DESCRIPTION (provided by applicant): This is a renewal application for an R15 AREA grant to continue the research funded by our previous award ("Long-term effects of early-life antipsychotic drug treatment"). These grants are intended to stimulate research at educational institutions like Northern Kentucky University that support baccalaureate training but are not recipients of major NIH support. Over the past 20 years, the use of antipsychotic drugs (APDs) in pediatric populations has increased eight-fold - a phenomenon that has garnered considerable attention in the scientific community and national media. This trend continues despite the relative absence of basic research documenting the effects of early-life APD exposure on later brain and behavioral function. One concern is that APD exposure during early brain development alters later sensitivity to drugs of abuse. Over the last three years, our funded studies have shown that adult rats administered risperidone early in life are hyperactive and impulsive, and demonstrate an enhanced locomotor response to D-amphetamine (AMPH) and a decreased density of forebrain dopamine transporters, a primary target of psychostimulant drugs. Together, these data suggest that early-life risperidone administration permanently alters the sensitivity of forebrain dopamine systems in ways that could magnify the behavioral effects of psychostimulant drugs. To continue investigating this hypothesis, we propose to answer the following questions: 1) Does early-life APD administration alter the rewarding and cognitive-impairing effects of AMPH during adulthood? Conditioned place preference and an operant, spatial working memory task will be used to determine if adult rats administered risperidone early in life are more sensitive to the rewarding and cognitive-impairing effects of AMPH, respectively. 2) Does early-life APD administration alter the effects of AMPH on striatal dopamine and glutamate release during adulthood? AMPH elevates dopamine and glutamate release in the striatum - actions that are associated with AMPH's locomotor effects. The effects of AMPH on striatal dopamine and glutamate release will be characterized in adult rats administered risperidone early in life. 3) Does early-life APD administration alter markers of
forebrain synaptic function during adulthood? Since dopamine and norepinephrine transporters are the primary targets of AMPH, the density of each transporter will be quantified in various forebrain regions of adult rats administered risperidone early in life. We will also compare the densities of dopamine and serotonin receptors, as well as indices of dendritic architecture revealed via Golgi staining, between adult rats as a function of early-life risperidone administration. Continued AREA funding will enable us to immerse undergraduates in enriching interdisciplinary research experiences in psychopharmacology, developmental neuroscience, and neurochemistry. Moreover, it will ensure that researchers, policy-makers, and practitioners are provided with critically sought-after data regarding the long-term impact of prolonged APD treatment during childhood.