Using Twin Data To Identify Alternative Drug Abuse Phenotypes
Ming T. Tsuang, M.D., Ph.D.

SUMMARY: Undoubtedly, some of the difficulty in identifying the susceptibility genes for drug abuse stems from the underlying etiologic complexity of this phenotype. In his study, Dr. Ming Tsuang suggests that the most genetically informative alternative phenotypes could be applied to existing molecular genetic datasets utilizing linkage analysis in an efficient approach that would capitalize on existing resources. These alternative phenotypes may be subtypes and/or quantitative traits. Tsuang shows how twin data can be used to assess the genetic and environmental determinants of the subtypes and/or quantitative traits with an emphasis on identifying maximally heritable alternative phenotypes that can be applied in molecular genetic research.

Common and Specific Genetic Factors in the Development of Substance Dependence
Laura J. Bierut, M.D.

[Slides not available.]

SUMMARY: Dr. Laura Bierut compares and contrasts genetic findings for alcohol dependence with other substance dependence diagnoses (habitual smoking, and marijuana and cocaine dependence) using COGA-identified individuals with alcoholism in chemical dependency treatment centers. All subjects were assessed using SSAGA to evaluate alcohol and other substance dependence, and genetic analyses using affected sibling pair methods were conducted. Genetic analyses of COGA data provided further support for chromosomal regions that may be specific in the development of alcohol dependence, but not other substance dependence. There was also evidence of chromosomal regions that may represent shared genetic factors for the development of multiple substance dependence diagnoses.

Addiction Molecular Genetics: Remarkably Converging Results
George R. Uhl, M.D., Ph.D.

SUMMARY: Dr. George Uhl’s presentation focused on results from his laboratory and others’ that identify several genomic regions highly likely to contain allelic variants that confer vulnerability to addictions, and the nature of some of the candidates for this allelic variability. Association and linkage-based genome scans of polysubstance, alcohol, and nicotine abuse were utilized to study samples of European-Americans, African-Americans, and Asians in several sites. Uhl concluded that substance abuse vulnerability is conferred, in part, by common allelic variants that predispose to abuse of multiple substances. Allelic variants present in several populations are good candidates for direct use in several clinical applications at this time, including identifying responders/nonresponders to different drug treatments, and identifying allelic variants that could predispose to addiction comorbidities.

Using the Systems Biology of Motivation for Genetic Studies in Psychiatry
Gregory P. Gasic, Ph.D.

[Slides not available.]

SUMMARY: Dr. Gregory Gasic’s objective was to show use of mMRI and fMRI as a screen for heritable quantitative markers for addictions and mood disorders. He used fMRI and mMRI combined with multiple paradigms that cover brain systems processing reward/aversion stimuli to probe individuals/families with at least one proband that met criteria for (1) cocaine addiction, (2) recurrent major depressive disorder, or (3) controls to produce a systems biology map. Circuit-based endophenotypes were derived from high throughput multimodal imaging paradigms to produce a saturated sampling of a functional domain. He determined that circuit-based endophenotype delineation may allow a more biological-based classification of these disorders, and ultimately lead to the identification of susceptibility alleles, loci, and genes.

Genetic and Environmental Factors Modulate Cocaine Abuse in Monkey Models
Michael A. Nader, Ph.D.

[Slides not available.]

SUMMARY: Dr. Michael Nader investigated the relationship between D2 receptors, the environment, and vulnerability to self-administer cocaine in monkey models of drug abuse. PET was used to examine D2 levels in adult male macaques. In individually housed monkeys, there was a significant negative correlation between baseline D2 levels and rates of cocaine self-administration. Social housing produced changes in D2 levels such that subordinate monkeys had lower D2 levels than dominants; moreover, subordinates self-administered cocaine at higher rates. In all monkeys, cocaine exposure produced large and robust reductions in D2 levels, highlighting the importance of D2 receptors and the powerful influence of environmental variables on drug abuse.