This resubmission of a renewal application for Years 11-15 of grant DA-009842 (a NIDA R-37 MERIT Award in Years 06-10) responds to NIDA's Program Announcement PA-02-085. We also request a secondary assignment to NIAAA. We treat and study adolescents with substance dependence (SD) and conduct disorder (CD). Biologic, genetic mechanisms contribute to the expression of CD, SD, and behavioral disinhibition. Failures to desist from risky behavior could result from biological differences in brain processing of reward, punishment, or decision-making. We propose functional and morphological MRI studies, comparing control adolescents with substance-dependent patients. We also will examine patients'at-risk 9-11 year-old younger siblings, and control youngsters, before any of the siblings engage in extensive substance use. We will pursue these hypotheses: Treatment subjects (TS;patients and their siblings) will differ from controls: (a) TS will make more risk-taking behavioral responses, (b) While deciding to make, or to desist from, a risky behavior, TS will show significantly different intensity of activation in orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC). (c) While being rewarded for a risky behavior TS will show significantly different intensity of activation in caudate, thalamus, and nucleus accumbens (ventral striatum), as well as in OFC and ACC. (d) While being punished for a risky behavior TS will show significantly different intensity of activation in cerebellar vermis, as well as in OFC, ACC, caudate, and accumbens. (e) TS will have significantly reduced gray matter volume in both left OFC and right OFC. (f) Similarly, TS will show significant white matter volume reductions in right inferior parietal lobule, left inferior parietal lobule, and right frontal lobe, (g) After examining the regions of interest in pre-hoc hypotheses (b) - (f), we also will conduct exploratory analyses of differences in other brain areas, (h) Separately, examining only adolescent patients, we will seek correlations between the severity of clinical problems (CD symptom count, count of substance- dependence symptoms) and the severity of morphological and functional abnormalities, (i) Analyses will account for (when appropriate) gender, age, severity of comorbid ADHD, depression, and conduct problems;and extent of substance involvement.
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