Functional neuroimaging of alcoholism vulnerability: glutamate, reward, impulsivity, and Pavlovian-to-instrumental transfer (PIT), part II Saracatinib

To assess the effect of oral AZ D0530 at various doses on neuroimaging parameters associated with various forms of impulsivity mediated through glutamate-dopamine interactions, as ascertained through functional magnetic resonance imaging. -- --NOTE-- AZD0530 dosage of 50mg was discontinued by manufacturer. Adjustments were made to account for the removal of the 50mg dosage in all arms of the study.

Inclusion Criteria:

• Clear History of a father having a history of alcoholism, OR a mother AND another 1st or 2nd degree relative having a history of alcoholism, OR no 1st or 2nd degree relatives with alcoholism or substance abuse

Exclusion Criteria:

1. Current diagnosis of DSM-IV-TR Axis I disorder, or past diagnosis of any substance use disorder or moderate alcohol use disorder
2. Report of psychotic disorder in a 1º relative
3. Auditory or visual impairment that interferes with test taking
4. History of prenatal exposure to alcohol plus currently meeting criteria for features of fetal alcohol syndrome
5. Not speaking English fluently or being a non-native English speaker, or being educated in a primary language other than English >grade 1
6. Mental retardation (Full Scale IQ<70) using 2 WASI subtests for IQ estimate
7. Traumatic brain injury with loss of consciousness > 30 minutes, or concussion in last 30 days
8. 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)
9. Current pregnancy (all females will be tested with urine screens on the day of MRI and prior to each phase of drug treatment)
10. Positive urine screen for the presence of marijuana, cocaine, opiates or breath screen to detect the presence of alcohol, administered at each lab visit.
11. Inability to comprehend the consent form appropriately
12. Ferromagnetic metal devices, clips or fragments in body (orbital x-ray performed if needed).
13. Current use (within 30 days of screening) of specific psychoactive medications (e.g., typical neuroleptics, narcotic analgesics, antiparkinsonian medications, systemic corticosteroids, or medications with significant central anticholinergic activity, etc.). Current use of warfarin.
14. Current use of the following medications (CYP3A4 substrates whose metabolism may be slowed by AZD0530): carbamazepine, colchicine, cyclosporine, disopyramide, fluticasone, quinidine, vinblastine, vincristine, nifedipine. Patients taking sildenafil, tadalafil, and vardenafil will be advised to stop taking these medications for the duration of the trial. Patients cannot take the following drugs which inhibit the CYP3A4 isoenzyme: cimetidine, cyclosporine, danazol, fluconazole, grapefruit juice, HIV protease inhibitors, itraconazole, ketoconazole, macrolides, miconazole, nefazodone, omeprazole, ritonavir, and verapamil, aromatase inhibitors, docetaxel
15. Neutropenia defined as absolute neutrophils count of <1,500/microliter.
16. Thrombocytopenia defined as platelet count <100x103/microliter.
17. AST, ALT, total bilirubin >1.5 times upper normal; serum creatinine, >2 time upper normal limit, total bilirubin>1.5 times ULN; Serum creatinine >2.0 times ULN.
18. History of interstitial lung disease.