems as primary complaint among substance use disorders, and alcohol use within the last month.
  2. Age 21 65
  3. Right handed

  4. For women:

     1. post-menopausal or surgically sterile (tubal ligation or hysterectomy); or
     2. if sexually active with a male partner and able to get pregnant, documented agreement to use an effective form of birth control. Acceptable forms of contraception for this study include: hormonal contraceptives (birth-control pills, injectable hormones, vaginal-ring hormones); intrauterine device (IUD); diaphragm with spermicide; condom with spermicide.

EXCLUSION CRITERIA:

1. Any medical illness that in the view of the investigators would compromise participation in research, as determined by medical history, physical examination, laboratory tests (see details under Screening measures below), including, but not limited to:

   1. Diabetes mellitus Type I or Type II
   2. Past or current diagnosis of congestive heart failure
   3. Signs and symptoms suggestive of congestive heart failure
   4. Cardiovascular disease (e.g., history of congenital heart defect, heart disease, symptomatic coronary-artery disease, heart attack, clinically significant arrhythmia, etc.)
   5. Cerebrovascular disease
   6. Infection, autoimmune disease, or fever of unknown origin
   7. Unexplained history of syncope
   8. History of seizures, except for febrile seizures during childhood
   9. History of head injury with loss of consciousness of more than 30 minutes or with postconcussive sequelae lasting more than two days, regardless of loss of consciousness
   10. Chronic renal failure as estimated by glomerular filtration rate (GFR) <60 milliliters per minute 1.73 per Square
   11. HIV infection
   12. Active bladder cancer, history of bladder cancer, or persistent hematuria
   13. Allergy, hypersensitivity, or intolerance to pioglitazone, other thiazolidinediones, or the metabolites of any of those drugs (determined by medical history)
   14. Pregnancy or breastfeeding (urine pregnancy test; self-report)
   15. Diabetes medications (e.g., sulfonylureas, metformin, insulin, etc.)
   16. Contraindicated or strongly interacting medications: Gemfibrozil (inhibitor of CYP2C8) and rifampin (inducer of CYP2C8), atorvastatin, ketoconazole, nifedipine
   17. Any ongoing, or regular use of central nervous system (CNS) active medications within the last week (fluoxetine: last 4 weeks), with the exception of withdrawal medication, obtained according to the NIAAA clinical guidelines if needed
   18. Use of docosahexaenoic acid (DHA) dietary supplements, or consumption of oily fish >3 times per week (because of effects of DHA on inflammatory parameters)
   19. History of Rhabdomyolysis

2. Psychiatric history:

   1. Cognitive impairment severe enough to preclude informed consent or valid responses on questionnaires, as established by clinical exam, in questionable cases aided by a Mini Mental State Examination (with a score of <21, indicating more than mild cognitive impairment, being exclusionary)
   2. Current diagnosis of schizophrenia or any other DSM-IV psychotic disorder, bipolar disorder, or major depressive disorder, in each case as established by clinical evaluation and SCID.

3. Substance use disorders:

   1. Current alcohol intoxication on breathalyzer test or positive urine drug screen on enrollment
   2. Current dependence on drugs other than alcohol or nicotine, as established by SCID interview

4. Inability or unwillingness to participate in an fMRI scan, including

   1. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head (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) or fear of enclosed spaces. Eligibility will be determined by a MRI Safety Screening Questionnaire and verified, if necessary, by a physician.
   2. Subjects that cannot lie comfortably flat on their back for up to 2 hours in the MRI scanner.