Chronic repeated stress during childhood has been recognized to be a risk factor for substance abuse and addictive behaviors later in life. At the present time there is little understanding of mechanisms through which this may occur. These studies are designed to test the hypothesis that exposure to chronic repeated stressors during childhood produces a cascade of molecular and cellular events that exert enduring effects on structural and functional brain development, and that these changes are responsible for the enhanced vulnerability to substance use, addiction or relapse. Specifically, 18-22 year old subjects with a history of exposure to harsh stressful corporal punishment (n = 50) will be compared to healthy controls with no history of early stress (n = 50) MRI measures will examine the effects of stress exposure on the morphometry of the corpus callosum, amygdala and cerebellar vermis. Neuronal density/viability in the neocortex and corpus callosum will be assessed using magnetic resonance spectroscopy. The corpus callosum will also be assessed using diffusion tensor imaging to provide information on the orientation and quality of nerve fibers passing through the region. T2-relaxometry will be used to assess left-right hemisphere differences in blood flow, and extent of functional activity in the cerebellar vermis. Subjects will receive probe dose challenge of methylphenidate to test the hypothesis that exposure to chronic early stress enhances risk for substance abuse by sensitized dopamine system hemodynamic response to psychostimutants. Subjects will also be exposed to a social stress test to ascertain whether subjects with a history of early repeated stress show enhanced stress responses as late adolescents - early adults. Stress response will be assessed by fluctuations in cortisol, ACTH, vasopressin, oxytocin and heart rate during and following the stressor. Subjects with a history of exposure to repetitive early stress are predicted to have an increased cortisol and ACTH responses to stress, a diminished oxytocin response, and to require a longer recovery period to return to baseline. Overall, these studies will provide new insight into the possible effects of early stress on neural substrates that may mediate substance abuse liability.
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