Prolonged blockade of NMDA receptors and positive modulation of a5 GABA A receptors: No changes in depressive-like behavior, while the former slightly increased emotional reactivity in unstressed rats

Repeated administration of ketamine (an NMDA receptor antagonist) and GL-II-73 (a positive modulator of a5GABA A receptors) over seven days in adult male rats produced no changes in behavioral despair (forced swim test) or anxiety-like behavior (novelty suppressed feeding test). In spontaneous locomotor activity tests, all treatments reduced the percentage of time spent in the central area at 10 and 30 minutes. Only the higher 10 mg/kg dose of ketamine also reduced central distance traveled at both time points, suggesting a slight increase in emotional reactivity. The lower dose of ketamine and GL-II-73 produced minor changes of similar quality, hardly indicating an anxiety-inducing effect.

Study at a glance

Abstract

Introduction: Depression is a multifaceted disorder with a limited therapeutic repertoire. A significant breakthrough in depression research has been the discovery of fast-acting antidepressants that target the glutamate/GABA system, namely ketamine and neurosteroids. Positive modulation of GABA A receptors containing the a5 subunit (a5GABAARs) represents a promising new approach for targeted therapy of depression. The aim of this study was to investigate the effects of repeated administration of ketamine, an NMDA antagonist, and GL-II-73, a positive allosteric modulator at a5GABAARs, on behavioral despair, anxiety, and locomotor activity. Material and Methods: The experiments were performed on adult male Sprague-Dawley rats. Animals were treated for 7 days with either 6 mg/kg or 10 mg/kg ketamine in an intermittent dosing regimen, 10 mg/kg GL-II-73, or solvent. Following treatment, we performed a battery of behavioral tests consisting of forced swim test (FST), spontaneous locomotor activity (SLA), and novelty suppressed feeding test (NSFT). Results: No change was detected in any of the treatment groups regarding performance in the FST and NSFT. In SLA, all forms of treatment caused a decrease in the percentage of central time at both 10 and 30 minutes. Central distance was reduced at 10 and 30 minutes only after the 10 mg/kg dose of ketamine. Conclusion: Ketamine at the higher dose (10 mg/kg) elicited behavioral changes consistent with a slight increase in emotional reactivity, while minor changes of the same quality in the lower-dose ketamine and GL-II-73 groups hardly reflect any anxiety-inducing influence.