Dissociation of mGlu2/3 agonist effects on ketamine-induced regional and event-related oxygen signals.

RATIONALE: Validating preclinical biomarkers that predict treatment efficacy remains a critical imperative for neuropsychiatric drug discovery. With the establishment of novel in vivo imaging methods, it has become possible to think how such translational proof-of-concept studies may look.
OBJECTIVES: The aim of this study was to use in vivo oxygen (O2) amperometry to simultaneously assess the regional and event/task-related O2 changes induced by ketamine challenge in rats, and to determine whether both of these signals are equivalently affected by the mGlu2/3 receptor agonist LY379268.
METHODS: O2 signals were measured via carbon paste electrodes implanted in the anterior cingulate cortex (ACC) of rats trained to perform a simple reaction time task (SRT). SRT performance, event-related ACC O2 responses, and regional ACC O2 signal were recorded simultaneously in animals treated with ketamine (10 mg/kg) and/or LY379268 (3 mg/kg).
RESULTS: A consistent relationship was observed between baseline SRT performance and related ACC O2 signals, suggesting that ACC engagement is likely to be a requirement for optimal task performance. Ketamine induced a robust and consistent slowing in reaction times that was reflected by a delayed event-related ACC O2 signal increase compared to vehicle controls. Ketamine also produced a regional and task-independent 60-min increase in ACC O2 levels which was effectively attenuated by LY379268. However, LY379238 failed to reverse alterations in event-related O2 signals and associated SRT task performance.
CONCLUSIONS: These findings raise questions about the degree to which such reversals of regional ketamine O2 signals could potentially be claimed to predict drug treatment efficacy.