Novelty seeking behavior promotes the ability to discover and construct new knowledge about the environment. Greater preferences for novelty during infancy predict higher scores on tests of intelligence, language, memory, and speed of information processing in children and young adults. Novelty seeking can be costly, however, as it increases the prevalence of reckless driving, pathological gambling, unprotected sex, under-age drinking, and other forms of alcohol and drug abuse. Recently, we discovered that novelty seeking in an animal model mediates the effects of early social stress on subsequent resistance to extinction of a conditioned place preference for cocaine. Our preliminary evidence further suggests that early exposure to social stress induces long-lasting downregulation of dopamine D2 receptor (DRD2) gene expression in ventral but not dorsal striatum. Diminished ventral striatal DRD2 availability determined in vivo by positron emission tomography (PET) has been linked in humans and animal models to novelty seeking and related maladaptive forms of anticipatory impulsivity, but not in the context of early social stress. Therefore, we plan to test the hypothesis that early social stress downregulates DRD2 gene expression in ventral striatum via epigenetic mechanisms (i.e., increased DNA methylation) and thereby increases anticipatory impulsivity. Specifically, we address the following three aims.
Aim 1. Determine whether early social stress increases DRD2 gene promoter methylation in ventral but not dorsal striatum assessed by bisulfite sequencing of DNA from striatal brain tissues.
Aim 2. Determine whether early social stress decreases DRD2 availability in ventral but not dorsal striatum assessed in vivo by positron emission tomography.
Aim 3. Determine whether early social stress increases anticipatory impulsivity without impairing non-anticipatory forms of impulsive behavior. The studies designed to address these aims will provide mechanistic insights for understanding the pathways that mediate the long-term effects of early social stress on broadly important health-related aspects of behavior.

Public Health Relevance

The public health impacts of understanding the mechanisms that mediate the effects of social stress on health-related behavior are potentially quite high. According to the World Health Organization, stress- related mental health disorders will be the second leading cause of all medical disabilities by the year 2020. The American Institute of Stress has determined that currently more than 70% of all medical visits are stress-related and collectively cost the nation 42 billion dollars each year. Consequently, there is an urgent need for new mechanistic insights to guide the development of public health policies and interventions designed to alleviate the detrimental long-term effects of exposure to early social stress.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZRG1-BBBP-J (50))
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Lynch, Minda
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Stanford University
Schools of Medicine
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Lee, Alex G; Nechvatal, Jordan M; Shen, Bin et al. (2016) Striatal dopamine D2/3 receptor regulation by stress inoculation in squirrel monkeys. Neurobiol Stress 3:68-73
Brockhurst, J; Cheleuitte-Nieves, C; Buckmaster, C L et al. (2015) Stress inoculation modeled in mice. Transl Psychiatry 5:e537
Lee, Alex G; Buckmaster, Christine L; Yi, Esther et al. (2014) Coping and glucocorticoid receptor regulation by stress inoculation. Psychoneuroendocrinology 49:272-9
Nechvatal, Jordan M; Lyons, David M (2013) Coping changes the brain. Front Behav Neurosci 7:13