Principal Investigator Iiguez, Sergio Diaz ABSTRACT Pediatric major depressive disorder (MDD) is a common condition. Children and adolescents who suffer from MDD often develop conduct and anxiety disorders, and up to 25% develop substance abuse disorder. Consequently, this has resulted in a disproportionate increase in the prevalence of antidepressant medications prescribed to populations below 20 years of age. Despite the heightened rates in antidepressant prescriptions, juveniles are less likely to respond to traditional treatments (i.e., selective serotonin reuptake inhibitors) for the management of MDD. Recently, ketamine (KET), an anesthetic, has shown promise as a treatment for MDD. While exciting for the field of psychiatry ? that a novel pharmaceutical can be used to alleviate MDD symptoms ? the efficacy/safety of KET exposure during development has not been thoroughly examined. This is surprising, given that KET is known to have drug-abuse potential. Thus, to address this problem, the experiments described in this proposal will examine the enduring neurobehavioral consequences of early life (postnatal-day [PD] 35-44) exposure to KET, using C57BL/6 mice. This will be accomplished within the framework of the following specific aims: [1] assess the long-term consequences of chronic adolescent KET (with/without social stress exposure) on sensitivity to reward (drug), mood, and memory-performance in adulthood (PD80+), and [2] to evaluate the integrity of mood-related biological markers [mammalian target of rapamycin (mTOR)-related signaling], within the hippocampal formation. It is expected that juvenile KET exposure will mediate long-lived behavioral alterations associated with enhanced drug abuse potential (i.e., cocaine), altered responses to stress, and memory-related impairment(s). Furthermore, it is expected that site- specific neurochemical adaptations (mTOR fluctuations within the hippocampus) will be a factor mediating the drug-abuse and memory-associated behavioral adaptations as a function of adolescent KET exposure. Collectively, the results of this preclinical work will provide first-line evidence on the potential enduring risks of juvenile KET exposure. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

Public Health Relevance

Principal Investigator Iiguez, Sergio Diaz Narrative Mood-related disorders are highly prevalent in juvenile populations. Off-label pharmacological interventions with novel antidepressants, such as ketamine, are currently being used for the management of these disorders in populations younger than 20 years of age. Thus, the goal of this investigation is to examine whether adolescent ketamine exposure increases drug-abuse liability, and results in memory-related deficits, in adulthood. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM130467-03
Application #
10059143
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Krasnova, Irina N
Project Start
2018-12-26
Project End
2021-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Texas El Paso
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
132051285
City
El Paso
State
TX
Country
United States
Zip Code
79968