Alcoholism is a tremendous health and financial burden on our society. A growing literature indicates that a series of interconnected brain regions referred to as the extended amygdala plays a key role in alcohol-related behaviors. In isolated studies, we and others have identified adaptations that occur at synapses in these regions in response to acute and chronic ethanol exposure. Here, we propose experiments to in parallel examine key points in this circuitry for their responses to a common alcohol treatment regimen, to better determine the concerted effects of ethanol and ethanol withdrawal. Moreover, we will assess molecular mechanisms involved in these actions through the use of a new conditional knockout mouse for the NMDA receptor subunit NR2B combined with a viral-directed knockout strategy. In total, the proposed work will begin to define specific mechanisms likely to play key roles in pathological adaptations and behaviors associated with chronic alcohol intake, thus providing new potential opportunities for therapeutic development.

Public Health Relevance

Alcoholism poses an enormous health and financial burden on our society. Currently, our understanding of the brain circuitries involved in alcoholism is far from complete. The successful completion of these proposed studies will result in important new information about neurons that may be involved in alcoholism, potentially creating new targets for therapeutics development.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Schools of Medicine
United States
Zip Code
Conrad, Kelly L; Louderback, Katherine M; Milano, Elana J et al. (2013) Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement. Psychopharmacology (Berl) 227:109-16
Silberman, Yuval; Winder, Danny G (2013) Corticotropin releasing factor and catecholamines enhance glutamatergic neurotransmission in the lateral subdivision of the central amygdala. Neuropharmacology 70:316-23
Shonesy, Brian C; Wang, Xiaohan; Rose, Kristie L et al. (2013) CaMKII regulates diacylglycerol lipase-? and striatal endocannabinoid signaling. Nat Neurosci 16:456-63
Silberman, Yuval; Matthews, Robert T; Winder, Danny G (2013) A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis. J Neurosci 33:950-60
Wills, T A; Kash, T L; Winder, D G (2013) Developmental changes in the acute ethanol sensitivity of glutamatergic and GABAergic transmission in the BNST. Alcohol 47:531-7
Wills, Tiffany A; Klug, Jason R; Silberman, Yuval et al. (2012) GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis. Proc Natl Acad Sci U S A 109:E278-87
Conrad, Kelly L; Louderback, Katherine M; Gessner, Caitlin P et al. (2011) Stress-induced alterations in anxiety-like behavior and adaptations in plasticity in the bed nucleus of the stria terminalis. Physiol Behav 104:248-56
Conrad, Kelly L; Winder, Danny G (2011) Altered anxiety-like behavior and long-term potentiation in the bed nucleus of the stria terminalis in adult mice exposed to chronic social isolation, unpredictable stress, and ethanol beginning in adolescence. Alcohol 45:585-93
Gosnell, Heather B; Silberman, Yuval; Grueter, Brad A et al. (2011) mGluR8 modulates excitatory transmission in the bed nucleus of the stria terminalis in a stress-dependent manner. Neuropsychopharmacology 36:1599-607