Brain Development after Early-Life Antipsychotic Treatment

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This is an application for a Support of Research Enhancement (SuRE) R16 award. These grants are intended to support small scale research projects at institutions like Northern Kentucky University that do not receive substantial NIH funding, with an additional emphasis on providing biomedical research experiences to undergraduate students and enhancing the research environment at the university.
Antipsychotic drugs (APDs) are widely used in children mainly as off-label treatments for a multitude of pediatric psychiatric disorders, despite the lack of basic research documenting their effects on later brain and behavioral function. One concern is that APD exposure during early brain development alters later sensitivity to drugs of abuse. Our previous NIH-funded research showed that adult rats administered the APD, risperidone, early in life are hyperactive, exhibit enhanced locomotor and rewarding responses to the psychostimulant, D-amphetamine, and display alterations in forebrain dopamine transporters and receptors. These data were generated by undergraduate students at NKU, many of whom served as first- or co- authors on published papers, and some of whom went on to pursue graduate study in psychology.
Having ascertained that early-life risperidone modifies responses to psychostimulant drugs that directly target dopamine synapses, we now seek to determine if behavioral and neural sensitivity to other classes of drugs, such as opioids, that indirectly work though dopamine pathways is enhanced by early-life risperidone. The proposed work will ascertain whether behavioral, neural, and genetic responses to the opioid drug, oxycodone, are altered in adult rats administered risperidone early in life (daily injections from postnatal day 14-42). This issue is especially germane to NKU students since our geographic area is marked by relatively high rates of opioid use and overdose. Overall, the proposed research will address the following questions: 1) Does early-life APD administration enhance the rewarding effects of oxycodone during adulthood?, 2) Does early-life APD administration increase neural sensitivity to oxycodone in the forebrain during adulthood? and 3) Does early-life APD administration modify patterns of forebrain gene transcription induced by oxycodone during adulthood? The last aim will be achieved by collaborating with the nearby University of Louisville to quantify mRNA expression in tissue samples using next-generation RNA-Seq technology. A concomitant goal of this work will be to continue engaging NKU undergraduate students in the execution, analysis, and reporting of research. The proposed work will take advantage of training and pedagogical resources offered by NKU and the KY-INBRE program to enhance these experiences and, in turn, contribute to the overall research environment at NKU.

Grant Number: 5R16GM149498-04
NIH Institute/Center: NIH
Principal Investigator: MARK BARDGETT