Investigation of how sex steroids and nicotinic acetylcholine receptors promote cocaine self-administration

项目总结

PROJECT SUMMARY Alcohol use disorder (AUD) affects an estimated 16 million individuals, including about 5.1 million women. This number is on the rise as more women are increasing the amount of alcohol they drink, are partaking in more high-risk drinking behaviors, and are being diagnosed with AUD more often. Individuals with AUD exhibit compulsive alcohol drinking defined as excessive, uncontrolled alcohol intake and persistent use despite negative consequences. Because most preclinical studies have historically used only male subjects, current understanding of the neural mechanisms behind female vulnerability to AUD is limited. My published and preliminary studies demonstrate that females are more likely to drink and to respond for alcohol compulsively. In the proposed studies, I will investigate mechanisms underlying this vulnerability. Work in both humans and rodents suggests a role for the nucleus accumbens (NAc) core in driving compulsive-like alcohol intake in male subjects. Glutamate receptors in the NAc core are also implicated in compulsive-like alcohol intake in male subjects. Prior work on sex differences suggests that gonadal hormones may contribute to female vulnerability to drugs of abuse. Therefore, I am exploring the overarching hypothesis that female vulnerability to compulsive- like alcohol drinking is influenced by sex hormones and alcohol-induced increases in NAc core glutamate receptor expression. My proposed experiments (F99) will 1) show that activity in the NAc core contributes to female vulnerability to compulsively drink alcohol, 2) demonstrate that gonadal hormones influence heightened compulsive-like intake in females, but not males, and 3) determine whether gonadal hormones drive differential increases in NAc core glutamate receptor subunit mRNA and protein expression following exposure to chronic intermittent ethanol vapor. Overall, the proposed experiments will increase our knowledge about female alcohol addiction and will significantly impact the treatment of vulnerable populations such as women with AUD. My Sponsor, Dr. Anna Radke (Miami University), and Co-Sponsor, Dr. Frederic W. Hopf (Indiana University School of Medicine), are both experienced and highly regarded addiction neuroscientists known for their work studying compulsive-like alcohol drinking. The proposed Research and Training Plan will deepen my knowledge of the reward system, mechanisms underlying sex differences in addiction liability, and preclinical models of AUD. My training in chemogenetics, chronic intermittent ethanol vapor exposure, RT-PCR, and western blots will prepare me to learn more complex techniques, such as fiber photometry/ calcium imaging and optogenetics, as a postdoctoral researcher (K00). Collectively, this training will propel me toward my goal of establishing an independent research program focused on how sex differences in neuroplasticity, defined as changes in neuronal activity post-alcohol exposure, contribute to female vulnerability to alcohol addiction.