Ketamine Prevents the Development of Avoidance Behavior after Social Defeat Stress in Adolescent Male Mice

Approximately 10% of children and adolescents are diagnosed with major depressive disorder (MDD). Currently, there are limited therapeutic agents to treat MDD in juvenile populations, when compared to numerous options available for adults. To make matters worse, about 50% of adolescents with MDD are unresponsive to available treatments, which demonstrates the need to identify alternative pharmaceutical compounds for the management of juvenile MDD. In adult populations, ketamine an Nmethyl-D-aspartate (NMDA) receptor antagonist has recently shown the capacity for rapid-acting and long-lasting antidepressant efficacy in both preclinical and clinical studies. Thus, to examine whether ketamine could be potential rapid and effective therapeutic agent for juvenile MDD, we exposed adolescent male c57BL/6 mice (postnatal day [PD]35) to 10 days of social defeat stress – a common paradigm used to induce depression-like behaviors in rodents. Specifically, separate groups of defeated and non-defeated (control) adolescent mice were administered with saline or ketamine (20 mg/kg) either after each (chronic), or the last (acute) episode of defeat stress. Twenty-four hr later (PD45), all mice were tested for depression-like behavior, as inferred from the social interaction test (n= 7-12 per group). As expected, adolescent defeated mice administered with saline (chronic and acute) exhibited a depressive-like phenotype (increased social avoidance). Conversely, both chronic and acute exposure to ketamine prevented the development of the stress-induced avoidance phenotype seen after social defeat stress. Together, these findings indicate that the anesthetic ketamine may be a promising novel agent for the treatment of juvenile MDD