We propose a multidisciplinary, translational genetic study to identify genes that influence sensitivity to the stimulant drugs methamphetamine and amphetamine in mice and humans. We will use mice to better define chromosomal regions (also called quantitative trait loci or QTL) that contain genes that influence sensitivity to the acute locomotor stimulant effects of methamphetamine. This will be accomplished using two complimentary approaches: congenic strains, and advanced intercross lines. Using these techniques, we will be able to determine, with some precision, the location of genes that influence this trait. We will then use a variety of experimental and bioinformatic approaches to parse among the genes located in those regions, which will allow us to identify a small number of high probability candidate genes. We expect that this list of genes will include those responsible for differences in the response to methamphetamine in the mice. We will then explore the effect of polymorphisms in these genes on the subjective response to amphetamine in a sample of carefully screened, healthy human volunteers. All volunteers will give informed consent prior to participation in the study. We will use a double-blind, within-subject design in which each subject receives each dose (placebo, 5,10 and 20 mg) of amphetamine once, in a randomized order, over the course of 4 sessions. During the sessions when drug or placebo has been administered, subjects will self-report their emotional and cognitive experiences, which are expected to include a subjective feeling of being under the influence of a drug, as well as varying degrees of euphoria and anxiety. We will also evaluate their performance on behavioral tasks, and record physiological data over the course of the sessions. We will then examine the relationship between the response to amphetamine and polymorphisms in the genes selected in the mouse studies. We expect that some of the genes have polymorphisms that are associated with, and may cause, differences in the response to amphetamine among the human volunteers. We believe that differences in the acute response to stimulant drugs like amphetamine, methamphetamine and cocaine are important for determining the genetic risk for the development of drug abuse. Identification of these genes may be useful for developing new therapeutic strategies to treat or prevent drug abuse and addiction.

Public Health Relevance

Mice are useful for studying how genes can influence behavior. Because the genetic risk for drug abuse depends in part on the initially pleasurable responses to drugs, we are interested in identifying the genes that cause some individuals to like the effects of drugs better than others. By using powerful behavioral models, molecular genetic techniques, and appropriate statistical methodology, we can identify these genes in mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA021336-07
Application #
8281455
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Satterlee, John S
Project Start
2006-09-15
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
7
Fiscal Year
2012
Total Cost
$413,455
Indirect Cost
$128,732
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Zhou, Lili; Bryant, Camron D; Loudon, Andrew et al. (2014) The circadian clock gene Csnk1e regulates rapid eye movement sleep amount, and nonrapid eye movement sleep architecture in mice. Sleep 37:785-93
Zhou, Lili; Bryant, Camron D; Loudon, Andrew et al. (2014) The circadian clock gene Csnk1e regulates rapid eye movement sleep amount, and nonrapid eye movement sleep architecture in mice. Sleep 37:785-93, 793A-793C
Li, Yan; Cheng, Riyan; Spokas, Kurt A et al. (2014) Genetic variation for life history sensitivity to seasonal warming in Arabidopsis thaliana. Genetics 196:569-77
Hart, Amy B; Gamazon, Eric R; Engelhardt, Barbara E et al. (2014) Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder. Proc Natl Acad Sci U S A 111:5968-73
Wang, T; Han, W; Wang, B et al. (2014) Propensity for social interaction predicts nicotine-reinforced behaviors in outbred rats. Genes Brain Behav 13:202-12
Carbonetto, P; Cheng, R; Gyekis, J P et al. (2014) Discovery and refinement of muscle weight QTLs in B6 × D2 advanced intercross mice. Physiol Genomics 46:571-82
Parker, Clarissa C; Chen, Hao; Flagel, Shelly B et al. (2014) Rats are the smart choice: Rationale for a renewed focus on rats in behavioral genetics. Neuropharmacology 76 Pt B:250-8
Gonzales, Natalia M; Palmer, Abraham A (2014) Fine-mapping QTLs in advanced intercross lines and other outbred populations. Mamm Genome 25:271-92
Fitzpatrick, Christopher J; Gopalakrishnan, Shyam; Cogan, Elizabeth S et al. (2013) Variation in the form of Pavlovian conditioned approach behavior among outbred male Sprague-Dawley rats from different vendors and colonies: sign-tracking vs. goal-tracking. PLoS One 8:e75042
Cheng, Riyan; Palmer, Abraham A (2013) A simulation study of permutation, bootstrap, and gene dropping for assessing statistical significance in the case of unequal relatedness. Genetics 193:1015-8

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