A major issue in the alcohol field is the lack of animal models of the voluntary induction and maintenance of alcohol dependence, considerably hindering the discovery of the neurobiological mechanisms underlying voluntary intoxication to the point of dependence. While rats will readily self-administer alcohol, the amount of alcohol consumed is very low (typically 10-90 mg% for less than 1 h per day) and therefore do not produce blood alcohol levels that are clinically relevant for alcoholism (100-200 mg% for several hours per day). Other paradigms have been developed to produce alcohol dependence in rats, but these models use either forced or passive exposure to a high dose of alcohol, thus preventing the investigation of the neurobiological mechanisms that underlie the voluntary induction and maintenance of alcohol dependence. The current application directly addresses this issue. We recently developed a novel apparatus that allows rats to self- administer alcohol vapor. We obtained evidence that outbred rats will self-administer alcohol vapor for 12+ h per day to the point of reaching blood alcohol levels in the 100-200 mg% range. We propose to characterize and develop a novel animal model of the voluntary induction and maintenance of alcohol dependence using alcohol vapor self-administration in rats and use brain mapping techniques to identify the neuronal networks mediating the voluntary (vs. forced) induction and maintenance of alcohol dependence. We recently demonstrated that prefrontal cortex neurons producing GABA and corticotropin-releasing factor (CRF) are recruited during withdrawal from alcohol binge drinking, but the role of these neurons in the voluntary induction of alcohol dependence is unknown. The current application will directly test the hypothesis that GABA and CRF neurons in the prefrontal cortex are recruited during the voluntary (vs. forced) induction and maintenance of alcohol dependence. Results from these studies have the potential to radically change preclinical research on alcoholism and may pave the ground for the development of animal models of vapor self-administration for other drugs of abuse, such as cannabis, cocaine, nicotine, methamphetamine, or toluene. Moreover, the proposed set of studies has the potential to unveil neuronal targets specifically recruited during the voluntary (v. passive) induction of alcohol dependence that could be useful for the development of novel therapeutic approaches.

Public Health Relevance

A major issue in the alcohol field is the lack of animal models of the voluntary induction and maintenance of alcohol dependence, considerably hindering the discovery of the neurobiological mechanisms underlying voluntary intoxication to the point of dependence. Based on recent evidence obtained in our laboratory, we propose to characterize and develop a novel animal model of the voluntary induction and maintenance of alcohol dependence using alcohol vapor self-administration in rats and use brain mapping techniques to identify the neuronal networks that mediate the voluntary induction and maintenance of alcohol dependence. Results from these studies have the potential to unveil neuronal targets specifically recruited during the voluntary induction and maintenance of alcohol dependence that could be useful for the development of novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA022977-01
Application #
8674356
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Egli, Mark
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
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
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
George, Olivier; Hope, Bruce T (2017) Cortical and amygdalar neuronal ensembles in alcohol seeking, drinking and withdrawal. Neuropharmacology 122:107-114
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
Kallupi, Marsida; George, Olivier (2017) Nicotine Vapor Method to Induce Nicotine Dependence in Rodents. Curr Protoc Neurosci 80:8.41.1-8.41.10
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; 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

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