Tuesday, April 23, 2024
4/23/2024
Project Summary / Abstract 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.
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