61st Nebraska Symposium on Motivation:
Genes and the Motivation to Use Substances
25-26 April 2013
Coordinated by: Scott Stoltenberg, Ph.D.
Arpana Agrawal, Ph.D. (Washington University, St. Louis)
BIOGRAPHICAL SKETCH: Arpana Agrawal received her Ph.D. in Human Genetics (Quantitative) in 2004 from Virginia Commonwealth University. She moved in Washington University School of Medicine for postdoctoral training and subsequently transitioned to a faculty position in 2006. Her research for the past decade has focused on genetic and environmental influences on cannabis involvement. She is particularly interested in the interplay between genetic vulnerability and environmental factors, and in particular in the role of the endocannabinoid system and its interface with childhood stress. Arpana is funded by the National Institute for Drug Abuse to study the genetic etiology of cannabis involvement via a mid-career development award and to examine the comorbidity between cannabis and tobacco involvement. Arpana serves as a senior editor for genetics-related submissions to Addiction and serves as a consulting editor for the Journal of Abnormal Psychology. She has published 130 peer reviewed publications as well as 5 book chapters.
TITLE: "Has the Genetics of Cannabis Involvement Gone to Pot?"
ABSTRACT: Cannabis is amongst the most commonly used drugs in the United States and in developed nations. With its recent legalization for medical and recreational use, cannabis is back in the limelight for its public health significance. Twin and family studies suggest that cannabis use and misuse are heritable with 50-60% of individual differences attributable to the additive effects of genes. Yet, gene finding efforts have experienced markedly limited success. This presentation examines the genetic architecture of cannabis involvement from a phenotypic and genetic perspective. Our work explores the various neurotransmitter systems that may underlie addiction to cannabis as well as advances in the measurement of cannabis-related problems.
John C. Crabbe, Ph.D. (Oregon Health & Science University)
BIOGRAPHICAL SKETCH: John Crabbe has been at the VA Medical Center and in Behavioral Neuroscience at the Oregon Health & Science University in Portland since 1979. He is director of the NIH Portland Alcohol Research Center. He entered graduate school at the University of Colorado to obtain a Ph.D. in social psychology. Fortuitously, Crabbe was sidetracked into studying behavioral neuroscience at the fledgling Institute for Behavioral Genetics in Boulder. He has been surrounded by mice ever since. His interest is in understanding individual differences in behavioral susceptibility to drugs of abuse, and their neurobiological bases. He uses inbred strains, selectively bred lines, specialized populations for genetic mapping, and mice with null mutations for various genes. He has recently been devoting energy to improving mouse behavioral assays so they can capture and dissect genetic contributions to different aspects of related responses. For example, he is studying how it is that some genes can affect one measure of motor coordination but not other tasks that seem to the experimenter virtually identical. He is developing new measures of alcohol withdrawal. Most recently, he has begun to selectively breed mouse lines that voluntarily drink alcohol until they become intoxicated, i.e., a mouse model of university students.
TITLE: "Rodent Models of Genetic Contributions to Alcohol Abuse"
ABSTRACT: The distinction between alcohol use, which is normative, and abuse, which is unfortunately common, implies dysregulation of motivation directed toward the drug. Genetic contributions to human alcohol abuse comprise personality differences and other predispositions to drink excessively as well as differences in sensitivity to the consequences of the drug. Rat and mouse studies offer immense power to characterize genetic contributions to individual differences, as well as to manipulate the genome of the animals. This review will discuss efforts to address the motivational aspects of individual differences surrounding alcohol use and abuse in rodent genetic animal models. Not surprisingly, the biggest challenge remains relating human motivation (which can be inferred but also self-reported) in a convincing way to the underlying motivation for rodent behavior directed toward and resulting from alcohol. Despite the intrinsic difficulty, substantial progress has been made.
