Craving can be reliably elicited in the laboratory with humans, is associated with alcohol dependence, and is a primary target of biological and behavioral interventions. Activation of mesolimbic and mesocortical structures has been implicated in the development and expression of craving for alcohol and other drugs. Dopamine (D4) receptors are localized to these same structures and our preliminary work has suggested that a D4 antagonist moderates the experience of craving after exposure to alcohol. Our preliminary research has also suggested that the DRD4 VNTR polymorphism is a genetic factor that influences alcohol-elicited craving.
The aims of this competitive continuation are to expand and improve this line of research by incorporating imaging technology (BOLD fMRI). Specifically, the aims are to determine whether exposure to alcohol increases activation of mesolimbic and prefrontal brain structures using BOLD fMRI, to determine whether this activation is correlated with the subjective experience of craving, to determine whether the DRD4 VNTR polymorphism influences this activation, and to determine whether a medication targeting dopamine receptors attenuates this activation. Two separate studies are proposed to meet the specific aims of the proposed research. In the first study, the hemodynamic activation of specific brain structures will be compared after exposure to an alcoholic stimulus versus exposure to an isocaloric control stimulus. To test the influence of the DRD4 VNTR, individuals with the risk allele will be compared to individuals without the risk allele in terms of their hemodynamic activation and subjective craving. It is expected that exposure to the alcoholic stimulus will increase subjective craving as well as increase activation of the brain structures of interest, and it is expected that the individuals with the 7 repeat allele will demonstrate the greatest craving and activation. In the second study, subjects will be randomly assigned to pretreatinent with olanzapine (5 mg) or an active control prior to exposure to the alcoholic and control stimuli. It is expected that olanzapine will attenuate subjective craving and hemodynamic activation associated with the alcoholic stimuli and that this effect will be significantly more pronounced among individuals with the risk allele. The proposed work should establish the influence of alcohol cues on mesocortical and mesolimbic structures and elucidate important biological mechanisms that moderate the expression of craving and loss of control over drinking. The successful completion of the proposed research is also expected to advance our understanding of the role of genetic factors in the development of craving and loss of control drinking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012238-11
Application #
7617721
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Matochik, John A
Project Start
1998-09-21
Project End
2010-08-09
Budget Start
2009-05-01
Budget End
2010-08-09
Support Year
11
Fiscal Year
2009
Total Cost
$495,466
Indirect Cost
Name
The Mind Research Network
Department
Type
DUNS #
098640696
City
Albuquerque
State
NM
Country
United States
Zip Code
87106
Chen, Jiayu; Hutchison, Kent E; Bryan, Angela D et al. (2018) Opposite Epigenetic Associations With Alcohol Use and Exercise Intervention. Front Psychiatry 9:594
Vergara, Victor M; Weiland, Barbara J; Hutchison, Kent E et al. (2018) The Impact of Combinations of Alcohol, Nicotine, and Cannabis on Dynamic Brain Connectivity. Neuropsychopharmacology 43:877-890
Bidwell, L Cinnamon; Karoly, Hollis C; Thayer, Rachel E et al. (2018) DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity. Addict Biol :
Karoly, Hollis C; Thayer, Rachel E; Hagerty, Sarah L et al. (2017) TLR4 Methylation Moderates the Relationship Between Alcohol Use Severity and Gray Matter Loss. J Stud Alcohol Drugs 78:696-705
Thayer, Rachel E; YorkWilliams, Sophie; Karoly, Hollis C et al. (2017) Structural neuroimaging correlates of alcohol and cannabis use in adolescents and adults. Addiction 112:2144-2154
Gardiner, Casey K; YorkWilliams, Sophie L; Bryan, Angela D et al. (2017) Body mass is positively associated with neural response to sweet taste, but not alcohol, among drinkers. Behav Brain Res 331:131-134
Hagerty, Sarah L; Bidwell, L Cinnamon; Harlaar, Nicole et al. (2016) An Exploratory Association Study of Alcohol Use Disorder and DNA Methylation. Alcohol Clin Exp Res 40:1633-40
Thayer, Rachel E; Hagerty, Sarah L; Sabbineni, Amithrupa et al. (2016) Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry. Hum Brain Mapp 37:2276-92
Weiland, Barbara J; Sabbineni, Amithrupa; Calhoun, Vince D et al. (2015) Reduced executive and default network functional connectivity in cigarette smokers. Hum Brain Mapp 36:872-82
Weiland, Barbara J; Thayer, Rachel E; Depue, Brendan E et al. (2015) Daily marijuana use is not associated with brain morphometric measures in adolescents or adults. J Neurosci 35:1505-12

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