Metabotropic Glutamate Receptor-5 (mGlur5) Effects on Reward-Related fMRI-BOLD Activation in FHP and FHN

This project explores the effects of 1 dose of AZQ056, an experimental non-competitive
antagonist to metabotropic glutamate receptor-5 (mGlur5) developed by Novartis, in a
double-blind, randomized, counterbalanced manner on alcoholism risk-relevant tasks.

Drug/placebo will be administered on 2 separate visits separated by 1 week. More
specifically, this project examines 4 functional MRI tasks related to different aspects of
reward and/or impulsivity-related behavior in different contexts, compares the underlying
neural circuitry across tasks, and uses a pharmacologic probe of the glutamatergic system to
examine N-methyl-D-Aspartate and Dopamine (NMDA/DA) interactions.

The combined measures provide the opportunity to advance our understanding of specific
aspects of brain function related to familial alcoholism vulnerability in an already well
characterized population as some members evolve into alcohol abuse. In addition, as well as
conventional within-task analyses, functional network connectivity and allied approaches will
be used to examine brain networks across the above tasks.

Inclusion Criteria:

- Subjects will be first screened toxicologically for drugs of abuse (and for women of
childbearing age, pregnancy) by urine testing, any positive test results in exclusion.

- Participants will be able to understand the procedures as judged by their ability to
clearly repeat back to the PI or his designee correctly, the purpose and content of
the planned research, and willingly agree to participate.

Exclusion Criteria:

1. a diagnosis of DSM-IV psychiatric disorder

2. report of psychotic disorder in a 1º relative, auditory or visual impairment that
interferes with test-taking

3. prenatal exposure to alcohol plus currently meeting criteria for features of fetal
alcohol syndrome

4. not speaking English fluently or being a non-native English speaker, or being educated
in a primary language other than English > grade 1

5. mental retardation (Full Scale IQ<70)

6. traumatic brain injury with loss of consciousness > 30 minutes or concussion in last
30 days

7. presence or history of any medical/neurologic illness that may affect brain physiology
(e.g., epilepsy, Multiple Sclerosis), including focal brain lesion seen on structural
MRI (all structural scans are read by a licensed radiologist)

8. current pregnancy (all females will be tested with urine screens on the day of MRI);

9. All participants will receive a urine screen for the presence of marijuana, cocaine,
opiates and a breath screen to detect the presence of alcohol

10. Inability to comprehend the consent form appropriately

11. Other specific fMRI exclusions include metal devices, clips or fragments in body
(orbital x-ray performed if needed).

- Individuals will be excluded who have taken, within the prior 14 days, the
following strong inhibitors or inducers of CYP1A, CYP2C, and CYP3A and CYP3A4:
iprofloxacin, enoxacin, fluvoxamine; gemfibrozil; fluconazole, fluvoxamine,
ticlopidine; boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir,
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone,
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin,
voriconazole; bupropion, fluoxetine, paroxetine, quinidine; avasimibe,
carbamazepine, phenytoin, rifampin, and St. John's wort.

- Individuals will also be excluded who have taken, within 14 days, the following
moderate inhibitors and inducers of CYP3A: Amprenavir, aprepitant, atazanavir,
ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin,
fluconazole, fosamprenavir, imatinib, and verapamil; and bosentan, efavirenz,
etravirine, modafinil, and nafcillin.