The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/Glycine_B-Site Inhibition

Abstract

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 glycine B 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 a-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 glycine B site for the rapid treatment of treatment-resistant depression without the negative side effects seen with ketamine or other channelblocking NMDA receptor antagonists.

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

“…Each of these trials was randomly presented five times. The dose of ketamine (30 mg/kg) was selected based on a dose-response experiment we performed in a previous study 36 . The % pre-pulse inhibition (PPI) was calculated using the following formula: [(magnitude on pulse alone trial – magnitude on pre-pulse + pulse trial)/magnitude on pulse alone trial] × 100.…”

Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity

“…Recently, the NMDA glycine B -site antagonist and prodrug 4-Chlorokynurenine (4-Cl-KYN) and has shown promise as a rapid acting antidepressant [78]. Similar to ketamine, a single treatment with 4-Cl-KYN is sufficient to produce antidepressant-like effects in the FST, novelty-suppressed feeding test (NSFT), and learned helplessness test.…”

Wuling powder prevents the depression-like behavior in learned helplessness mice model through improving the TSPO mediated-mitophagy

“…The mice were considered immobile when floating in the water without struggling and making only those movements necessary to keep their heads above the water. Total immobility times during the last 4 min of the 6-minute test period were recorded (Bambico et al, 2010;Tang et al, 2015;Zanos et al, 2015).…”