The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition.
Currently approved antidepressant drug treatment typically takes several weeks to be effective. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment of depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycineB co-agonist site of the NMDA receptor, located on the GluN1 subunit, by the selective full antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-chlorokynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pretreatment with glycine or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression without the negative side effects seen with ketamine or other channel-blocking NMDA receptor antagonists.
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Panos
P
Zanos
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Sean C
SC
Piantadosi
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Hui-Qiu
HQ
Wu
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Heather J
HJ
Pribut
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Matthew J
MJ
Dell
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Adem
A
Can
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
H Ralph
HR
Snodgrass
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Carlos A
CA
Zarate
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Robert
R
Schwarcz
Department of Psychiatry (P.Z., S.C.P., H.-Q.W., H.J.P., M.J.D., A.C., R.S., T.D.G.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), Department of Pharmacology (R.S., T.D.G.), Department of Anatomy and Neurobiology (T.D.G.), University of Maryland School of Medicine, Baltimore, Maryland; VistaGen Therapeutics, Inc., San Francisco, California (H.R.S.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.) gouldlab@me.com.
Todd D
TD
Gould
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D005998:Glycine; D019417:Hindlimb Suspension; D007649:Ketamine / Q000009:adverse effects / Q000494:pharmacology*; D007737:Kynurenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D017551:Microdialysis; D011355:Prodrugs / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013550:Swimming
D011355:Prodrugs; D016194:Receptors, N-Methyl-D-Aspartate; D007737:Kynurenine; D007649:Ketamine; C027883:4-chlorokynurenine; D005998:Glycine