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

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Abstract

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.

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Financial disclosure

Jennifer Francois, Francois Gastambide, Michael Warwick Conway, Mark Tricklebank and Gary Gilmour declare being employees of Eli Lilly & Co Ltd. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013).

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Authors and Affiliations

  1. In Vivo Pharmacology, Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK

    Jennifer Francois, Francois Gastambide, Michael Warwick Conway, Mark Tricklebank & Gary Gilmour

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  1. Jennifer Francois
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  2. Francois Gastambide
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  3. Michael Warwick Conway
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  4. Mark Tricklebank
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  5. Gary Gilmour
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Corresponding author

Correspondence to Francois Gastambide.

Additional information

Jennifer Francois and Francois Gastambide contributed equally to this work.

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Francois, J., Gastambide, F., Conway, M.W. et al. Dissociation of mGlu2/3 agonist effects on ketamine-induced regional and event-related oxygen signals. Psychopharmacology 232, 4219–4229 (2015). https://doi.org/10.1007/s00213-015-3948-4

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  • DOI: https://doi.org/10.1007/s00213-015-3948-4

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