Imaging CRF X NOP Interactions in CUD

Cocaine use disorder (CUD) is a chronic disorder associated with numerous relapses and periods of abstinence.

Studies in CUD suggest that ~ 60 to 75% of abstinent addicts relapse over twelve months Documenting specific neurochemical abnormalities that lead to relapse in individuals with CUD has the potential to accelerate the development of medications to prevent relapse. Basic investigations postulate an imbalance between brain stress and anti-stress/resilience systems as the underlying mechanism that drives negative reinforcement, craving, and relapse in addiction. Nociceptin (N/OFQ), which binds to the nociceptive opioid peptide receptors (NOP) is a critical component of the brain's anti-stress system. N/OFQ counteracts the functional effects of the primary stress-promoting neuropeptide corticotrophin releasing factor (CRF) in the brain to exert its anti-stress effects. Studies have also shown that acute increases in CRF and stress are countered by increased NOP receptor expression (~ 10% ) in brain regions that regulate stress such as bed nucleus of the stria terminalis. PET studies with the NOP radiotracer [11C]NOP-1A show increased binding to NOP in CUD compared to HC. PET studies also show NOP receptors to upregulate (~ 15%) in response to an acute intravenous hydrocortisone challenge (1 mg/Kg). NOP upregulation may represent an adaptive mechanism in the brain to counteract stress-induced increases in cortisol and CRF. Here, we postulate a failure in this adaptive mechanism as a reason that leads to relapse in CUD. CUD subjects and HC will be studied with [11C]NOP-1A before and after an intravenous hydrocortisone challenge (aim 1). Hydrocortisone is used as a challenge because it increases cortisol and CRF in brain regions that regulate stress. We hypothesize that hydrocortisone-induced increases in [11C]NOP-1A binding (DELTA VT) will be smaller in CUD relative to HC, and this will be associated with less time to relapse in a 12-week follow up.

Cocaine use disorders (CUD)

• Males or females between 18 and 55 years old
• Fulfil DSM-5 criteria for cocaine use disorder
• No other current DSM-5 psychiatric or addictive disorders (such as major depressive disorder, bipolar disorders, psychotic disorders, etc.,)
• No current abuse (six months) of opiates, sedative-hypnotics, amphetamines, MDMA, etc., as well as moderate to severe alcohol or cannabis use (twice a week). Nicotine use will be quantified and controlled between groups using the Fagerstrom Test for Nicotine Dependence (Heatherton et al., 1991);
• Not currently on prescription medical or psychotropic medications
• No current or past severe medical, endocrine or neurological illnesses including glaucoma, seizure disorders, hypertension, hypercholesterolemia as assessed by a complete medical history and physical
• Not currently pregnant or breastfeeding
• No history of significant radioactivity exposure in past year from another research study or occupation that exceeds RDRC guidelines
• No metallic objects in the body that are contraindicated for MRI

Healthy Controls (HC)

• Males or females between 18 and 55 years old
• No present or past DSM-5 disorders (other than nicotine dependence)
• Criteria 5 to 9 as listed previously.