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
Djordje Djorović, Jana Ivanović, Kristina Jezdić, Dishary Sharmin, Jovana Aranđelović, James M. Cook, Miroslav M. Savić
Medicinska istrazivanja January 1, 2025 Peer reviewed DOI: 10.5937/medi0-57913 via OpenAlex
Summary
Ketamine at a higher dose (10 mg/kg) led to slight increases in emotional reactivity in male Sprague-Dawley rats, while no significant changes were observed in behavioral tests for despair or anxiety with either ketamine or GL-II-73 treatments. Both doses of ketamine and GL-II-73 decreased central time in spontaneous locomotor activity tests, but only the higher dose of ketamine reduced central distance significantly. Overall, the results indicate minimal effects on anxiety-related behaviors.
Study at a glance
| Design | experimental study |
|---|---|
| Population | adult male Sprague-Dawley rats |
| Key finding | Ketamine at the higher dose (10 mg/kg) elicited behavioral changes consistent with a slight increase in emotional reactivity. |
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.