Enduring effects of juvenile ketamine exposure

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Principal Investigator Iñiguez, 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