Alcoholism is a chronic disease with severe consequences to society, and stress plays a key role in precipitating relapse of ethanol (EtOH) consumption in dependent alcoholics. Even in non-dependent populations, evidence supports a key role for neural stress networks in binge EtOH intake. Therefore, further research is required to advance scientific knowledge of the intricate neurobiology underlying stress-related behavior and excessive EtOH drinking. Indeed, multiple stress neuropeptide systems contribute to EtOH- related behaviors in complex ways. C57BL/6J (B6) mice serve as an ideal for model interrogating the neurobiology of excessive EtOH intake, as they voluntarily consume sufficient quantities of EtOH within discrete periods of the circadian dark cycle to produce blood EtOH concentrations (BECs) that surpass the NIAAA's criteria for binge drinking (80 mg/dL, or .08 percent). This proposal will integrate in vivo optogenetic stimulation/inhibition experiments with models of long-term intermittent binge drinking and aversive place conditioning in order to establish (or refute) causal relationships between the hypothalamic hypocretin system, stress-like states of hyperarousal, and pathological EtOH consumption. In addition, these experiments will use viral tracing and double fluorescent immunohistochemistry to anatomically define the pathways connecting the corticotropin-releasing factor (CRF) and hypocretin systems, and determine how these interactions control the stress response and EtOH drinking behavior. Stress hormone measurements, subtype-specific pharmacology, and transcription factor mapping will provide complementary measures to confirm the findings and further define the precise neural substrates underlying these behaviors. Knowledge gained from the proposed experiments will inform future strategies for mitigation of drug abuse and relapse.

Public Health Relevance

Brain stress systems contribute to binge alcohol consumption, and life stress can precipitate relapse in alcoholics that attempt to quit drinking. In addition to providing structured opportunities for my professional development, these experiments will advance our understanding of the brain systems that control stress- related arousal and excessive binge drinking. Future studies will build upon these findings to improve behavioral and pharmacological strategies designed to mitigate drug abuse and relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AA022832-01
Application #
8648432
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Grandison, Lindsey
Project Start
2013-12-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$47,114
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Giardino, William J; de Lecea, Luis (2014) Hypocretin (orexin) neuromodulation of stress and reward pathways. Curr Opin Neurobiol 29:103-8