DESCRIPTION: (Applicant's Abstract) We have found spatial learning deficits after exposure to methamphetamine (MA) and MDMA on postnatal days 11-20. Based on comparative CNS ontogeny, this period in rats is analogous to human 2nd-3rd trimester development. Exposures from weaning to puberty in rodents (equivalent to childhood to adolescent development) are poorly understood, despite the fact that children and adolescents sometimes abuse stimulants. Neurochemically, we have found significant changes in dopamine and GFAP between postnatal day 20 and 60 in response to MA, ages spanning the so-called periadolescent period of rodent development. Based on these data, it appears that there are changes occurring during these stages of brain development which could affect MA-induced neurotoxicity. The purpose of this application is to investigate the cognitive effects of exposure to MA to determine if there are later periods of vulnerability. Assessments will include the Morris water maze test of spatial navigation, tests of working and sequential learning, and conditioned place preference (CPP) behavior. Effects on hippocampal norepinephrine will be investigated based on new data showing that MDMA increases NE after preweaning exposure. Split-litter-by-exposure-age experiments will first determine the most vulnerable ages for learning and CPP effects; these will be followed by split-litter dose-response experiments for those periods showing the largest effects and will investigate effects on working memory. Exposure periods will be postnatal days 21-30, 31-40, 41-50, and 51-60. A final experiment to differentiate the previously found preweaning vulnerable period will be investigated after treatment on postnatal days 11-15 or 16-20. Experiments will begin with MA treatment and proceed to treatment with MDMA depending on the outcome of the MA experiments. NIDA has identified an important gap in our understanding of the effects of drugs of abuse on cognitive development and its neurobiological substrates and this application will develop data to fill this gap in an animal model of MA and MDMA-induced neurotoxicity."