Acute Elevations in Cortisol Increase the In Vivo Binding of [11C]NOP-1A to Nociceptin Receptors: A Novel Imaging Paradigm to Study the Interaction Between Stress- and Antistress-Regulating Neuropeptides.

BACKGROUND: An imbalance between neuropeptides that promote stress and resilience, such as corticotropin-releasing factor and nociceptin, has been postulated to underlie relapse in addiction. The objective of this study was to develop a paradigm to image the in vivo interaction between stress-promoting neuropeptides and nociceptin (NOP) receptors in humans. METHODS: [11C]NOP-1A positron emission tomography was used to measure the binding to NOP receptors at baseline (BASE) and following an intravenous hydrocortisone challenge (CORT) in 19 healthy control subjects. Hydrocortisone was used as a challenge because in microdialysis studies it has been shown to increase corticotropin-releasing factor release in extrahypothalamic brain regions such as the amygdala. [11C]NOP-1A total distribution volume (VT) in 11 regions of interest were measured using a 2-tissue compartment kinetic analysis. The primary outcome measure was hydrocortisone-induced ΔVT calculated as (VT CORT - VT BASE)/VT BASE. RESULTS: Hydrocortisone led to an acute increase in plasma cortisol levels. Regional [11C]NOP-1A VT was on average 11% to 16% higher in the post-hydrocortisone condition compared with the baseline condition (linear mixed model, condition, p = .005; region, p < .001; condition × region, p < .001). Independent Student's t tests in all regions of interest were statistically significant and survived multiple comparison correction. Hydrocortisone-induced ΔVT was significantly negatively correlated with baseline VT in several regions of interest. CONCLUSIONS: Hydrocortisone administration increases NOP receptor availability. Increased NOP in response to elevated cortisol might suggest a compensatory mechanism in the brain to counteract corticotropin-releasing factor and/or stress. The [11C]NOP-1A and hydrocortisone imaging paradigm should allow for the examination of interactions between stress-promoting neuropeptides and NOP in addictive disorders.

Failure to detect amphetamine-induced dopamine release in the cortex with [11 C]FLB 457 positron emission tomography (PET): Methodological considerations.

Studies in nonhuman primates and humans have demonstrated that amphetamine-induced dopamine release in the cortex can be measured with [11 C]FLB 457 and PET imaging. This technique has been successfully used in recent clinical studies to show decreased dopamine transmission in the prefrontal cortex in schizophrenia and alcohol dependence. Here, we present data from a cohort of twelve healthy controls in whom an oral amphetamine challenge (0.5 mg kg-1 ) did not lead to a significant reduction in [11 C]FLB 457 BPND (i.e., binding potential relative to non-displaceable uptake). Two factors that likely contributed to the inability to displace [11 C]FLB 457 BPND in this cohort relative to successful cohorts are: (a) the acquisition of the baseline and post-amphetamine scans on different days as opposed to the same day and (b) the initiation of the post-amphetamine [11 C]FLB 457 scan at ∼5 hours as opposed to ∼3 hours following oral amphetamine. Furthermore, we show [11 C]FLB 457 reproducibility data from a legacy dataset to support greater variability in cortical BPND when the test and retest scans are acquired on different days as compared to the same day. These results highlight the methodological challenges that continue to plague the field with respect to imaging dopamine release in the cortex.