Does a hyperactive nociceptin opioid peptide receptor system promote relapse in heavy drinking AUD subjects: a [11C]NOP-1A and hydrocortisone PET study

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Koob and colleagues have postulated that an imbalance between neurotransmitters in the brain stress and anti-stress systems drives negative reinforcement and compulsive alcohol use in alcohol use disorder (AUD). Nociceptin (N/OFQ), which binds to the nociceptive opioid peptide receptors (NOP), is one such neurotransmitter in the brain that regulates stress and resilience in animal models of addiction. N/OFQ, when infused in the brain, increases corticosterone, adrenocorticotropic hormone, and corticotrophin- releasing factor (CRF), all components of the hypothalamic-pituitary-adrenal axis that regulate stress responses. CRF infusions have also been shown to upregulate NOP, presumably to enhance N/OFQ signaling, in brain regions that regulate stress. Surprisingly, both NOP agonists and antagonists show therapeutic effects in rodent models of AUD. However, rodent models do not clarify which, if any, subtype of AUD subjects (e.g., heavy drinking) will benefit from treatment with NOP agonists Vs. antagonists. Previous [11C]NOP-1A PET studies conducted by our group in humans with AUD have demonstrated lower binding (VT) to NOP receptors in heavy relative to nonheavy drinking AUD subjects. In these AUD PET studies, lower NOP receptors also predicted relapse to alcohol in a 12-week contingency management protocol that incentivized subjects with money to abstain. Assuming lower NOP receptors reflect higher N/OFQ levels; these results suggest that increased N/OFQ signaling in heavy drinkers contributes to their inability to abstain during treatment. Blocking excessive N/OFQ signaling with a NOP antagonist drug (LY2940094) has also been shown to decrease heavy drinking days and increase abstinent days in AUD subjects in clinical trials. An emerging view in the field is that a hyperactive N/OFQ-NOP receptor system, in response to increases in CRF transmission, induces hyperkatifeia, negative reinforcement, and relapse in AUD. To investigate CRF X NOP interactions in humans, we designed a PET experiment to measure [11C]NOP-1A VT before and after an intravenous (IV) hydrocortisone challenge in healthy controls (HC). Hydrocortisone administration led to a 10 to 15% increase in [11C]NOP-1A VT in brain regions, including the amygdala. Increased NOP measured in response to cortisol, and by extension, CRF, in this paradigm reflects an individual’s ability to enhance N/OFQ transmission during stress. Here, we propose to use this novel imaging paradigm to compare hydrocortisone-induced increases in [11C]NOP-1A binding (DVT) in the amygdala (and secondary reward regions) in heavy drinking AUD subjects Vs. HC. We hypothesize that hydrocortisone-induced increases in [11C]NOP-1A binding (DVT) will be larger in heavy drinking AUD relative to HC (aim 1), and this will predict relapse to alcohol (aim 2). Such a result will support the presence of a hyperactive NOP receptor system in response to increases in cortisol/CRF during conditions such as stress, chronic pain, etc., promoting relapse in heavy drinking AUD subjects.