A major issue in the alcohol field is the lack of animal models of the voluntary induction and maintenance of alcohol dependence. Rats will readily self-administer alcohol, but the amount of alcohol consumed is very low and thus does not produce blood alcohol levels that are clinically relevant for alcoholism (100-200 mg% for several hours per day). In the previous funding period, we successfully developed a novel model of the voluntary induction and maintenance of alcohol dependence in rats using chronic intermittent ethanol vapor self- administration (EVSA). In this model, animals exhibit severe addiction-like behaviors, including somatic signs of withdrawal, anxiety-like behavior, hyperalgesia, and responding despite adverse consequences (on a progressive-ratio schedule of reinforcement) after 6 weeks of EVSA. The current proposal seeks to further develop this paradigm, identify the neuronal networks of the voluntary induction of alcohol dependence, and characterize a novel model of voluntary ?extreme binging.? Extreme alcohol binging is a critical societal issue and one of the priorities of the NIAAA Strategic Plan 2017-2021. Binge and extreme binge drinking are particularly troubling because they increase the risks for blackouts, alcohol poisoning, sexual assault, sexually transmitted diseases, poor academic performance, and developing AUD. By combining alcohol vapor self- administration with state-of-the-art brain mapping techniques, we will identify neuronal networks that drive alcohol drinking and relapse after the voluntary induction of alcohol dependence. Our data show that both the passive and active administration of alcohol vapor produces the escalation of alcohol drinking, increases the motivation to obtain alcohol, and increases relapse, but the voluntary induction of dependence is characterized by the specific recruitment of dorsomedial striatum (DMS) and dorsolateral striatum (DLS) neurons during withdrawal. We also propose to further characterize alcohol drinking and relapse in animals that are previously made dependent by EVSA vs. animals that are made dependent by passive exposure to alcohol vapor. Finally, we propose to validate and fully characterize a novel model of extreme alcohol binging, in which animals self- administer alcohol vapor to the point of reaching blood alcohol levels of ~400 mg%, losing consciousness (?blacking out?), and exhibiting short-term memory loss. Results from these studies will provide a full characterization of alcohol drinking and relapse in animals that voluntarily develop dependence and will unveil neuronal circuits that underlie the voluntary induction and maintenance of alcohol dependence. Results from this proposal will also provide a novel animal model to study and characterize extreme alcohol binging in rodents. The proposed studies have the potential to have a sustained and powerful impact on the field of addiction because they could unveil neuronal targets that are specifically recruited during the voluntary induction of alcohol dependence and extreme binging that could be used to develop novel therapeutic approaches.

Public Health Relevance

We recently developed a novel model of the voluntary induction and maintenance of alcohol dependence in rodents using chronic intermittent ethanol vapor self-administration (EVSA). We propose to use brain mapping techniques to identify the neuronal networks that mediate the voluntary induction and maintenance of alcohol dependence and use the EVSA model to study extreme alcohol binging. Results from these studies will uncover neuronal targets that are specifically recruited during the voluntary induction and maintenance of alcohol dependence and will characterize a novel model of voluntary extreme alcohol binging, a key priority of the NIAAA Strategic Plan.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA022977-07
Application #
10019440
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Egli, Mark
Project Start
2014-09-01
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
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; 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
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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