title: Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects.
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 vivo1H-[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 with13C, followed by rapid euthanasia. The mPFC was dissected, extracted with ethanol and metabolite13C enrichments were measured. We found a clear dose-dependent effect of ketamine and Ro 25-6981 on behavior and the percentage of13C 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.
authors.affiliation: Department of Psychiatry and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: G M I
authors.initials: GM
authors.lastname: Chowdhury
authors.affiliation: Department of Psychiatry and the Ribicoff Research Facilities, Yale University School of Medicine, Yale University, New Haven, CT, USA.|Mental Health Centre, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Department of Psychiatry and the Ribicoff Research Facilities, Yale University School of Medicine, Yale University, New Haven, CT, USA.|Centre for Addiction and Mental Health Toronto, Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Banasr
authors.affiliation: Department of Psychiatry and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Psychiatry and the Ribicoff Research Facilities, Yale University School of Medicine, Yale University, New Haven, CT, USA.
authors.forename: B
authors.initials: B
authors.lastname: Pittman
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bristow
authors.affiliation: Janssen Research and Development, Titusville, NJ, USA.
authors.forename: E
authors.initials: E
authors.lastname: Schaeffer
authors.affiliation: Department of Psychiatry and the Ribicoff Research Facilities, Yale University School of Medicine, Yale University, New Haven, CT, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Duman
authors.affiliation: Diagnostic Radiology and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Rothman
authors.affiliation: Department of Psychiatry and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Behar
authors.affiliation: Department of Psychiatry and the Ribicoff Research Facilities, Yale University School of Medicine, Yale University, New Haven, CT, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sanacora
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D010636:Phenols; D010880:Piperidines; C109643:Ro 25-6981; D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D012601:Scopolamine