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.
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.
|Wang, Xixi; He, Yu; Ye, Yang et al. (2018) SILAC-based quantitative MS approach for real-time recording protein-mediated cell-cell interactions. Sci Rep 8:8441|
|de Guglielmo, Giordano; Conlisk, Dana E; Barkley-Levenson, Amanda M et al. (2018) Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats. Pharmacol Biochem Behav 167:36-41|
|Kimbrough, Adam; de Guglielmo, Giordano; Kononoff, Jenni et al. (2017) CRF1 Receptor-Dependent Increases in Irritability-Like Behavior During Abstinence from Chronic Intermittent Ethanol Vapor Exposure. Alcohol Clin Exp Res 41:1886-1895|
|de Guglielmo, Giordano; Matzeu, Alessandra; Kononoff, Jenni et al. (2017) Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats. J Pharmacol Exp Ther 362:378-384|
|Chen, B; Zhang, D; Wang, X et al. (2017) Proteomics progresses in microbial physiology and clinical antimicrobial therapy. Eur J Clin Microbiol Infect Dis 36:403-413|
|George, Olivier; Koob, George F (2017) Individual differences in the neuropsychopathology of addiction. Dialogues Clin Neurosci 19:217-229|
|Varodayan, Florence P; de Guglielmo, Giordano; Logrip, Marian L et al. (2017) Alcohol Dependence Disrupts Amygdalar L-Type Voltage-Gated Calcium Channel Mechanisms. J Neurosci 37:4593-4603|
|de Guglielmo, Giordano; Kallupi, Marsida; Cole, Maury D et al. (2017) Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration. Psychopharmacology (Berl) 234:2009-2018|
|Liu, Jingjing; He, Yu; Zhang, Dan et al. (2017) In vitro anticancer effects of two novel phenanthroindolizidine alkaloid compounds on human colon and liver cancer cells. Mol Med Rep 16:2595-2603|
|Kimbrough, Adam; Kim, Sarah; Cole, Maury et al. (2017) Intermittent Access to Ethanol Drinking Facilitates the Transition to Excessive Drinking After Chronic Intermittent Ethanol Vapor Exposure. Alcohol Clin Exp Res 41:1502-1509|
Showing the most recent 10 out of 32 publications