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Background: Major depressive disorder is prevalent in children and adolescents and is associated with a high degree of morbidity throughout life, with potentially devastating personal consequences and public health impact. The efficacy of ketamine (KET) as an antidepressant has been demonstrated in adolescent rodents; however, the neurobiological mechanisms underlying these effects are unknown. Recent evidence showed that KET reverses stress-induced (i.e., depressive-like) deficits within major mesocorticolimbic regions, such as the prefrontal cortex, nucleus accumbens (NAc), and hippocampus, in adult rodents. However, little is known about KET's effect in the ventral tegmental area (VTA), which provides the majority of dopaminergic input to these brain regions., Methods: We characterized behavioral, biochemical, and electrophysiological effects produced by KET treatment in C57BL/6J male mice during adolescence (n = 7-10 per condition) within the VTA and its major projection regions, namely, the NAc and prefrontal cortex. Subsequently, molecular targets within the VTA-NAc projection were identified for viral gene transfer manipulations to recapitulate the effects of stress or KET treatment., Results: Repeated KET treatment produced a robust proresilient response to chronic social defeat stress. This effect was largely driven by Akt signaling activity within the VTA and NAc, and it could be blocked or recapitulated through direct Akt-viral-mediated manipulation. Additionally, we found that the KET-induced resilient phenotype is dependent on VTA-NAc, but not VTA-prefrontal cortex, pathway activity., Conclusions: These findings indicate that KET exposure during adolescence produces a proresilient phenotype mediated by changes in Akt intracellular signaling and altered neuronal activity within the VTA-NAc pathway., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Major depressive disorder afflicts up to 10% of adolescents. However, nearly 50% of those afflicted are considered nonresponsive to available treatments. Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist has shown potential as a rapid-acting and long-lasting treatment for major depressive disorder in adults. Thus, the effectiveness and functional consequences of ketamine exposure during adolescence were explored., Methods: Adolescent male rats (postnatal day [PD] 35) received two ketamine (0, 5, 10, or 20 mg/kg) injections, 4 hours apart, after exposure to day 1 of the forced swim test (FST). The next day, rats were reexposed to the FST to assess ketamine-induced antidepressant-like responses. Separate groups were exposed to chronic unpredictable stress to confirm findings from the FST. After these initial experiments, adolescent naive rats were exposed to either 1 or 15 consecutive days (PD35-49) of ketamine (20 mg/kg) twice daily. Ketamine's influence on behavioral reactivity to rewarding (i.e., sucrose preference) and aversive (i.e., elevated plus-maze, FST) circumstances was then assessed 2 months after treatment. To control for age-dependent effects, adult rats (PD75-89) were exposed to identical experimental conditions., Results: Ketamine (20 mg/kg) reversed the chronic unpredictable stress-induced depression-like behaviors in the FST. Repeated ketamine exposure resulted in anxiolytic- and antidepressant-like responses 2 months after drug exposure. None of the ketamine doses used were capable of inducing drug-seeking behaviors as measured by place preference conditioning., Conclusions: Repeated ketamine exposure induces enduring resilient-like responses regardless of age of exposure. These findings point to ketamine, and its repeated exposure, as a potentially useful antidepressant during adolescence., (© 2013 Society of Biological Psychiatry.)