Sex‐Specific Relationships Between Nociceptin/Orphanin FQ Peptide (NOP) Receptors and Alcohol Drinking: Longitudinal PET Studies in Cynomolgus Monkeys

ABSTRACT

Drugs that interact with brain nociceptin/orphanin FQ (NOP) receptors can decrease ethanol consumption in preclinical models of alcohol use disorder (AUD). Studies using positron emission tomography (PET imaging) in humans with AUD reported lower levels of NOP receptors compared to controls. Here, uptake of the NOP receptor–selective PET radiotracer [ ¹¹ C]NOP‐1A was measured in monkeys (six males, five females) when ethanol‐naïve and again after a 4‐month induction procedure plus 6 months of ethanol drinking (22 h/day, 5 days/week). Although there were no sex differences in brain uptake of [ ¹¹ C]NOP‐1A before ethanol self‐administration, sex differences were observed in relationships between [ ¹¹ C]NOP‐1A uptake and ethanol‐related measures. Baseline [ ¹¹ C]NOP‐1A uptake in the orbitofrontal cortex in males and caudate nucleus in females predicted future ethanol intakes. Moreover, chronic ethanol self‐administration produced changes in [ ¹¹ C]NOP‐1A uptake in AUD‐related brain areas. Increases in uptake were observed in the putamen of both sexes and in the nucleus accumbens and amygdala of males; females showed a decrease in the insula. Changes in [ ¹¹ C]NOP‐1A uptake in the orbitofrontal cortex, putamen and hypothalamus of males and caudate nucleus of females were related to ethanol intake. These results demonstrate bidirectional relationships between brain NOP receptors and ethanol self‐administration and provide evidence of subtle sex differences in these interactions.