Date of Award


Degree Name

Doctor of Philosophy




Sergio D. Iñiguez


Ketamine is administered to manage major depressive disorder in adolescent patients. However, the long-term effects of juvenile ketamine exposure on memory-related tasks have not been thoroughly assessed. Thus, we examined whether exposure to ketamine, psychological stress, or both, results in long-lasting alterations in spatial memory in C57BL/6 mice. Furthermore, we evaluated how ketamine and/or psychological stress history influenced hippocampal protein kinase b¬–mammalian target of rapamycin (AKT-mTOR)-related signaling, since this molecular cascade is associated with ketamine’s acute/fast-acting antidepressant properties. Male and female postnatal day (PD)-35 mice underwent 10-days of vicarious defeat stress (VDS), a form of psychological stress, with or without ketamine exposure (20 mg/kg/day; PD35-44). Later in adulthood (PD70) mice were assessed for spatial memory performance by adopting a water maze task or were euthanized for hippocampal tissue collection. Juvenile pre-exposure to ketamine or VDS, individually, increased the latency (sec) to locate the escape platform in adult male, but not female, mice. However, juvenile history of concomitant ketamine and VDS exposure prevented spatial memory impairment in adulthood. Furthermore, individual ketamine or VDS pre-exposure, unlike their combined history, resulted in long-term decreases of AKT-mTOR signaling within the hippocampus of male mice. Conversely, in female mice, ketamine pre-exposure alone increased hippocampal AKT-mTOR signaling. Our preclinical model demonstrates that ketamine, as a prophylactic treatment for adolescent psychological stress-induced sequalae, does not lead to long-term changes in spatial memory. However, juvenile recreational ketamine misuse, like psychological stress history, results in long-term spatial memory deficits, along with alterations of hippocampal AKT-mTOR signaling, in a sex-specific manner.




Recieved from ProQuest

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Rights Holder

Israel Garcia Carachure

Available for download on Friday, June 13, 2025