Format

Send to

Choose Destination
See comment in PubMed Commons below
Mol Psychiatry. 2017 Jan;22(1):120-126. doi: 10.1038/mp.2016.34. Epub 2016 Apr 12.

Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects.

Author information

1
Department of Psychiatry and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Psychiatry and the Ribicoff Research Facilities, Yale University School of Medicine, Yale University, New Haven, CT, USA.
3
Mental Health Centre, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
4
Centre for Addiction and Mental Health Toronto, Toronto, Ontario, Canada.
5
Bristol-Myers Squibb, Wallingford, CT, USA.
6
Janssen Research and Development, Titusville, NJ, USA.
7
Diagnostic Radiology and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT USA.

Abstract

Several drugs have recently been reported to induce rapid antidepressant effects in clinical trials and rodent models. Although the cellular mechanisms involved remain unclear, reports suggest that increased glutamate transmission contributes to these effects. Here, we demonstrate that the antidepressant-like efficacy of three unique drugs, with reported rapid onset antidepressant properties, is coupled with a rapid transient rise in glutamate cycling in the medial prefronal cortex (mPFC) of awake rats as measured by ex vivo 1H-[13C]-nuclear magnetic resonance spectroscopy. Rats were acutely pretreated by intraperitoneal injection with a single dose of ketamine (1, 3, 10, 30 and 80 mg kg-1), Ro 25-6981 (1, 3 and 10 mg kg-1), scopolamine (5, 25 and 100 μg kg-1) or vehicle (controls). At fixed times after drug injection, animals received an intravenous infusion of [1,6-13C2]glucose for 8 min to enrich the amino-acid pools of the brain with 13C, followed by rapid euthanasia. The mPFC was dissected, extracted with ethanol and metabolite 13C enrichments were measured. We found a clear dose-dependent effect of ketamine and Ro 25-6981 on behavior and the percentage of 13C enrichment of glutamate, glutamine and GABA (γ-aminobutyric acid). Further, we also found an effect of scopolamine on both cycling and behavior. These studies demonstrate that three pharmacologically distinct classes of drugs, clinically related through their reported rapid antidepressant actions, share the common ability to rapidly stimulate glutamate cycling at doses pertinent for their antidepressant-like efficacy. We conclude that increased cycling precedes the antidepressant action at behaviorally effective doses and suggest that the rapid change in cycling could be used to predict efficacy of novel agents or identify doses with antidepressant activity.

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center