This is the second submission of a Phase II Cutting Edge Basic Research Award (CEBRA) that follows the Principal Investigator's Phase I application entitled, Evoked potentials and vulnerability to ketamine in mice (5-R21-DA-017082-02). All of the reviewers'concerns have been fully addressed in this revised application. Rationale: Experimentation with drugs of abuse is common among adolescents and young adults. Although the immediate consequences of intoxication are known, the ubiquitous nature of casual use leads many clinicians to discount mild drug abuse during high school and college as causal of later psychiatric symptoms and syndromes. Despite such assumptions, the lasting consequences of drugs that are emerging on campuses and in clubs across the nation, such as ketamine, are not known. During the Phase I portion of this study, the PI demonstrated persistent changes in Event Related Potentials (ERPs) following chronic ketamine exposure in adult mice. Preliminary data and previous literature also demonstrate that ketamine causes cellular pathology in brain. Questions that will be addressed: These findings lead to the following two overarching questions: 1) Does intermittent exposure to NMDA receptor antagonists during adolescence cause persistent physiological and cognitive deficits in adults? 2) Can adolescent ketamine abuse cause persistent alterations in cellular constituents and/or receptor signaling mechanisms in adults? Approach and Methods: Therefore, proposed studies will determine the duration of persistent ERP and cognitive deficits following ketamine exposure during adolescence in mice (Aim 1). Complementary studies will determine which cell classes are selectively altered by ketamine using stereological population estimates in adult animals following immunohistochemistry for cell-specific markers. Additionally, we will analyze measures of immediate cellular pathology directly following ketamine exposure during adolescence (Aim 2).
Aim 3 will then utilize ex-vivo studies to determine the pattern of functional alterations of intracellular mechanisms of NMDA receptor mediated signal transduction among surviving cell populations following developmental exposure to ketamine. Significance: These three parallel Aims will address the degree of physiological, anatomical and biochemical functional neuroplasticity that exits following adolescent ketamine exposure. Therefore, completion of the proposed body of work will provide valuable evidence regarding the long-term, possibly irreversible, consequences of intermittent drug abuse during adolescence and early adulthood. Furthermore, these studies will address the potential roles of early drug abuse in later cognitive and psychiatric disorders throughout life.Although ketamine (Special K) abuse is common among adolescents, the consequences of this behavior are not known. To address this issue, we previously demonstrated that ketamine causes short-term changes in brain activity and signs of brain damage in adult mice. Proposed studies will determine the duration of abnormal brain function and the extent of brain damage following ketamine in adolescent mice to assess the potential for lasting, irreversible consequences of drug abuse during adolescence.
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