David Goldman, M.D. (National Institute on Alcohol Abuse and Alcoholism)
BIOGRAPHICAL SKETCH: Dr. Goldman received his B.S. from Yale University in 1974. He received his M.D. degree in 1978 and completed residency training in psychiatry in 1979, both at the University of Texas Medical Branch. Dr. Goldman joined the NIAAA in 1979 and has been Chief of the Laboratory of Neurogenetics since 1991. Throughout his career, Dr. Goldman has focused on the identification of genetic factors responsible for inherited differences in behavior, and he has authored over 300 papers. This laboratory has recently completed projects including functional genomics studies identifying genetic studies identifying genetics variants that alter in vitro and in vivo response. These include multilevel studies on NPY, GCH1 and the serotonin transporter. His laboratory is currently exploring the genetics of alcoholism and related psychiatric diseases, and is well-known for his work identifying effects of functional genetic variants on intermediate phenotypes for complex behavioral diseases. Awards that Dr. Goldman has received include NIMH Director’s Honor Award for genetic factors that my alter susceptibility to schizophrenia, James Isaacson Research Award, International Society for Biological Research on Alcoholism, and the NIH Director’s Award for the years 2002 and 2010. Dr. Goldman is author of, “Our Genes, Our Choices.”
TITLE: "Discovery of genes influencing addiction by deep sequencing humans and model organisms"
ABSTRACT: Rare and uncommon alleles contribute to vulnerability to addictions and other behavioral disorders. They are a major part of the missing heritability or “dark matter” subsequent to genome wide association studies. To identify these variants and tie them to behavior we apply deep sequencing in contexts where effects of rare alleles can be measured. In Finns, a founder population, we discovered a stop codon in the HTR2B serotonin receptor. It leads to uncompensated loss of function, can lead to severe impulsivity and alcoholism, and is restricted to Finns in line with the founder characteristics of this population. The behavioral effects of loss of Htr2b function were validated in the Htr2b knockout mouse and extended to the level of neural function, including the role of this receptor in regulating phasic dopamine release in the mesolimbic system. Via exome sequencing of the alcohol preferring (P) rat, one of the most widely accepted model organisms for alcoholism, we found a stop codon in the Grm2 metabotropic glutamate receptor gene. This stop codon was genetically fixed by selection in the P rat, leads to uncompensated effects on glutamate function, and – as shown by genetic studies- is partially responsible for the increased alcohol preference in these rats.
Matt McGue, Ph.D. (University of Minnesota)
BIOGRAPHICAL SKETCH: Matt McGue is a Regents Professor in the Department of Psychology at the University of Minnesota and a Guest Professor in Institute of Public Health at the University of Southern Denmark. Broadly construed, his research has been concerned with the use of longitudinal and behavioral genetic methods to characterize the nature of behavioral development from early adolescence through late adulthood. At the University of Minnesota, he co-directs, along with William Iacono, the Minnesota Center for Twin and Family Research (MCTFR). The MCTFR consists of a series of longitudinal behavioral genetic investigations spanning early adolescence through early adulthood and including nearly 10,000 individuals clustered in 2,500 families. In Denmark, he is part of an interdisciplinary group of investigators using longitudinal methods with samples of more than 20,000 individuals to understand the contribution of genetic and environmental factors to normative aging processes. He is Past President of both the Behavior Genetics Association and the International Society for Twin Studies, and the recipient of the Dobzhansky Award for his lifetime contributions to behavioral genetic research and the Shields Award for his contributions to twin research.
TITLE: The adolescent origins of substance use disorders: A behavioral genetic perspective
ABSTRACT: Individuals who initiate substance use early in adolescence are much more likely to develop a substance use disorder as an adult than are individuals who initiate substance use in late-adolescence or early-adulthood. While the existence of this association is without dispute, the reason why early substance use is associated with an increased risk for adult disorder continues to be debated. It has been hypothesized, for example, that early substance use perturbs the normative course of adolescent development in a way that makes it more likely that the individual will use substances heavily and chronically. Alternatively, individuals who use substances early in adolescence are not a random subset of all adolescents and the factors that lead to early substance use in adolescence may also be the factors that contribute to risk for a substance use disorder in adulthood. Using findings from a series of longitudinal studies that have included twins as well as adopted and non-adopted siblings as they pass through adolescence through early adulthood, I will describe how behavioral genetic methodologies can help characterize the developmental nature of substance use disorders. It is concluded that while early substance use is a marker of broad profile of risk, typically called behavioral disinhibition, early substance also affects the course of adolescent substance use in a way that increases the likelihood of adult psychopathology.
