Alcoholism is a chronic relapsing disorder characterized by compulsive use and loss of control over intake. Alcoholism produces significant cost to society in the United States and worldwide. The excessive use of alcohol has long been shown to have detrimental effects on prefrontal cortex function including impairment in decision making, executive function, and memory and learning. In addition, many studies have established that brain stress systems are activated by excessive drinking. However, few studies have explored how chronic alcohol and activation of the brain stress system interacts with the prefrontal cortex to produce cognitive dysfunction and contribute to compulsive alcohol intake. The overall hypothesis of this project is that activation of the brain stress systems [corticotropin releasing factor (CRF) and norepinephrine (NE)] in the prefrontal cortex disrupts cognitive function that exacerbates the powerful motivation for alcohol seeking associated with compulsive use. To address this hypothesis, the present proposal has been designed to (1) To further characterize the time course of development of cognitive dysfunction and compulsive drinking in animal models of excessive drinking. (2) To determine the pattern of changes in the stress systems in the prefrontal cortex in the development of compulsive drinking and (3) To test if chronic inactivation of the stress systems in the prefrontal cortex prevents cognitive deficits and the development of compulsive alcohol drinking. The approach combines neuroanatomical, neuropharmacological, and molecular techniques and the use of innovative animal models of alcohol dependence, such as the escalation-binge and dependence-induced drinking models, combined with very specific measures of compulsive alcohol drinking, working memory and perseverative responding. Understanding the neurobiological mechanisms within the prefrontal cortex that produce cognitive deficits and contribute to the compulsivity of ethanol dependence will provide key information for understanding the individual differences in vulnerability to develop alcoholism and new targets for the treatment and prevention of alcoholism.

Public Health Relevance

Dysregulation of the brain stress system and impaired cognitive functions are well-established phenomena associated with the development of Substance Dependence on alcohol;however, the neurobiological mechanisms linking stress, cognitive function and compulsive alcohol drinking is poorly known. The present proposal will elucidate brain stress system mechanisms in the prefrontal cortex that cause the impaired cognitive function and how these impairments relate to compulsive alcohol intake. Key information will be gained in understanding the neurobiological mechanisms underlying individual differences in vulnerability to develop alcoholism, and in discovering new targets for the treatment and prevention of alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Egli, Mark
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Chen, Ke; Zhang, Jing; Guo, Zhongqiang et al. (2016) Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer. Cell Res 26:103-18
Zhang, Dan; Ma, Wen; He, Yu et al. (2016) Data of the interacting protein networks and nucleotide metabolism pathways related to NDK and NT5. Data Brief 9:1063-1066
de Guglielmo, Giordano; Crawford, Elena; Kim, Sarah et al. (2016) Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala Is Required for Alcohol Dependence. J Neurosci 36:9446-53
Leão, Rodrigo M; Cruz, Fábio C; Vendruscolo, Leandro F et al. (2015) Chronic nicotine activates stress/reward-related brain regions and facilitates the transition to compulsive alcohol drinking. J Neurosci 35:6241-53
Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52
Vendruscolo, Leandro F; Estey, David; Goodell, Vivian et al. (2015) Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. J Clin Invest 125:3193-7
Zhu, Chaoyang; Wei, Jinxing; Tian, Xin et al. (2015) Prognostic role of PPAR-γ and PTEN in the renal cell carcinoma. Int J Clin Exp Pathol 8:12668-77
Zorrilla, Eric P; Logrip, Marian L; Koob, George F (2014) Corticotropin releasing factor: a key role in the neurobiology of addiction. Front Neuroendocrinol 35:234-44
Buck, Cara L; Malavar, Jordan C; George, Olivier et al. (2014) Anticipatory 50 kHz ultrasonic vocalizations are associated with escalated alcohol intake in dependent rats. Behav Brain Res 271:171-6
Koob, George F; Buck, Cara L; Cohen, Ami et al. (2014) Addiction as a stress surfeit disorder. Neuropharmacology 76 Pt B:370-82

Showing the most recent 10 out of 18 publications