Glutamate-Glutamine Cycling (VCYC) during Cocaine Abstinence using 1H-MRS

Aim 1: To measure ventral striatal (VS) glutamate (GLU), as assessed by 1H-MRS, in cocaine dependent (CD) as compared to healthy control (HC) subjects. Thirty CD and 30 HC subjects will be studied by 1H-MRS at 7 Tesla (7T). We hypothesize that dysregulated GLU homeostasis will be associated with decreases in VS GLU in CD as compared to HC subjects. Concurrent 18F-FDG and 11C-APP311 PET scans will be obtained to confirm/control for relationships between VS GLU and glucose metabolism and synaptic density, respectively.

Aim 2: To measure changes in VS GLU, as assessed by 1H-MRS, in CD subjects after N-acetylcysteine (NAC) vs. placebo administration. The same 30 CD subjects studied by 7T 1H-MRS at baseline (week 0) in Aim 1 will undergo two additional 1H-MRS scans (at weeks 2 and 4) after double-blind, placebo-controlled, two-week NAC administration (an agent shown to restore GLU homeostasis in preclinical models). Specifically, CD subjects will undergo both 2 weeks of NAC (3600 mg/day) and placebo (0 mg/day) administration as part of a randomized, double-blind, counterbalanced (placebo/active, N=15; active/placebo, N=15) design. We hypothesize that NAC, but not placebo will increase VS (but not occipital cortex) GLU levels (Aim 2a; N=30; within-subject active NAC vs. placebo) in a dose-dependent manner (Aim 2b; N=15 per group; between-subject 3600 mg/d vs. 1800 mg/d vs. placebo) in CD subjects.

Aim 3: To establish the reproducibility of our measures of VS GLU, as assessed by 1H-MRS, in HC subjects and demonstrated the specificity of changes in VS GLU at baseline and following NAC vs. placebo administration. The same 30 HC subjects studied by 7T 1H-MRS at baseline (week 0) in Aim 1 will undergo two additional 1H-MRS scans (at weeks 2 and 4) after double-blind, placebo-controlled, counterbalanced, two-week NAC administration (i.e., procedures identical to those for CD subjects in Aim 2). We hypothesize that VS GLU will be unchanged both by placebo administration (i.e., our 1H-MRS measures will be reproducible) and NAC (i.e., NAC-induced changes in VS GLU will be specific for CD).

Inclusion Criteria:

1. Age 18-55 years;
2. Voluntary, written, informed consent;
3. Physically healthy by medical history, physical, neurological, ECG and laboratory examinations;
4. DSM-IV criteria for Cocaine Dependence (304.20) (Note: subjects will also meet DSM-5 criteria for Cocaine Use Disorder);
5. Documented evidence (by urine toxicology) of abstinence from cocaine (2 weeks for scan 1, and 2 and 4 weeks for scans 2 and 3, respectively)
6. Full scale and verbal IQs > 80;
7. For females, a negative serum pregnancy test (β-HCG) at screening and negative urine pregnancy test on PET scan day prior to imaging.

Exclusion Criteria:

1. A history of other substance dependence (e.g., alcohol, opiates, sedative hypnotics), except for nicotine;
2. A primary DSM-IV Axis I major psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depression, etc.) as determined by the Structured Clinical Interview for DSM-IV (SCID);
3. A history of significant medical (e.g., cardiovascular, diabetic/metabolic) or neurological (e.g., cerebrovascular, seizure, traumatic brain injury) illness;
4. Current use of psychotropic and/or potentially psychoactive prescription medications;
5. Medical contraindications to participation in a magnetic resonance imaging procedure (e.g., ferromagnetic implants/foreign bodies, claustrophobia, cardiac pacemaker, prosthetic valve, otologic implant, etc.);
6. For females, laboratory (β-HCG) evidence of pregnancy, physical evidence of pregnancy;
7. For subjects interested in pharmacotherapy component, history of allergies to NAC and current elevation on liver function tests above twice the normal limit;
8. Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year;
9. Subjects with current, past or anticipated exposure to radiation in the work place within one year of proposed research PET scans;
10. History of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto);
11. Blood donation within eight weeks of the start of the study.