This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term objective of our research is to better understand the neural underpinnings of enhanced vulnerability to substance abuse and dependence in survivors of childhood maltreatment and trauma. The goal of this project is to examine the effects of a specific intervention [unreadable]voluntary exercise [unreadable]on behavioral responses and neural adaptations to psychostimulant drugs in a rat model of early life stress. Our central hypothesis is that voluntary exercise during adolescence will normalize the altered psychostimulant sensitivity previously observed in rats exposed to chronic stress during early postnatal development. Neonatal maternal separation, a rat model of early life stress, is known to produce stress hyper-responsiveness and enhanced sensitivity to psychostimulants that persist into adulthood. Starting at the time of weaning, we will house previously-separated rats and briefly handled controls in cages with or without access to running wheels for three weeks. After the three-week exercise manipulation, we will carry out two experiments with separate cohorts of rats. In experiment 1, we will test rats for their sensitivity to the psychomotor stimulant and reinforcing effects of cocaine in a conditioned-place preference paradigm. In experiment 2, we will test rats for psychomotor sensitization after repeated cocaine injection. We will also measure expression of the dopamine transporter (DAT) and brain-derived neurotrophic factor (BDNF) in limbic brain regions implicated in drug abuse. These proteins were chosen because both are regulated in limbic brain regions by maternal separation and repeated cocaine exposure. We expect that regular exercise will normalize the altered psychostimulant sensitivity and associated neural adaptations induced by maternal separation. The proposed studies will enhance understanding of the mechanisms by which early life stress and physical activity interact to impact substance abuse vulnerability. The outcomes could provide the scientific basis for novel behavioral interventions to prevent or reduce substance abuse in high-risk individuals.