This is a revised competing renewal. We found that d-methamphetamine (MA) induces spatial learning and memory (L&M) deficits in Morris water maze (MWM) after exposure on P11-20 but not P1-10, and increases corticosterone (CORT). During the most recent period we found that MA causes dose-dependent MWM spatial and 'strategies' but not cued deficits, reference but not working memory deficits and spares sequential learning. Spatial deficits generalize to Barnes maze to aversive, but were unclear for appetitive reinforcement. MA results in ~15% reductions in striatal DA, D2 receptors, PKA, and in dendritic spines and arbors. MWM deficits emerge by P40 and persist until at least P360. Fractionating P11-20 reveals MWM deficits after P11-15 but not P16-20. The stress hyporesponsive period (SHRP) is P4-14. We find a MA-related SHRP of P7-13 to single doses, but 5-day MA overrides this with a CORT rise at 24 hours. New hypotheses: (1) Developmental exposure to MA from P11-15 results in altered response to stressors and L&M. We will test this in offspring measuring CORT after stressor exposure or on hippocampally-mediated L&M; (2) Inhibition of CORT synthesis in MA exposed rats will reduce CORT release during MWM testing, resulting in improved performance. We will test this in offspring pretreated with metyrapone; (3) MA induced increases in CORT during the SHRP are the cause of the subsequent L&M deficits observed later and preventing this increase will prevent the deficits. We will test this by adrenal removal following by alloengraftment, causing a 7-10 day interruption of adrenal function during the treatment interval and test the offspring for L&M as adults; (4) Exposure to MA during periods outside the SHRP will not result in the L&M deficits or NMDA receptor changes observed from exposures within the SHRP. We will test this with 4 exposure intervals, 2 within and 2 outside (1 before and 1 after) the SHRP and determine the effects on L&M and hippocampal NMDA receptors by 3H-MK-801 autoradiography and receptor complex-associated immunocytochemistry for PSD95, nNOS, CAPON, Dexras1, and Synapsin I-III. We will also determine the contribution of drug-induced undernutrition on multiple types of spatial learning, on hippocampus-dependent non-spatial learning, and on attention. The number of prenatally MA exposed children continues to grow. Our goal is to develop models of early MA exposure that permit an understanding of the long-term consequences on brain development and cognition.
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