Robert Philibert, M.D., Ph.D. (University of Iowa)
BIOGRAPHICAL SKETCH: Rob Philibert is a genuine Iowa farm boy received an M.D. and a PhD from the University of Iowa, then finished his training in psychiatry at the University of Iowa. He then completed a Pharmacology Research Associate Training (PRAT) Fellowship at the National Institutes of Health in Bethesda and lingered as a Senior Staff Fellow for 4 more years. Subsequently, he returned to the University of Iowa which nurtured a deep and abiding interest in understanding the genetic and environmental determinants of behavioral illness, with a bent towards focusing on those factors amenable to intervention. In this regard, he has developed methods through which to use epigenetic signatures to detect exposure to critical factors involved in behavioral illness and is a member of a NIH funded training center focused on preventive interventions. He is also the founder and the chief scientific officer for Behavioral Diagnostics, Inc., which is developing methylation-based diagnostic measures for the clinical market.
TITLE: "The DNA Methylation Signature of Smoking: An Emerging Archetype for the Identification of Biomarkers for Behavioral Illness"
ABSTRACT: In a series of rapidly emerging studies, we and others have demonstrated that cigarette smoking is associated with changes in the DNA methylation signature of peripheral blood cells. The changes associated with this type of substance use are both dose and genotype dependent. These changes in DNA methylation are also accompanied by changes in gene transcription and protein expression whose patterns are furthermore indicative of increased vulnerability to other forms of complex illness. In our presentation, we will review the latest advances in this field and discuss how these advances allow us insight as to methods through which to stem the smoking epidemic and shed insight into optimizing strategies through which to identify biomarkers for other behavioral illnesses which share similar contributions from environmental and gene- environmental interaction effects.
Robert A. Zucker, Ph.D. (University of Michigan)
BIOGRAPHICAL SKETCH: Robert Zucker is Professor of Psychology in the Departments of Psychiatry and Psychology at the University of Michigan Medical School. He is also Director of both the UM Addiction Research Center and the Department of Psychiatry’s Substance Abuse Section. He received his Ph.D. in clinical psychology from Harvard University’ and has been on the faculty at Michigan since 1994. Zucker has had a career long interest in the etiology and course of substance use disorders, and the development of methods for early identification and intervention that can change high risk life course trajectories. Over the past 30 years he has been collaborating with an interdisciplinary group of scientists in the description of risk development for substance abuse and disorder at multiple levels ranging from the behavioral to the neurophysiological to the genetic. He has published over 200 papers and 7 books, is a member of the editorial boards of five substance abuse and developmental science journals, and is a past president of Society of Addiction Psychology. He has been a MERIT awardee from NIAAA, is a founding member of the Polish Society on Addiction Research and in 2007 was elected to the Polish Psychiatric Society’s Hall of Fame. In 2010 was awarded the Distinguished Researcher Award of the Research Society on Alcoholism.
TITLE: "Genes, Brain, Behavior and Context: the developmental matrix of addictive behavior"
ABSTRACT: Addiction science largely has individual behavior as its focus, albeit at increasingly differentiated levels of analysis ranging from behavior to brain to genes. Context is rarely brought into the causal matrix, although without the addictive object, addiction could not occur. Moreover, although the emergence of addiction is a developmental process, developmental changes in these relationships are rarely examined. My presentation reports results from a 28 year long prospective high-risk for alcoholism family study designed to evaluate these cross-development linkages from early childhood to early adulthood, across multiple levels of analysis involving genes, neural circuitry, behavior, and social context. Results focus on the network of GABA2 relationships to nucleus accumbens responsivity, to externalizing behavior, and to drinking, and illustrate the moderating effect of social relationships—only in specific portions of adolescence.